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] A compound represented by the following formula (I). TIFF2026082970000648.tif43170 In the formula, Q is CH or N, and Z is CR. 5 Alternatively, N is N, where X is a 5-membered heteroarylene such as pyrazolylene or isoxazolylene, 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. Patent No. 088589, and U.S. Provisional Patent Application No. 63 / filed on December 15, 2020 Patent No. 125,747, and U.S. Provisional Patent Application No. 63 / 060 filed on 3 August 2020 , claiming priority to No. 331. The entire application is referred to by reference as a whole. This specification 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 of cancer. 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, sulfur, and oxygen. It is a heteroarylene, and the 5-membered heteroarylene is arranged with 0, 1, or 2 R2s. It was replaced, Y is 2 * ,3-substituted furanilen, 2,3 * - Substituted furanilen, 3 * ,4-substituted franile Hmm, 1* ,2-substituted imidazolidene, 1 * ,5-substituted imidazolidene, 1,5 * -substituted i midazolidene, 4,5 * -substituted 1,2,3-oxadiazolidene, 3,4 * -substituted 1,2 -oxazolidene, 4 * ,5-substituted 1,2-oxazolidene, 4,5 * -substituted 1,2-o xazolidene, 4,5 * -substituted 1,3-oxazolidene, 1 * ,2-substituted phenylene, 1 ,5 * -substituted pyrazolidene, 4 * ,5-substituted pyrazolidene, 3,4 * -substituted pyridazinylene n, 4 * ,5-substituted pyridazinylene, 2,3 * -substituted pyridinylene, 3 * ,4-substituted py ridinylene, 3,4 * -substituted pyridinylene, 4,5 * -substituted pyrimidinylene, 1 * ,2-sub stituted pyrrolylene, 1,2 * -substituted pyrrolylene, 2,3 * -substituted pyrrolylene, 3 * ,4-substituted pyrrolylene, 4,5 * -substituted 1,2,3-thiadiazolidene, 3,4 * -substituted 1,2-t hiazolidene, 4 * ,5-substituted 1,2-thiazolidene, 4,5 * -substituted 1,2,3-thia diazolidene, 3,4 * -substituted 1,2-thiazolidene, 4 * ,5-substituted 1,2-thiazoli dene, 4,5 * -substituted 1,2-thiazolidene, 4,5 * -substituted 1,3-thiazolidene, 2 * ,3-substituted thiophenylene, 2,3 * - Substituted thiophenylene, 3 * ,4-substituted thiophene Ren, 4, 5 * - Substitution of 1,2,3-triazinylene, 1,5 * -Substitution 1,2,3-tria Zoliene, and 3,4 * - Selected from the group consisting of substituted 1, 2, 4-triazolylenes. It 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 that is beta relative to the point is carbon, oxygen, or sulfur. R1 is selected from the group consisting of H, methyl, and hydroxymethyl. Each example of R2 is independently CN, Halo, 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 a group consisting of heterocyclines, Each example of R3 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, Each of R4 and R5 is independently either H or F. However, the compound is [ka] It is assumed that this is not the case.

[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". is intended to include a square, the latter being a substitution replacing hydrogen on one or more carbons of a hydrocarbon skeleton refers to an alkyl moiety having a group. Such substituents, unless otherwise specified, are, for example, halo gen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, etc.), thiocarbonyl (such as thioester, thioacetate, or thioform ate, etc.), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, a mino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkyl thio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, he terocyclic, aralkyl, or may contain an aromatic or heteroaromatic moiety. Those skilled in the art will understand that a moiety substituted on a hydrocarbon chain may itself be substituted, where appropriate For example, substituents of a substituted alkyl include substituted and unsubstituted forms of amino, azido, i mino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (s ulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate r, and ester), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, alkylthio , aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc. .

[0024] The term "C x-y ", when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkyn yl, or alkoxy, etc., contains x to y carbons in the chain means containing a mu group. For example, the term "C x-y alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group including linear alkyl and branched alkyl groups containing x to y [[ID=SS]] carbons in the chain, and includes haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents hydrogen when the group is in a terminal position and a bond when it is internal. The terms "C 2-y alkenyl" and "C 2-y alkynyl" are similar in length and possible substitutions to the above alkyl, but each refers to a substituted or unsubstituted unsaturated aliphatic group containing at least one double bond or triple bond, respectively.

[0025] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

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

[0027] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", and the latter refers to an alkynyl moiety having a substituent replacing hydrogen on one or more carbons of the alkynyl group. Such substituents can be included in one or more triple bonds or can be present on one or more carbons that do not contain them. Further, such substituents include all those contemplated for the above alkyl groups, except when stability is inhibited. For example, by one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups alkyl​​​​​​​​​​​​​​​​​​ 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. also includes polycyclic ring systems having two or more cyclic rings, at least one of which is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. An aryl group includes benzene, naphthalene, phenanthrene, phenol, aniline, etc. etc.

[0032] The term "carbamate" is recognized in the art and refers to the group

Chemical formula

[0033] As used herein, the terms "carbocyclic" and "carbocyclic ring" refer to saturated or unsaturated rings 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 the bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. 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" means that each ring is adjacent to the other ring by two adjacent atoms This refers to a bicyclic carbocyclic ring that shares a common ring. Each ring in a fused carbocyclic ring can be a saturated ring, an unsaturated ring, or an aromatic ring. These can be selected. In exemplary embodiments, the aromatic ring, for example, phenyl, is a saturated ring or an impure ring. It can condense into a saturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is acceptable, as long as the valence allows, and is a carbocyclic ring. It is included in the definition. Examples of "carbocyclic compounds" include cyclopentane, cyclohexane, and bicarbonate. 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 This refers to a methyl group substituted with a carbon ring group containing a carbon atom.

[0038] The term "carbonate" is recognized in the relevant technical field, and the group -OCO2-R 3 4 This refers to R 34 This represents a hydrocarbyl group.

[0039] As used herein, the term "carboxyl" is represented by the formula -CO2H. It refers to the base.

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

[0041] As used herein, the term "ether" refers to another hydrocarbil via oxygen. This refers to the hydrocarbyl group bonded to the base. Therefore, the ether substituent of the hydrocarbyl group is , it can be hydrocarbyl-O-. The ether may be symmetric or asymmetric. Examples include heterocycle-O-heterocycles and aryl-O-heterocycles, but these Not limited to ethers. Ethers contain an "alkoxyalkyl" group, which is a general formula A It can be represented by lukyl-O-alkyl.

[0042] As used herein, the terms "halo" and "halogen" mean halogen. It contains chloro, fluoro, bromo, and iodine.

[0043] As used herein, the terms "hetallarkil" and "hetallarkil" are used in a general sense. This refers to an alkyl group substituted with a talil 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]

[0047] For example, regarding Y, "1 * ,5-substituted imidazolylen" was substituted: [ka] It means...

[0048] 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.

[0049] An example ring with respect to X is shown below: "1,5 * - This is a substitution imidazoline. [ka]

[0050] 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.

[0051] 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.

[0052] 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.

[0053] As used herein, the term "heterocyclylalkyl" means a group substituted with a heterocyclic group. This refers to the alkyl group that has been modified.

[0054] 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.

[0055] As used herein, the term "hydroxyalkyl" refers to a group substituted with a hydroxyl group. It refers to a defined alkyl group.

[0056] 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.

[0057] 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.

[0058] The term "silyl" refers to the silicon portion formed by the bonding of three hydrocarbyl moieties.

[0059] 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.

[0060] The term "sulfate" is recognized in the relevant technical field, and the base -OSO3H, This refers to a medicinally acceptable salt.

[0061] 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.

[0062] The term "sulfoxide" is recognized in the relevant technical field and includes the group -S(O)-R 3 8It refers to R 38 This represents hydrocarbyl.

[0063] The term "sulfonate" is recognized in the art and refers to the base SO3H, or This refers to a medicinally acceptable salt.

[0064] 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.

[0065] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group. It refers to the kill group.

[0066] 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.

[0067] As used herein, the term "thioether" refers to a type in which oxygen is replaced by sulfur. It corresponds to ether.

[0068] 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. .

[0069] 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.

[0070] 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.

[0071] 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...

[0072] 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 .

[0073] 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.

[0074] 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.

[0075] 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.)

[0076] 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).

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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-member heteroarylene, and the 5- or 6-member heteroarylene is 0, 1, or is substituted with two R3s, In Y, the bonding points to the methylene group bonded to X and Y and the bonding point to the aromatic ring containing Z are on adjacent atoms, alpha to the bonding point to the methylene group, and beta to the bonding point to the aromatic ring containing Z. The ring atoms of the 5- or 6-member heteroarylene are carbon, oxygen, or sulfur, R1 is selected from the group consisting of H, methyl, and hydroxymethyl, 1-4 Each example of R2 is independently H, CN, halo, C 1-4 alkoxy, C alkyl, halo-C 1-4 alkyl, C 3-4 cycloalkylmethyl, C 3-6 cycloalkyl, and C 3-6 heterocyclyl, [[ID=3z]]Each example of R3 is independently H, halo, CN, C 1-4 alkoxy, halo-C 1-4 alkyl, and C 1-4 alkyl, Each of R4 and R5 is independently H or F, but X is not 3 * ,4-substituted pyrazolylene, * represents the bonding point to the methylene group bonded to X and Y and the bonding point of X or Y.

[0083] In one embodiment, what is disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0084] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene A 5-member heterozygous selected from the group consisting of , imidazolylen, and triazolilen. In some embodiments, X is a group consisting of pyrazolylene and triazolylene. Selected from. In a particular embodiment, X is 4 * ,5-substituted pyrazolylene, 4,5 * - Substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene Hmm, 3 * ,4-substituted isoxazolylene, 3 * ,4-substituted isothiazolylene, 4 * ,5- Substituted isothiazolylene, 4 * ,5-substituted imidazoylene, 1 * ,5-substituted imidazoline , 1 * ,5-substituted triazolylene, and 4 * Select from the group consisting of ,5-substituted triazolylenes It will be selected.

[0085] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene A 5-member heterozygous selected from the group consisting of , imidazolylen, and triazolilen. In some embodiments, X is a group consisting of pyrazolylene and triazolylene. Selected from. In a particular embodiment, X is 4 * ,5-substituted pyrazolylene, 4,5 * - Substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene Hmm, 4, 5* -substituted isoxazolylene, 3 * ,4-substituted isoxazolylene, 3 * ,4 - Substituted isothiazolylene, 4 * ,5-substituted isothiazolylene, 4,5 * - Substituting isothiaz Lilen, 4 * ,5-substituted imidazoylene, 1 * ,5-substituted imidazoylene, 1 * ,5-position Substitute triazolylene, and 4 * Selected from the group consisting of ,5-substituted triazolylenes.

[0086] In a particular embodiment, X is selected from the group consisting of: [ka] * This indicates the bonding site of X to the methylene group bonded to X and Y, R2 is independently H, CN, Halo, C 1-4 Alkoxy, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3- It is selected from a group consisting of 6 heterocyclines.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] In a particular embodiment, X is selected from the group consisting of: [ka]

[0095] In some embodiments, Y is 4 * ,5-substituted pyrazolylene, 1,5 * - Substitution pyraz Lilen, 3, 4 *- Substituted pyrazolylene, 1 * ,2-substituted imidazoylene, 5 * ,1-substitution Imidazoliene, 4,5 * -Substitution of 1,3-thiazolylen, 3,4 * -Substitution 1,2-oxa Zolilen, 4 * ,5-substituted 1,2-oxazolylene, 3,4 * -Substitution 1,2-thiazole Hmm, 4 * ,5-Substitution 1,2-thiazolylen, 2,3 * - Substituted pyridinylene, 3 * ,4-position Pyridinylene, 4 * ,3-substituted pyridinylene, 4,5 * - Substituted pyrimidinylene, 1,5 * -Substitution 1,2,3-triazolylene and 3,4 * -Substitution 1,2,4-triazolylene It is selected from the group consisting of the following.

[0096] In a particular embodiment, Y is selected from the group consisting of: [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.

[0097] 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 4 * It is a ,5-substituted pyrazolylene. In one embodiment Y is 3,4* - Substituted pyrazolylene. 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 imidazoylene. In one embodiment, Y is 1 * It is a 2-substituted imidazoylene. In one embodiment, Y is 5 * ,1-Substitution Imidaz It is rilen. In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0099] In one embodiment, Y is 1,2-thiazoylene. In one embodiment, Y is , 3,4 * - Substituted 1,2-thiazoylene. In one embodiment, Y is 4 * ,5- Substituting 1,2-thiazoylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0100] In one embodiment, Y is 1,3-thiazoylene. In one embodiment, Y is , 4, 5 * - Substituted 1,3-thiazoylene. In one embodiment, Y is [ka] That is the case.

[0101] In one embodiment, Y is 1,2-oxazolylene. 3,4 * - Substituted 1,2-oxazolylene. In one embodiment, Y is 4 * , It is a 5-substituted 1,2-oxazolylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0102] In one embodiment, Y is triazolylene. In one embodiment, Y is 1 * ,5-substituted 1,2,3-triazolylene. In one embodiment, Y is 3,4 * - Substituting 1,2,4-triazolylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0103] In one embodiment, Y is a 6-membered heteroarylene. is pyridinylene. In one embodiment, Y is 2,3 * - Substituting pyridinylene In one embodiment, Y is 3 * It is a ,4-substituted pyridinylene. In one embodiment Y is 4 * It is a ,3-substituted pyridinylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] 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.

[0104] In one embodiment, Y is pyrimidinylene. In one embodiment, Y is 4, 5 * - Substituted pyrimidinylene. In one embodiment, Y is [ka] That is the case.

[0105] 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.

[0106] 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.

[0107] 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 1,2-thiazoylene provided herein. In another embodiment, Y is 1,3-thiazolyene provided herein. In another embodiment, Y is 1,3-thiazolyene provided herein. The provided material is 1,2-oxazolylene. In another embodiment, Y is provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyrimidinylene provided herein.

[0108] 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. This is midazolylene. In another embodiment, Y is 1,2-thiazolylene provided herein. In another embodiment, Y is 1,3-thiazoylene provided herein. In another embodiment, Y is 1,2-oxazolylene provided herein. In one embodiment, Y is triazolylene provided herein. In another embodiment, Y is The pyridinylene provided herein. In another embodiment, Y is provided herein. It is pyrimidinylene.

[0109] 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. This is dazolylene. In another embodiment, Y is 1,2-thiazoylene provided herein. In another embodiment, Y is 1,3-thiazolyene provided herein. In this embodiment, Y is 1,2-oxazolylene provided herein. Another embodiment In this embodiment, Y is triazolylene provided herein. In another embodiment, Y is The pyridinylene provided in the specification. In another embodiment, Y is the pyridinylene provided herein. It is limidinylene.

[0110] 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. It is zolylene. In another embodiment, Y is 1,2-thiazoylene provided herein. Yes. In another embodiment, Y is 1,3-thiazolyene provided herein. In the embodiment, Y is 1,2-oxazolylene provided herein. Another embodiment In this embodiment, Y is triazolylene provided herein. In another embodiment, Y is The pyridinylene provided herein. In another embodiment, Y is the pyridinylene provided herein. It is Mijiniren.

[0111] 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. It is zolylene. In another embodiment, Y is 1,2-thiazoylene provided herein. Yes. In another embodiment, Y is 1,3-thiazolyene provided herein. In the embodiment, Y is 1,2-oxazolylene provided herein. Another embodiment In this embodiment, Y is triazolylene provided herein. In another embodiment, Y is The pyridinylene provided herein. In another embodiment, Y is the pyridinylene provided herein. It is Mijiniren.

[0112] In some embodiments, Q is CH. In other embodiments, Q is N.

[0113] In some embodiments, Z is CR5. In certain embodiments, R5 is H. In certain embodiments, R5 is F. In other embodiments, Z is N.

[0114] In some embodiments, R4 is H. In other embodiments, R4 is F.

[0115] In some embodiments, the compound of formula (I) has structure (IA): [ka]

[0116] In other embodiments, the compound of formula (I) has structure (IB): [ka]

[0117] 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] [ka]

[0118] In a particular embodiment, R2 is independently H, CN, methyl, ethyl, and isop Ropyr, chloro, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl Lu, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl Selected from the group consisting of chlorobutyl, cyclobutyl, and oxetanil.

[0119] In certain embodiments, R3 is H, fluoro, chloro, bromo, CN, methoxy, Selected from the group consisting of difluoromethyl, trifluoromethyl, methyl, and ethyl. .

[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 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.

[0124] 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.

[0125] 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] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0139] 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.

[0140] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0141] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0142] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0143] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0144] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0145] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0146] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0147] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0148] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0149] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0150] In a particular embodiment, the compound is selected from the group consisting of: [ka]

[0151] 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.

[0152] 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.

[0153] 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.

[0154] In a particular embodiment, the compound comprises the following group: [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0155] In one embodiment, the compounds provided herein are those listed in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] or a pharmaceutically acceptable salt thereof.

[0156] 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.

[0157] 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.

[0158] In certain embodiments, the pharmaceutically acceptable salt of the compound is alkylammonium Salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium L-arginine salt, benenthamine salt, benzathine Salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts , diethylamine salt, 2-(diethylamino)ethanol salt, ethanolamine salt, eth Rediamine salt, N-methylglucamine salt, hydravamin salt, 1H-imidazole salt, Thium salt, L-lysine salt, magnesium salt, 4-(2-hydroxyethyl)morpholine salt , piperazine salt, potassium salt, 1-(2-hydroxyethyl)pyrrolidine salt, sodium Salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Z Selected from the group consisting of n salts.

[0159] In certain embodiments, the pharmaceutically acceptable salt is water, methanol, ethanol, and It is a solvate selected from the group consisting of dimethylformamide.

[0160] In certain embodiments, the compound comprises a pharmaceutically acceptable carrier or excipient. It is a pharmaceutical composition.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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].

[0171] 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.

[0172] 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.

[0173] 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 50It is measured by its ratio to a given value.

[0174] 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.

[0175] 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.

[0176] 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).

[0177] 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.

[0178] 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.

[0179] 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).

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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).

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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).

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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).

[0202] 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.

[0203] 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+.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is It is resistant to rosin kinase inhibitors (TKIs).

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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. .

[0238] 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.

[0239] In one embodiment, the patient is an adult patient. In one embodiment, the patient is a small The patient is a child.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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).

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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].

[0265] 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.

[0266] 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.

[0267] 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].

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] Formulations of pharmaceutical compositions for oral administration include mouthwashes or oral sprays, It may also be provided as an oral ointment.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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).

[0302] 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.

[0303] 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 certain embodiments, the active compound is administered once daily.

[0304] 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.

[0305] 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.

[0306] 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, Benenthamine, benzathine, betaine, calcium hydroxide Choline, Deanol, Diethanolamine, Diethylamine, 2-(Diethylamino) Ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabum N, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxy Ethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine Examples include sodium, triethanolamine, tromethamine, and zinc salts, but these Not limited to these. In certain embodiments, the salts of the present disclosure intended may include Na, Ca Examples include, but are not limited to, K, Mg, Zn, or other metal salts.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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. .

[0311] 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.

[0312] 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.

[0313] 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. [Table 3-1] [Table 3-2] [Table 3-3]

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] Analysis method LCMS data was collected using one of the following methods: [Table 4-1] [Table 4-2] [Table 4-3]

[0332] Synthesis example intermediate Synthesis of 3-chloro-4-iodo-1H-pyrazole [ka] Stirring DMF with 3-chloro-1H-pyrazole (25.00 g, 243.8 mmol) Add NIS (71.3g, 317 mmol) to 250 mL of solution over 30 minutes at 0°C. The mixture was added in batches. After addition, the mixture was stirred at 25°C for 1 hour, and then concentrated using an oil pump. Then, DMF was removed. The residue was diluted with ethyl acetate and saturated NaHCO3 (250 mL) Wash with (x2) and brine (250 mL x 2), dry with Na2SO4, concentrate to dryness. Crude 3-chloro-4-iodo-1H-pyrazole (55.7g, 96%) was used as a brown oil. The result obtained was: LC / MS (ESI) m / z: 229 [M+H] + .

[0333] The following intermediates were synthesized using a similar experimental protocol: [Table 5]

[0334] Synthesis of 1-methyl-3-vinyl-1H-pyrazole [ka] 3-iodo-1-methyl-1H-pyrazole (14.00 g, 67.31 mmol) and A mixture of potassium vinyltrifluoroborate (27.06 g, 201.9 mmol) 1,4-dioxane (200 mL) and water (50 mL) are mixed with K2CO3 (27.9 g) (202 mmol) and Pd(dppf)Cl2 (0.98 g, 1.4 mmol) were heated at room temperature. It was added. The mixture was degassed three times under an N2 atmosphere, and this mixture was baked at 100°C for 12 hours. The mixture was stirred. The mixture was filtered, and the filtrate was diluted with HCl (100 mL) and water (100 mL). Washed with (mL) and brine (100mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue was then subjected to silica gel column chromatography (PE:SiO=20:1). Purified, 1-methyl-3-vinyl-1H-pyrazole (4.25 g, yield 58%) was obtained as yellow Obtained as oil. LC / MS (ESI) (m / z): 10⁹ [M+H] + .

[0335] The following intermediates were synthesized using a similar experimental protocol: [Table 6]

[0336] Synthesis of (4-bromooxazol-5-yl)methanol [ka] Ethyl 4-bromooxazole-5-carboxylate (5.0 g, 22.7 mmol) ) in a THF (100 mL) solution, add diisobutylaluminum hydride (1.5 M THF The solution (45.5 mL, 68.2 mmol) was added dropwise at 0°C. The mixture was left at 0°C for 2 hours. Stirring, then diluted with EA (50 mL). To this mixture, first water (3 mL), then A 15% NaOH aqueous solution (3 mL) was followed by water (27 mL) at 0°C. After heating to room temperature, stir the mixture for 15 minutes, add anhydrous MgSO4, and further The mixture was stirred for 15 minutes, then filtered to remove any solids. The filtrate was then placed under vacuum. Concentrated to crude (4-bromooxazole-5-yl)methanol (2.9g, 72%) It was obtained as a yellow solid. LC / MS ESI (m / z): 178 [M+H] + .

[0337] The following intermediates were synthesized using a similar experimental protocol: [Table 7-1] [Table 7-2]

[0338] Synthesis of 1-ethyl-3-iodo-1H-pyrazole [ka] 3-iodo-1H-pyrazole (10g, 51.5 mmol) dissolved in DMF (50mL) To the solution, add iodoethane (12.4 mL, 155 mmol) and K2CO3 (21.4 g, 1 55 mmol) was added at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was filtered. The filtrate was diluted with methoxy (100 mL). This solution was washed with brine ( Three 30 mL samples were dried over anhydrous sodium 2SO4 and concentrated. The residue was then laid on a silica gel column. Purified by chromatography (PE containing 0-20% EA), 1-ethyl-3-iodine was obtained. D-1H-pyrazole (8.4g, yield: 73%) was obtained as a colorless oil. LC / MS ( ESI (m / z): 223 [M+H] + .

[0339] The following intermediates were synthesized using a similar experimental protocol: [Table 8-1] [Table 8-2]

[0340] 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 5-chloro-3-iodine -1-methyl-1H-pyrazole (100 mg, 94% yield) was obtained as a yellow liquid. You can use the materials as they are, or you can further use flash chromatography, high-pressure chromatography, etc. Purify by tography or supercritical fluid chromatography to identify possible positional isomers. The components may be separated. LC / MS (ESI) m / z: 243 [M+H] + .

[0341] The following intermediates were synthesized using a similar experimental protocol: [Table 9]

[0342] Synthesis of 5-bromo-4-iodo-1-methyl-1H-pyrazole [ka] 4-iodo-1-methyl-1H-pyrazole (10.00 g, 48.08 mmol) -70°C dry THF (100 mL) solution, LDA (2.0 M THF solution, 28.8 (mL, 57.7 mmol) was added dropwise over 20 minutes under an N2 atmosphere. After addition, this mixture Stir at -70°C for 30 minutes, then add TH4 (19.0 g, 57.7 mmol) to the mixture. Solution F (40 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour. The mixture was quenched with saturated NH4Cl solution and then diluted with EA (200 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE containing 2% EA). The target product was obtained as brown oil (11g, yield: 80%). LC / MS ESI (m / z): 287 [M+H] + .

[0343] The following intermediates were synthesized using a similar experimental protocol: [Table 10]

[0344] Synthesis of 3-bromo-4-iodo-1-methyl-1H-pyrazole [ka] DM of 3-bromo-1-methyl-1H-pyrazole (10.0 g, 62.1 mmol) NIS (16.8 g, 74.5 mmol) was added to F (32 mL) solution. After addition, The resulting solution was stirred at 50°C for 5 hours. The mixture was diluted with water and extracted into EA. The combined organic phases were washed with brine (30 mL x 4), dried with anhydrous Na2SO4, and then subjected to vacuum. The residue was concentrated. The residue was subjected to flash chromatography (PE containing 0-10% EA). Further purification was performed, and 3-bromo-4-iodo-1-methyl-1H-pyrazole (15.0g, condensed 76% was obtained as a yellow solid. LC / MS (ESI) m / z: 287 [M+H] + .

[0345] The following intermediates were synthesized using a similar experimental protocol: [Table 11]

[0346] 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] + .

[0347] The following intermediates were synthesized using a similar experimental protocol: [Table 12-1] [Table 12-2]

[0348] 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. ) was added dropwise under an N2 atmosphere. After addition, the mixture was stirred at 0°C for 2 hours. This mixture The mixture was concentrated to dryness, and crude 4-(chloromethyl)-1-ethyl-1H-pyrazole (1.60g) was prepared. The result was a yellow oil yielding 100%. LC / MS (ESI) m / z: 145 [M+ H] + .

[0349] The following intermediates were synthesized using a similar experimental protocol: [Table 13]

[0350] 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 Following mmol, thionyl chloride (2.8 mL, 39 mmol) is added over 10 minutes at 0°C. It was added. After the addition, the reaction mixture was stirred under N2 at room temperature for 5.0 hours. The mixture was cooled to 0°C and quenched with a 10% NaCl aqueous solution. Then, this mixture was treated with DCM. The extracts were extracted twice, combined, washed with saturated NaHCO3 aqueous solution, and dried with anhydrous Na2SO4. The residue was dried and concentrated in a vacuum. The residue was subjected to silica gel column chromatography (10 → 3 Purified with PE containing 0% EA, 5-(chloromethyl)-3-ethyl-1,2-oxazo A yellow oil (4.20 g, yield: 90%) was obtained. LC / MS ESI (m / z) : 146 [M+H] + .

[0351] Synthesis of 3-bromo-1-methylpyrazole-4-carbaldehyde [ka] Add POCl3 (12.00 mL) dropwise to a DMF (12.00 mL) flask at 0°C. The mixture was then stirred at room temperature for 30 minutes. 3-bromo-1-methyl Chilpyrazole (4.00 g, 24.8 mmol) was added dropwise at room temperature. The resulting mixture The mixture was then stirred at 95°C for 3 hours. The reaction product was quenched with H2O at room temperature. The mixture was concentrated under reduced pressure. The residue was subjected to reverse-phase flash chromatography (C18, 0). →Purified with water containing 30% MeCN + 0.1% FA) to obtain 3-bromo-1-methylpyrazo 3.94 g of 4-carbaldehyde (84%) was obtained as a light brown solid. LC / MS ESI (m / z): 189 [M+H] + .

[0352] Synthesis of 4-bromo-2-methylthiazole-5-carbaldehyde [ka] 2,4-Dibromo-1,3-Thiazol-5-Caraldehyde (2.00g, 7.38 1,4 containing a mixture of mmol) and methylboronic acid (486 mg, 8.12 mmol) - Dioxane (20 mL) with K2CO3 (2.00 g, 14.8 mmol) and Pd( PPh3)4 (853 mg, 0.740 mmol) was added at room temperature. The mixture was then converted to N2 The mixture was degassed three times below, and then stirred at 110°C for 12 hours under an N2 atmosphere. The reaction product was then left at room temperature. The residue was cooled, filtered, concentrated, and dried. Flash chromatography was performed on the silica The gel was purified with PE containing 25% ethyl acetate, and 4-bromo-2-methyl-1,3-thiosulfate was removed. Azole-5-carbaldehyde (728 mg, 31% yield) was obtained as a yellow solid. LC / MS (ESI) (m / z): 206 [M+H] + .

[0353] The following intermediates were synthesized using a similar experimental protocol: [Table 14-1] [Table 14-2]

[0354] Synthesis of 5-bromoisothiazole-4-carboxylic acid [ka] Isothiazole-4-carboxylic acid (800 mg, 6.20 mmol) THF (15 mg) (L) Solution, t-BuLi(1.3M heptane solution, 10.9 mL, 14) 0.3 mmol) was added. Next, CBr4 (4.10 g, 12.4 mmol) was added to the TH Solution F (10 mL) was added dropwise. The mixture was stirred at -78°C for 2 hours. This reaction solution The solution was quenched by adding a saturated NH4Cl aqueous solution and extracted with ethylacetate. The resulting aqueous layer was then... The pH was adjusted to 1 by adding an aqueous HCl solution (1M), and then extracted with HCl. The second organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain crude 5-bromoiso Thiazole-4-carboxylic acid (750 mg) was obtained as a pale yellow oil. LC / MS ESI (m / z): 208 [M+H] + .

[0355] Synthesis of 5-iodo-1-methyl-3-vinyl-1H-pyrazole [ka] Stirring of 1-methyl-3-vinyl-1H-pyrazole (4.25 g, 39.30 mmol) In a stirred THF (40 mL) solution was added n-BuLi (24 mL, 58.95 mmol, 2.5 M The THF solution was added dropwise via syringe under N2 at -78°C. The mixture was stirred at -78°C for 1 hour. After mixing, add a 25 mL THF solution of iodine (14.97 g, 58.95 mmol). The reaction mixture was then stirred under N2 at -78°C for a further 2 hours. The reaction mixture was then lowered to 0°C. The solution was heated, quenched with saturated NH4Cl aqueous solution (25 mL), and extracted with toluene (25 mL). (Lx2). Wash the combined organic phase with Na2S2O3 (20 mL) and then with anhydrous Na2SO4. The residue was dried and concentrated to dryness. The residue was subjected to silica gel column chromatography (5% EtO Purified with PE containing Ac, 5-iodo-1-methyl-3-vinyl-1H-pyrazole ( 2.70 g, yielding 29%, was obtained as yellow oil. LC / MS (ESI) (m / z): 235.0 [M+H] + .

[0356] 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] + .

[0357] The following intermediates were synthesized using a similar experimental protocol: [Table 15-1] [Table 15-2]

[0358] 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 yellow oil. LC / MS ESI (m / z): 239 [M+H] + .

[0359] The following intermediates were synthesized using a similar experimental protocol: [Table 16]

[0360] Synthesis of 3-chloro-1-ethyl-4-iodo-1H-pyrazole [ka] 3-Chloro-4-iodo-1H-pyrazole (55.34 g, 242.2 mmol) and A mixture of Cs2CO3 (118.7g, 364.1 mmol) and stirred DMF (15 EtI (29.3 mL, 370 mmol) was added dropwise to 0 mL at -10°C. After stirring for 3 hours, the reaction product was concentrated. The residue was diluted with and brine The sample was washed (150 mL x 2), dried with Na2SO4, and concentrated to dryness. The residue was silica. Purified by gel column chromatography (0-20% EA-containing PE), 3-chlorofluorocarbon Ro-1-ethyl-4-iodo-1H-pyrazole (37.5g, 60%) as yellow oil Got it. LC / MS (ESI) m / z: 257 [M+H] + .

[0361] 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] + .

[0362] The following intermediates were synthesized using a similar experimental protocol: [Table 17]

[0363] Synthesis of 1-ethyl-3-(propan-2-yl)-1H-pyrazole [ka] 1-Ethyl-3-iodo-1H-pyrazole (3.20g, 14.4 mmol) H2 A sealed tube containing 0.5 mL of O and 2.5 mL of 1,4-dioxane solution is filled with K2CO2. 3(7.97g, 57.6mmol), Pd(dppf)Cl2(1.05g, 1.44 mmol was added. The mixture was stirred at 100°C for 16 hours, and then water (80 mL) was added. The mixture was poured into a container and extracted with EA (80 mL). The organic layer was washed with brine (60 mL). The residue was dried with anhydrous Na2SO4 and concentrated in a vacuum. The residue was then subjected to silica gel column chromatography. Purified by Graph (PE / EA = 10 / 1 to 1 / 1), 1-ethyl-3-(propane-1 -en-2-yl)-1H-pyrazole (1.2g, yield: 61%) was obtained as a white solid. Ta. LC / MS (ESI): m / z = 137.1 [M+H] + .

[0364] 1-Ethyl-3-(propa-1-en-2-yl)-1H-pyrazole (1.0g, 7 In a 15 mL solution of 0.3 mmol of siRNA, add PtO2 (0.17 g, 0.73 mm (ol) was added, and the mixture was then stirred at room temperature under H2 (15 psi) for 16 hours. The reaction mixture is filtered, and the filtrate is concentrated to obtain crude 1-ethyl-3-(propane-2- Il-1H-pyrazole (800 mg, yield: 79%) was obtained as a white solid. LC / MS (ESI): m / z = 139.1[M+H] + .

[0365] Synthesis of 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde [ka] 1H-Pyrazole-4-carbaldehyde (2.00g, 20.8mmol), diethyl (bromodifluoromethyl)phosphonate (9.45g, 35.3 mmol) and KF( Mix the following in 20 mL of MeCN overnight at room temperature: 3.63 g, 62.4 mmol) The mixture was filtered and concentrated in a vacuum to obtain the residue, which was then subjected to silica gel column chromatography. Purified by matrixing (PE containing 10% phenylethylamine), 1-(difluoromethyl)- 1H-pyrazole-4-carbaldehyde (2.1g, 69%) was obtained as a pale yellow oil. C / MS (ESI) m / z: 147 [M+H] + .

[0366] The following intermediates were synthesized using a similar experimental protocol: [Table 18]

[0367] Synthesis of 3-chloro-1-(cyclopropylmethyl)-1H-pyrazole [ka] 3-Chloro-1H-pyrazole (2.00g, 19.5 mmol) MeCN (50m L) Add K2CO3 (5.40 g, 39.0 mmol) and (bromomethyl)cyclo Propane (2.90 g, 21.5 mmol) was added. This reaction mixture was heated at 80°C for 12 minutes. The mixture was stirred for a certain amount of time. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The residue The solution was purified by flash column chromatography (PE containing 0-30% Â), 3-Chloro-1-(cyclopropylmethyl)-1H-pyrazole (2.3g, 75%) It was obtained as a colorless oil. LC / MS (ESI) (m / z): 157 [M+H] + .

[0368] The following intermediates were synthesized using a similar experimental protocol: [Table 19]

[0369] 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] + .

[0370] The following intermediates were synthesized using a similar experimental protocol: [Table 20]

[0371] Synthesis of 3-bromo-1-(tert-butyl)-1H-pyrazole [ka] 3-bromo-1H-pyrazole (3.00 g, 20.4 mmol) and 2-methylpro A mixture of pan-2-ol (5 mL) and H2SO4 (1.98 mL, 20.4 mmol) The mixture was slowly added at room temperature. This mixture was heated at 100°C for 16 hours. The mixture was diluted with H2O (20 mL) and then extracted with ethyl acetate (20 mL). Wash the cell layer with brine (20 mL), dry with anhydrous Na2SO4, filter, concentrate, and Afterwards, the silica gel was purified by silica gel chromatography (PE containing 0-100% ethyl acetate). , 3-bromo-1-tert-butyl-1H-pyrazole (1.4g, yield 34%) yellow Obtained as a colored oil. LC / MS (ESI) m / z: 203.0 [M+H] + .

[0372] Synthesis of 1,3-diethyl-1H-pyrazole [ka] 3-Ethenyl-1-ethyl-1H-pyrazole (1.00 g, 8.18 mmol) and ELISA (10 mL) containing a mixture of platinum dioxide (0.190 g, 0.82 mmol) The mixture was stirred overnight at room temperature under H2 (15 psi). The mixture was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (0 → 100% acetyl). Purified by (PE), 1,3-diethyl-1H-pyrazole (1.00g, yield 98%) ) was obtained as a colorless oil. LC / MS (ESI) (m / z): 125 [M+H] +

[0373] The following intermediates were synthesized using a similar experimental protocol: [Table 21]

[0374] Synthesis of 3-(bromomethyl)-2-chloro-5-fluoropyridine [ka] (2-chloro-5-fluoropyridine-3-yl)methanol (4.0g, 25mO) l) Add tribromophosphan (2.4 mL, 26 mmol) to the DMF (20 mL) solution. The solution was added dropwise at 0°C. After stirring at 25°C for 1 hour, the mixture was diluted to pH 7 with saturated NaHCO3. The solution was basicized and extracted with EA (30 mL x 3). The combined organic phase was then treated with anhydrous Na2SO4. The residue was dried and concentrated in a vacuum. The residue was purified by preparative TLC (PE containing 8% EA). , 3-(bromomethyl)-2-chloro-5-fluoropyridine (2.7g, yield 46%) It was obtained as a colorless oil. LC / MS ESI (m / z): 224 [M+H] +

[0375] The following intermediates were synthesized using a similar experimental protocol: [Table 22]

[0376] Synthesis of 1-cyclobutyl-4-iodo-1H-pyrazole [ka] 4-iodo-1H-pyrazole (10.0g, 51.6 mmol), bromocyclobuta Mixture of 20.9g, 155 mmol and K2CO3 (28.5g, 206 mmol) The mixture was heated in DMF (200 mL) at 70°C for 12 hours. The reaction mixture was then filtered. The filtrate was extracted using EA (300 ml x 2). The combined organic layers were washed with brine. The residue was dried with anhydrous Na2SO4 and concentrated. The residue was then subjected to silica gel column chromatography. - Purified by (PE containing 0-5% siRNA) to obtain the desired product (9.73 g, yield 7 6% was obtained as yellow oil. LC / MS ESI (m / z): 249 [M+H] + .

[0377] The following intermediates were synthesized using a similar experimental protocol: [Table 23]

[0378] 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] + .

[0379] 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 (solvent chromatography). Release agent: Purified with PE / siRNA50 / 1~10 / 1), then 5-bromo-4-(bromo-4- Momethyl-1-ethyl-1H-pyrazole (3.0 g, yield 57%) as a white solid Got it. LC / MS ESI (m / z): 267 [M+H] + .

[0380] The following intermediates were synthesized using a similar experimental protocol: [Table 24]

[0381] Synthesis of 2-bromo-3-(bromomethyl)-5-fluoropyridine [ka] 2-Bromo-5-fluoro-3-methylpyridine (2.00g, 10.5 mmol), AIBN (52 mg, 0.32 mmol) and NBS (2.44 g, 13.7 mmol) A mixture consisting of the above is degassed three times with N2 in a 20 mL DCE and stirred for 1 hour at 85°C. It was heated to °C. After cooling to room temperature, the mixture was quenched with water and diluted with carboxylic acid. The mixture was washed with brine. The final organic layer was dried with Na2SO4, filtered, and the filtrate was vacuum-sealed. The residue is concentrated inside and then subjected to silica gel flash column chromatography (PE: Purified by EA=50:1), 2-bromo-3-(bromomethyl)-5-fluoropyrifolia Zin (1.20 g, 42%) was obtained as a white solid. LC-MS ESI (m / z): 268 [M+H] + .

[0382] The following intermediates were synthesized using a similar experimental protocol: [Table 25]

[0383] Synthesis of 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole [ka] 3-bromo-4-iodo-1H-pyrazole (5.42g, 19.9mmol) and di Ethyl (bromodifluoromethyl)phosphonate (7.95g, 29.8mmol) Add potassium fluoride (2.3g, 40 mmol) to a cetonitrile (50 mL) solution. The reaction mixture was stirred at 40°C for 3 hours. The reaction mixture was then cooled to room temperature and DCM(50 Dilute (mL), wash with water (50mL) and brine (50mL), and dry with Na2SO4. The residue was dried and concentrated to dryness. The residue was subjected to chromatography on silica gel (15% alkyl Purified with PE, 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyra Zol (5.12 g, 80% yield) was obtained as a white solid. LC / MS (ESI) m / z: 323 [M+H] + .

[0384] 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] + .

[0385] Synthesis of 3-(azidomethyl)-2-bromopyridine [ka] Me of 2-bromo-3-(chloromethyl)pyridine (1.15g, 5.58 mmol) NaN3 (1.09 g, 16.8 mmol) was added to a CN (20 mL) solution at room temperature. The mixture was stirred overnight at 40°C, and then between ELISA (20 mL) and water (20 mL) The organic phase was then distributed. The organic phase was washed with brine (20 mL) and dried with anhydrous Na2SO4. The residue was filtered and concentrated. The residue was then flash-machined (silica gel, 0 → 33%). Purified using PE containing EA, 3-(azidomethyl)-2-bromopyridine (955 mg, A yield of 80% was obtained as yellow oil in two stages. LC / MS (ESI) m / z: 213 [ M+H] + .

[0386] The following intermediates were synthesized using a similar experimental protocol: [Table 26]

[0387] 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] + .

[0388] Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanol [ka] 5-Bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (10.00g, 4 9.25 mmol) of THF (120 mL) solution, methylmagnesium bromide (18.8 A 56.4 mmol, 3.0 M THF solution was added dropwise over 10 minutes at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was then heated to 0°C with saturated NH4Cl (30 mL). Quench the solution, then extract with EA (100 mL x 3), and combine the extracts in anhydrous Na2S The residue was dried with O4, filtered, and concentrated in a vacuum. The residue was then subjected to silica gel column chromatography. Purified with Phi (PE containing 20% ​​ethyl), 1-(5-bromo-1-ethyl-1H Ethanol (-pyrazole-4-yl) was obtained as a pale yellow solid (9.28 g, yield 86%). ). LC / MS ESI (m / z): 219 [M+H] + .

[0389] The following intermediates were synthesized using a similar experimental protocol: [Table 27-1] [Table 27-2]

[0390] Synthesis of 3-(bromomethyl)-2-chloro-5-methoxypyridine [ka] 2-Chloro-5-methoxy-3-methylpyridine (500 mg, 3.17 mmol) To a CCl4 (12 mL) solution, add NBS (565 mg, 3.17 mmol) and ben peroxide. Zoyl (76.8 mg, 0.317 mmol) was added. The mixture was heated at 80°C for 3 hours. Stirring intermittently, then poured into water (80 mL) and extracted with EA (80 mL x 3). Combined Wash the cell layer with brine (60 mL), dry with Na2SO4, filter, and concentrate under vacuum. The residue was eluted by silica gel column chromatography (1 → 10% EtOA). PE containing c) is purified, and 2-chloro-3-(dibromomethyl)-5-methoxypyridine ( 200 mg was obtained as a white solid (yield: 20%). LC / MS (ESI): m / z = 315.8 [M+H] + .

[0391] 2-Chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, 0.63 To a 4 mmol THF (4 mL) solution, add diethoxyphosphinic acid (0.161 mL, Add 1.27 mmol) and DIPEA (164 mg, 1.27 mmol), then... The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (80 mL) and extracted with EA. (80 mL x 3). Wash the combined organic layer with brine (60 mL) and then with Na2SO4. The residue was dried, filtered, and concentrated in a vacuum. This residue was then subjected to silica gel column chromatography. - Elute with (1 → PE containing 10% SiO) and purify, then 3-(bromomethyl)-2- Chloro-5-methoxypyridine (100 mg, yield: 67%) was obtained as a white solid. C / MS (ESI): m / z = 236 [M+H] + .

[0392] 1-(3-iodo-1-methyl-1H-pyrazole-4-yl)-propa-2-in- Synthesis of 1-ol [ka] 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (1.00g, 4. In a 24 mmol THF (7 mL) solution at 0°C, add ethynyl magnesium bromide (12.7 (mL, 6.36 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction product The solution was quenched with saturated NH4Cl aqueous solution (13 mL) and extracted with EA (15 mL x 3). 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 containing 20-90% EA). Purified by 1-(3-iodo-1-methyl-1H-pyrazole-4-yl)propane 2-in-1-ol (780 mg, 70%) was obtained as a white solid. LC-MS (E SI) m / z: 262.9 [M+H] + .

[0393] The following intermediates were synthesized using a similar experimental protocol: [Table 28-1] [Table 28-2]

[0394] 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.

[0395] 4-fluoro-2-iodobenzoyl chloride in a 50 mL dry DCM cooled to 0°C Add a pre-cooled NH3 aqueous solution (14 mL, 370 mmol, 28% H2O solution) to the solution. The mixture was added dropwise over 10 minutes. The internal temperature was maintained below 5°C during the addition. The resulting mixture The material was stirred at room temperature for 4 hours, then concentrated to dryness. This white solid residue was pulverized with water and PE. Then, it is dried in a vacuum oven to obtain the desired product, 4-fluoro-2-iodobenzamide. (11g, 2 steps, yield 92%) was obtained as a white solid. LC / MS (ESI): m / z = 266 [M+H] + .

[0396] 3-bromo-5-methoxy-1-methyl-1H-pyrazole-4-carbaldehyde compound Growth [ka] 3,5-Dibromo-1-methyl-1H-pyrazole-4-carbaldehyde (5.00g) To a stirred MeOH (40 mL) solution of 20.8 mmol, add sodium methanol (1 Add 2.5 mL of 62.5 mmol of 5.0 M methanol solution to obtain the mixture. The mixture was stirred at 60°C for 1 hour. After 1 hour, the reaction mixture was concentrated under vacuum and the solvent was removed. The residue was then diluted with saturated NH4Cl aqueous solution (30 mL) and HCl (30 mL). Then, it was extracted with butyl (3 x 30 mL). The organic phase was combined, and brine (30 mL) was added. Wash with L), dry with anhydrous Na2SO4, filter, concentrate in vacuum to obtain crude 3-bromo -5-Methoxy-1-methyl-1H-pyrazole-4-carbaldehyde (3.31g, A 59% concentration was obtained as a pale yellow solid. LC / MS (ESI) (m / z): 219 [M+H] + .

[0397] Synthesis of 1-(2,4-dibromothiazole-5-yl)propa-2-in-1-ol [ka] 2,4-Dibromo-1,3-Thiazol-5-Caraldehyde (2.0g, 7.3mm) Add 7.3 mL of ethynyl magnesium bromide to a 20 mL THF solution at -78°C. A 7.3 mmol, 1 M THF solution was added under an N2 atmosphere. After addition, the mixture The mixture was stirred at -78°C for 2 hours. The reaction mixture was then mixed with saturated ammonium chloride aqueous solution (30 mL). Quenched. The reaction mixture was concentrated under vacuum and diluted with DCM (30 mL). Next... Then, wash the mixture with brine (30 mL), dry it with anhydrous Na2SO4, and filter it. The residue is obtained by concentrating it in a vacuum and then flash chromatography (using 30% ELISA). Purified by (including PE), 1-(2,4-dibromothiazole-5-yl)propane 2-in-1-ol (1.5 g, 68%) was obtained as a white solid. LC / MS ESI (m / z): 296 [M+H] + .

[0398] The following intermediates were synthesized using a similar experimental protocol: [Table 29]

[0399] 1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-carbadehy do's synthesis [ka] (1-methylcyclopropyl)methanol (0.56 mL, 5.8 mmol) and TE In a 20 mL solution of A (0.89 mL, 6.4 mmol) in DCM, methanesulfonyl chloride was added. 0.49 mL (6.4 mmol) was added. This mixture was stirred at 0°C for 1 hour. This solution contains 1H-pyrazole-4-carbaldehyde (836 mg, 8.70 mmol) A mixture of K2CO3 (1.60 g, 11.6 mmol) is added to DMF (10 mL). The mixture was added, and the reaction was stirred at 0°C for 2 hours. The mixture was filtered and concentrated in a vacuum to obtain the remaining residue. The residue was obtained and subjected to silica gel column chromatography (PE containing 25% siRNA). Purified by 1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-cal Valdehyde (350 mg, yield: 37%) was obtained as a pale yellow solid. LC / MS ESI (m / z): 165 [M+H] + .

[0400] Methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate Synthesis of te [ka] 5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-carboxylic acid (5. In a 70g, 30.9 mmol THF (80 mL) solution, under N2 conditions at 0°C, BH3·TH F (61.9 mL, 61.9 mmol, 1N) was slowly added. The reaction mixture was heated at room temperature. It was heated for 30 minutes, then heated to 65°C for 4 hours. After cooling to room temperature, MeO H (12 mL) was slowly added, and then the solvent was removed under reduced pressure. The residue was then MeOH. The solution was redissolved in (12 mL), stirred at room temperature for 20 minutes, and then evaporated to dryness. The residue was then rinsed with water. Dilution and extraction with DCM (50.0 mL x 3). Combined organic phases were treated with brine (50 mL). It was washed with (), dried with anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was then... The methyl silica gel was then purified by silica gel chromatography (33 → PE containing 100% EA) and methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate ( 3.2 g, yield: 61%, was obtained as a white solid. LC-MS ESI (m / z): 1 71 [M+H] + .

[0401] Synthesis of ethyl 5-ethyl-1,2-thiazole-3-carboxylate [ka] Toluene of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) (30 mL) Solution, ammonium acetate (3.36 g, 43.6 mmol), AcOH ( 3.0 mL (52 mmol) was added. The reaction mixture was stirred at 80°C for 18 hours and then released. It was cooled and then concentrated under reduced pressure. The residue was diluted with water and the pH was measured using a 10% Na2CO3 aqueous solution. The solution was adjusted to 8. The resulting mixture was extracted with ELISA (2 × 50 mL). The extract was dried with Na2SO4 and concentrated under reduced pressure. The residue was flushed with silica gel. Purified by column chromatography (PE containing 0-20% ethyl acetate), and ethyl 4 -Amino-2-oxohexa-3-enoate (1.2g, 40%) is obtained as a pale yellow oil. Ta. LC / MS (ESI): m / z = 172 [M+H] + .

[0402] Ethyl 4-amino-2-oxohexa-3-enoate (1.30g, 7.59mO) Add phosphorus pentasulfide (0.84 g, 3.8 mmol) to the THF (15 mL) solution (l). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue EA(50 It was dissolved in (mL). This solution was cooled to 0°C, and H2O2 (30%, 5 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (50 mL x 2). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was then frozen in silica gel. Purified by Rush column chromatography (PE containing 0-30% Â). Ethyl 5-ethyl-1,2-thiazole-3-carboxylate (0.75g, 53%) The substance was obtained as a white solid. LC / MS (ESI): m / z = 186 [M+H] + .

[0403] Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanone [ka] 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanol (9.28 Add DMP (21.5g, 50.8ml) to a 50mL solution of DCM (42.4 mmol). The mol was added gradually over 10 minutes at 0°C. After the addition, the mixture was further heated at 0°C for 1 The mixture was stirred for 0 minutes. The pH of the mixture was adjusted to 8 with saturated NaHCO3, and then extracted with EA. (100 mL x 3). The combined organic layers were dried with Na2SO4, filtered, and concentrated in a vacuum. It shrunk. The residue was subjected to silica gel column chromatography (containing 20% ​​RINKAN P Purified in E), 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanone It was obtained as a pale yellow oil (8.6g, yield 93%). LC / MS ESI (m / z): 2 17 [M+H] + .

[0404] 4-Bromo-3-methyl-1-(propan-2-yl)-1H-pyrazole-5-cal Synthesis of bonitrile [ka] 3-Methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrili( 470 mg (3.15 mmol), TFA (0.25 mL, 3.4 mmol), and NBS MeCN (20 mL) containing a mixture of (673 mg, 3.78 mmol) was left at room temperature for 1 hour. The mixture was stirred. The reaction mixture was diluted with butyl (30 mL) and saturated with Na2S2O3 (2 Washed with 0 mL, dried with Na2SO4, filtered, and concentrated to dryness. The residue was then siliceous. Purified by flash chromatography (PE containing 25% ethyl acetate), 4-bro Mo-3-methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrile (460 mg, 64% yield) was obtained as a pale yellow solid. LC / MS (ESI) m / z: 228 [M+H] + .

[0405] Synthesis of 5-bromo-N-methoxy-N-methylisothiazole-4-carboxamide [ka] 5-bromoisothiazole-4-carboxylic acid (700 mg, crude) in DCM (15 mL) ) Add HATU (1.6g, 4.4 mmol) and TEA (1.0g, 10 mmol) to the solution. And N,O-dimethylhydroxylamine hydrochloride (427 mg, 4.40 mmol) is added. The mixture was added. After stirring at 25°C for 16 hours, the reaction product was diluted with DCM. The resulting mixture The mixture was washed with H2O, then with brine. The organic layer was dried with anhydrous Na2SO4 and filtered. The residue was concentrated under vacuum. The residue was then analyzed by silica gel column chromatography (0 → 17% Et). Purified with PE containing OAc, 5-bromo-N-methoxy-N-methylisothiazole- 4-Carboxamide (220 mg, 14% yield in two steps) was obtained as a yellow oil. LC / M S ESI (m / z): 251 [M+H] + .

[0406] The following intermediates were synthesized using a similar experimental protocol: [Table 30]

[0407] 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. It was heated. The mixture was concentrated and diluted with alkyl (50 mL) and brine (30 mL). The residue was washed, dried with anhydrous Na2SO4, and concentrated. The residue was then subjected to neutral Al2O3 chromatography. Refined with Graphy (100% petroleum ether), 3-bromo-5-fluoro-2-(tri Methylstanyl pyridine (1.2g, 90% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 340 [M+H] + .

[0408] Methyl 3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxy Silate synthesis [ka] Under a nitrogen atmosphere, 9-borabicyclo[3.3.1]nonane (31.34 mL, 15.67 ( mmol) methyl 3-ethenyl-1-methyl-1H-pyrazole-5-carboxylate Add (1.50 g, 9.04 mmol) to a 50 mL solution of dioxane at 0°C, and The mixture was stirred at 100°C for 1 hour. Water (10 mL), sodium hydroxide aqueous solution (3. (50 mL, 31.0 mmol, 10% aqueous solution) and hydrogen peroxide (3.2 mL, 10% aqueous solution) The solution was continuously added dropwise to the reaction mixture at 0°C. The mixture was stirred at room temperature for 0.5 hours. Next, water (20 mL) and ethyl acetate (30 mL) were added. The layers were separated, and the aqueous layer The mixture was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL). The residue was dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuum. The residue was then passed through a silica gel column. Purified by chromatography (DCM containing 1.6% MeOH), methyl 3-(2 (hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxylate (1.1 0g, 66%) was obtained as a white solid. LC / MS ESI (m / z): 185 [M+ H] + .

[0409] Synthesis of methyl 2-chloro-4-methoxynicotinate [ka] Methyl 2,4-dichloropyridine-3-carboxylate (2.40g, 11.6mm) Me containing a mixture of (11.6 mmol) and sodium methoxide (2.06 g, 11.6 mmol) OH (20 mL) was refluxed under N2 for 16 hours. The mixture was filtered through Celite. The filtrate was diluted with EA (30 mL). This solution was washed with brine and anhydrous sodium 2SO4. The residue was dried and concentrated in step 4. The residue was then subjected to silica gel column chromatography (0 → 30%). Purified by PE (containing EA), methyl 2-chloro-4-methoxynicotinate (1.7 0g, yield: 72%, was obtained as a white solid. LC / MS (ESI) (m / z): 2 02 [M+H] + .

[0410] Potassium(E)-3-cyano-1-ethoxy-1-oxopenta-2-ene-2-ole Synthesis of te [ka] t-BuOK (8.10g, 72.4 mmol) and 18-Crown-6 (1.91g) To a stirred THF (60 mL) solution of 7.24 mmol, diethyl oxalate (10.57 mmol) A 10 mL solution of THF (72.35 mmol) was instilled under N2 conditions at 0°C via syringe. It was added. The reaction mixture was heated to 60°C, and then butyronitrile (5.00 g, 72.3 A solution of mmol of THF (10 mL) was added, and stirring was continued at 60°C for 30 minutes. The corresponding material was evaporated to dryness to obtain crude potassium(E)-3-cyano-1-ethoxy-1-oxopene. Ta-2-en-2-oleate (14.20 g, yield: 93%) was obtained as a yellow solid. C / MS ESI (m / z): 170 [M+H] + .

[0411] Synthesis of 2-(2-bromo-4-fluorophenyl)-1H-imidazole [ka] 2-Bromo-4-fluorobenzaldehyde (50.00 g, 246.3 mmol) and Mixing of oxalaldehyde (52.56 mL, 492.6 mmol, 40% H2O solution) To EtOH (200 mL) containing the compound, add NH3·H2O (113.8 mL, 738.9 mL) A mol (25% H2O solution) was added dropwise at room temperature under an N2 atmosphere. The resulting mixture was obtained after the addition. The mixture was degassed, heated to 50°C, and stirred for 72 hours. The reaction mixture was concentrated in a vacuum. The residue was diluted with EA, washed with brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was then subjected to silica gel flash column chromatography (PE / EA=3:1 Purify in a ratio of approximately 2:1 to obtain 2-(2-bromo-4-fluorophenyl)-1H-imidazo Lu (35.0 g, 59% yield) was obtained as a yellow solid. LC / MS ESI (m / z): 241 [M+H] + .

[0412] The following intermediates were synthesized using a similar experimental protocol: [Table 31]

[0413] [5-Bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4- Synthesis of methanol [ka] 5-Bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4-ca Rubaldehyde (1.80 g, 7.41 mmol) in EtOH (15 mL) solution, NaB H4 (0.33 g, 9.6 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. This reaction was concentrated, diluted with H2O (10 mL), and extracted with ethyl acetate. (15 mL x 3). Wash the combined organic solution with brine (15 mL) and anhydrous Na2SO4 It is dried and then concentrated to obtain crude (5-bromo-1-(cyclopropylmethyl)-3-methyl (Tyl-1H-pyrazole-4-yl)methanol (1.4g, yield: 77%) solidified into a pale yellow solution. Obtained as a physical sample. LC-MS (ESI) m / z: 245 [M+H] + .

[0414] The following intermediates were synthesized using a similar experimental protocol: [Table 32]

[0415] Synthesis of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane [ka] 2-Bromo-5-fluorobenzaldehyde (10.0 g, 49.3 mmol) and E A mixture of tan-1,2-diol (9.16 g, 148 mmol) in a 25°C True In 100 mL of water, add 4-methylbenzenesulfonic acid (1.69 g, 9.87 mmol) The mixture was added all at once under an N2 atmosphere. After addition, the mixture was stirred at 120°C for 16 hours. The resulting mixture was cooled to 2-5°C and then diluted with water and ethyl acetate. The organic layer The sample was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to silica gel column chromatography (PE containing 20-30% Â). The product was purified by LC to obtain the desired product as yellow oil (10.0 g, yield: 82%). / MS ESI (m / z): 247 [M+H] + .

[0416] Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole [ka] 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] + .

[0417] The following intermediates were synthesized using a similar experimental protocol: [Table 33]

[0418] Synthesis of (5-ethyl-1,2-thiazole-3-yl)methanol [ka] Ethyl 5-ethyl-1,2-thiazole-3-carboxylate (750 mg, 4.0 Add DIBAL-H (13.5 mL, 20.2 mL) to a 5 mmol THF (15 mL) solution. (mol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and then MeOH( Quenched by sequentially adding 0.5 mL of water (15 mL) and then water (0.5 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extract was then treated with Na2SO4. The residue was dried and concentrated under reduced pressure. The residue was then subjected to flash column chromatography using silica gel. Purified by (PE containing 0-50% ethyl), (5-ethyl-1,2-thiazole) -3-yl)methanol (510 mg, 88%) was obtained as a colorless oil. LC / MS (E SI): m / z = 144 [M+H] + .

[0419] The following intermediates were synthesized using a similar experimental protocol: [Table 34]

[0420] Synthesis of 5-fluoro-2-(1H-imidazole-2-yl)benzaldehyde [ka] n-BuLi (21.54 mL, 53.86 mmol, 2.5 N) and N,N-Dimethicone 2-(2-bromo-4-fluformamide) (6.25 mL, 80.79 mmol) Olophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imida Two solutions of zole (10.00 g, 26.93 mmol) in anhydrous THF (20 mL) The solution is simultaneously administered via different syringes over 30 minutes, while maintaining an internal temperature of -78°C. After adding the mixture, it was stirred at -78°C for 10 minutes, and then diluted with saturated NH4Cl aqueous solution. Enchymized. Slowly warm the resulting mixture to room temperature and acidify it to pH 6 with 2N HCl. The mixture was then extracted with ether (150 mL). The organic layer was then mixed with water and br The residue was washed in the line, dried with MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (PE containing 30% phenylethylamine). and 5-fluoro-2-(1-{[2(trimethylsilyl)ethoxy]methyl}-1H- Imidazole-2-yl)benzaldehyde (6.0g, yield 70%) in orange oil The result obtained was: LC / MS ESI (m / z): 321 [M+H] + .

[0421] In a flask of TFA (209 mL), add 5-fluoro-2-(1-{[2(trimethyl sulfate). [Lyl]ethoxy]methyl}-1H-imidazole-2-yl)benzaldehyde (45. (0g, 141 mmol) was added gradually at 20°C. The resulting solution was stirred at room temperature for 6 hours. The reaction mixture was then concentrated in a vacuum to remove most of the TFA. The residue was slowly... It was then poured into a saturated NaHCO3 aqueous solution at 0°C. The resulting mixture was then extracted with EA (3 (x200mL) The combined extract was dried with anhydrous Na2SO4 and concentrated in a vacuum. The residue was analyzed using silica gel flash column chromatography (0 → 3% MeOH-containing D Purified by CM, 5-fluoro-2-(1H-imidazole-2-yl)benzalkonium Ludehyde (23.0 g, 86% yield) was obtained as a white solid. LC / MS ESI (m / z): 191 [M+H] + .

[0422] Methyl 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carboc Silate synthesis [ka] 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole(2.5 (0g, 9.54 mmol), triethylamine (2.90g, 28.6 mmol), Me OH (50 mL) and Pd(dppf)Cl2 (698 mg, 0.950 mmol) The mixture was degassed three times under a CO atmosphere and stirred at 60°C for 12 hours under a CO balloon. The reaction mixture was cooled to room temperature, filtered, and concentrated to dryness. The residue was then subjected to silica gel column chromatography. Purified by matrix (PE:EA=5:1), methyl 5-(cyclopropylmethyl) -1-methyl-1H-pyrazole-3-carboxylate (1.50g, yield 81%) It was obtained as a brown oil. LC / MS (ESI) (m / z): 195.1 [M+H] + .

[0423] The following intermediates were synthesized using a similar experimental protocol: [Table 35]

[0424] 1-((4-bromothiazole-5-yl)methyl)-1H-imidazole-4-methyl Synthesis of bonitrile [ka] (4-bromo-1,3-thiazole-5-yl)methanol (480 mg, 2.40 ml) (mol), 1H-imidazole-4-carbonitride (276 mg, 2.90 mmol) and a mixture of triphenylphosphine (1.3g, 4.9 mmol) containing dry THF ( Add DIAD (0.98 mL, 4.9 mmol) dropwise to 30 mL over 10 minutes at 0°C. After addition, the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and The residue was subjected to flash chromatography on silica gel (PE containing 30% siRNA). Purified, 1-((4-bromothiazol-5-yl)methyl)-1H-imidazole-4 -Carbonitrile (220 mg, yield: 33%) was obtained as a pale yellow solid. LC / MS ESI (m / z): 269 [M+H] + .

[0425] The following intermediates were synthesized using a similar experimental protocol: [Table 36]

[0426] 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2- Synthesis of [ka] Toluene in 2-bromo-4-fluorobenzamide (4.43 g, 20.3 mmol) (50 mL) solution contains chloro(chlorosulfanyl)methanone (2.53 mL, 30.5 An mmol was added. This mixture was stirred at 100°C for 2 hours, concentrated in vacuum, and the remainder was obtained. The residue was analyzed by silica gel column chromatography (PE containing 0-50% dimethyl sulfate). After purification, 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazone Lu-2-one (3.90 g, 69% yield) was obtained as a white solid. LC / MS (ESI ) m / z: 276 [M+H] + .

[0427] The following intermediates were synthesized using a similar experimental protocol: [Table 37]

[0428] Synthesis of 5-ethyl-1,2-thiazole-3-carbaldehyde [ka] (5-ethyl-1,2-thiazole-3-yl)methanol (510 mg, 3.56 mg) Add MnO2 (3.10 g, 35.6 mmol) to a 15 mL solution of DCM (mol) The mixture was added. The reaction mixture was stirred at room temperature for 20 hours. After filtration, the filtrate was concentrated under reduced pressure. 5-ethyl-1,2-thiazole-3-carbaldehyde (120 mg, 24%) is pale yellow It was obtained as oil. LC / MS (ESI): m / z = 142 [M+H] + .

[0429] The following intermediates were synthesized using a similar experimental protocol: [Table 38]

[0430] Methyl 3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-cal Synthesis of Voxylates [ka] Under a nitrogen atmosphere, diethylaminosulfur trifluoride (0.40 mL, 3.0 mmol) methyl-1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxy Add 1.5g, 2.9 mmol of rate to a 20mL solution of crude DCM slowly at 0°C. It was added. The reaction mixture was stirred at this temperature for 0.5 hours, and then saturated NaHCO3 aqueous solution ( Quenched with 50 mL. The resulting mixture was extracted with DCM (3 × 10 mL). The extracted material was sequentially washed with water (1 x 30 mL) and brine (30 mL), and sodium sulfate was used. The residue was dried, filtered, and concentrated under reduced pressure. The residue was then separated into TLC (0 → 50% Â). Purified by (containing PE), methyl 3-(2,2-difluoroethyl)-1-methyl-1H -Pyrazole-5-carboxylate (500 mg, 85%) was obtained as a white solid. C / MS ESI (m / z): 205 [M+H] + .

[0431] The following intermediates were synthesized using a similar experimental protocol: [Table 39]

[0432] (R)-1-(5-fluoro-2-(1H-pyrazole-1-yl)phenyl)ethane Synthesis of -1-ol [ka] In a sealed tube, methyl[2-(methylamino)ethyl]amine (0.41 mL, 3.8 mm ol), (1R)-1-(5-fluoro-2-iodophenyl)ethane-1-ol (5 (0.0g, 19 mmol), 1H-pyrazole (1.09 mL, 22.6 mmol), K2 A mixture of CO3 (5.19 g, 37.6 mmol) and CuI (60 mg, 1.9 mmol) NMP (150 mL) containing the mixture was stirred under N2 at 120°C for 18 hours. The reaction mixture The mixture was poured into water (100 mL) and then extracted with SiO (100 mL x 2). The resulting organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated. The residue was then colored. Purification by microchromatography (silica gel, 1 → 10% ethyl acetate petroleum ether). (1R)-1-[5-fluoro-2-(1H-pyrazole-1-yl)phenyl] Ethane-1-ol (3.6g, 93%) was obtained as a yellow oil. LC / MS (ESI) m / z: 207.1 [M+H] + .

[0433] The following intermediates were synthesized using a similar experimental protocol: [Table 40]

[0434] Ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate compound Growth [ka] Ethyl 4-cyclobutyl-2,4-dioxobutanoate (6.2g, 31mmol) To a 15 mL solution of acetic acid, add 3.6 g of methylhydrazine (31 mmol) and obtain The mixture was stirred at 100°C for 3 hours. After 3 hours, the reaction mixture was cooled to room temperature. The solvent is removed by concentrating in a vacuum to obtain a residue, which is then diluted with toluene (20 mL) and the solution is obtained. The residue was concentrated in air. The residue was subjected to silica gel chromatography (0 → 50% EA-containing PE). Purified by ) and ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-cal A boxylate (4.2g, 20%) was obtained as a yellow oil. LC / MS ESI (m / z) : 209 [M+H] + .

[0435] 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) ), followed by the addition of triethylamine (2.94 mL, 21.2 mmol). The mixture was heated to 120°C and stirred for 24 hours. After cooling to room temperature, the reaction mixture was... Quenched with 1 mL of water, the mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration. The filtrate was concentrated. The residue was then subjected to silica gel column chromatography (0→20%). Purified by ethyl(PE) containing ethyl(PE), 3-ethyl-5-(((tetrahydro-2H -Pyran-2-yl)oxy)methyl)isoxazole (10.0g, yield 61%) It was obtained as a yellow syrup. LC / MS ESI (m / z): 212 [M+H] + .

[0436] The following intermediates were synthesized using a similar experimental protocol: [Table 41]

[0437] (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] + .

[0438] 1-[(2-bromopyridine-3-yl)methyl]-1H-1,2,3-triazole Synthesis of -4-Carbonitrile [ka] 3-(azidomethyl)-2-bromopyridine (955 mg, 4.48 mmol) and 2- Water containing a mixture of chloropropa-2-ennitrile (0.90 mL, 11 mmol) (3 The mixture (0 mL) was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, and DCM (20 mL) was added. Extracted using ), washed with saturated brine (20 mL), dried with anhydrous Na2SO4, filtered, The residue was concentrated. Flash chromatography was performed on the residue (silica gel, 0 → 100% EA). Purified by (including PE), 1-[(2-bromopyridine-3-yl)methyl]-1H- 1,2,3-Triazole-4-Carbonitrile (639 mg, yield 54%) is a white solid. The result obtained was: LC / MS (ESI) m / z: 264 [M+H] + .

[0439] The following intermediates were synthesized using a similar experimental protocol: [Table 42]

[0440] [5-Bromo-1-(2-fluoroethyl)-1H-pyrazole-4-yl]methanol Synthesis of Ru [ka] Ethyl 5-bromo-1-(2-fluoroethyl)-1H-pyrazole-4-carboxy In a 50 mL solution of THF containing 3.10 g of rate (11.3 mmol), add DIBAL-H Add (22.6 mL, 22.6 mmol, 1 M toluene solution) dropwise over 10 minutes at 0°C. After addition, the resulting solution was stirred at room temperature for a further 3 hours. After cooling to 0°C, the reaction The mixture was treated with SiO (100 mL) and 1N HCl (100 mL), and the organic layer was formed. The two components were separated, and the aqueous layer was extracted with ELISA (150 mL). The combined organic matter was concentrated in a vacuum. The residue was then subjected to flash chromatography (silica gel, 0-50% Â). Purified by (PE), [5-bromo-1-(2-fluoroethyl)-1H-pyrazole [Lu-4-yl]methanol (2.1 g, 83% yield) was obtained as a white solid. LC-MS (ESI) Measured value: 223 [M+H] + .

[0441] The following intermediates were synthesized using a similar experimental protocol: [Table 43]

[0442] 3-bromo-4-[(4-ethylimidazole-1-yl)methyl]-1-methylpyra Synthesis of zoles [ka] Stirring 4-ethyl-1H-imidazole (0.73 g, 7.6 mmol) in DMF (5. NaH (0.22 g, 9.1 mmol) was gradually added to the 00 mL mixture at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. 3-Bromo-4-(chlorochlorous acid) was added to the above mixture. DMF (5) containing methyl-1-methylpyrazole (1.91 g, 9.11 mmol) (mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for a further 1 hour, and then H2O was added. Quenched. The resulting mixture was subjected to reverse-phase flash chromatography (C18, 0→40). Direct purification was performed using %MeCN aqueous solution + 1%NH3 water, and 3-bromo-4-[(4-ethylimidiamine) Dazole-1-yl)methyl]-1-methylpyrazole (1.9g, 93%) in light brown oil The result obtained was obtained using LC-MS (ESI) at m / z: 269 [M+H]. + .

[0443] (5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)methanol synthesis [ka] Ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate In a 30 mL solution of THF (2.00 g, 7.43 mmol) of phosphate (DIBAL-H( Add 18.6 mL of 18.6 mmol of 1 M toluene solution over 30 minutes at -78°C. The mixture was added. During the addition, the internal temperature was monitored and maintained below -60°C. The reaction mixture was then heated to -78°C. The mixture was stirred for 1 hour, and then slowly added to an aqueous HCl solution (1M) at 0°C to quench it. The mixture was extracted twice with thiocyanate. The combined extract was washed with brine and anhydrous sodium. The residue was dried with 2SO4, filtered, and concentrated in vacuum. The residue was flash-clotted with silica gel. Purified by matrixing (PE containing 30% ethyl acetate), (5-bromo-1-( Difluoromethyl)-1H-pyrazole-4-yl)methanol (1.5g, yield 89%) ) was obtained as a colorless oil. LC / MS ESI (m / z): 227 [M+H] + .

[0444] (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazole-4-yl) Methanol synthesis [ka] (4-bromooxazol-5-yl)methanol (2.90g, 16.3 mmol) In a 5 mL solution of DCM, add Dess-Martin-Periodinane (10.4 g, 24.4 ml). (mol) was added. The reaction mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was concentrated under vacuum. It shrunk. The residue was subjected to flash chromatography (0-30% ELISA-containing PE). Purified to obtain 4-bromoxazole-5-carbaldehyde (2.49g, yield 87%). It was obtained as a pale yellow solid.

[0445] 1-Ethyl-4-iodo-1H-pyrazole (3.14g, 14.2 mmol) TH In solution F (30 mL), add isopropylmagnesium chloride-lithium chloride complex (13.1 mL). A 17.0 mmol, 1.3 M THF solution was added dropwise at -10°C. The mixture was then heated in a chamber. The mixture was stirred at warm temperature for 1 hour, then cooled to -10°C. 4-bromoxazole-5-carb A 10 mL THF solution of dehyde (2.49 g, 14.2 mmol) was added dropwise. An ice bath was then taken. Remove the container and continue stirring at room temperature for 1 hour. The reaction mixture was then mixed with a saturated NH4Cl aqueous solution (20 mL). Quenched with EA, then extracted with EA (3 x 20 mL). The combined organic phase was mixed with water (20 mL). Wash with brine (20 mL), dry with anhydrous Na2SO4, filter, and concentrate in a vacuum. It shrunk. The residue was subjected to flash chromatography (DCM containing 0-10% MeOH). Purified by (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazole Lu-4-yl)methanol (1.21 g, 31% yield) was obtained as a pale yellow solid. LC / MS ESI (m / z): 272 [M+H] + .

[0446] (E)-1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)-3-(dimethyl Synthesis of tilamino)propa-2-en-1-one [ka] 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethane-1-one(4 A mixture of 0.00g (18.4 mmol) and DMF-DMA (80 mL) is heated at 110°C. The mixture was stirred for 2 hours. After cooling to room temperature, the mixture was concentrated in a vacuum using an oil pump. Crude (E)-1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)-3- (dimethylamino)propa-2-en-1-one was obtained as a pale yellow solid (2.6g, saturates rate: 51%). LC / MS ESI (m / z): 272 [M+H] + .

[0447] The following intermediates were synthesized using a similar experimental protocol: [Table 44]

[0448] 5-((4-bromothiazol-5-yl)methyl)-1-methyl-1H-pyrazole Synthesis of -3-Carbonitrile [ka] 5-[(dibromo-1,3-thiazole-5-yl)methyl]-1-methyl-1H- Razole-3-carbonitride (0.700g, 1.93 mmol), Pd / C (0.0 A mixture of 7g, 10% by weight in MeOH (20mL) was heated under H2 at 1 atmosphere at 50°C. The mixture was stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. Purified by Rush chromatography (PE containing 0-25% EA), 5-((4- Bromothiazole-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbon Trill (0.45 g, yield 78%) was obtained as a colorless oil. LC / MS (ESI) (m / z): 283 [M+H] +

[0449] (5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol) Synthesis of 4-yl methanol [ka] 1-(5-bromoisothiazol-4-yl)propa-2-in-1-ol(100 In a solution of t-BuOH (1 mL) and H2O (1 mL) containing mg, 0.46 mmol, sodium Rium(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-O Xo-2,5-dihydrofuran-3-oleate (4.5 mg, 0.02 mmol), Aji Doethane (1.2 M THF solution, 2.0 mL, 2.3 mmol) and CuSO4 (3. 6 mg (0.02 mmol) was added under N2 conditions at 25°C. The mixture was stirred at 50°C for 16 hours. Next, the reaction product was diluted with phenylethylamine. The resulting mixture was washed with H2O and brine. It was dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was flash-filtered. Purified by matrixing (silica gel, PE containing 0-100% EA), (5-bromo (Isothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl) Methanol (60 mg, 45% yield) was obtained as yellow oil. LC / MS (ESI) m / z: 289 [M+H] +

[0450] The following intermediates were synthesized using a similar experimental protocol: [Table 45-1] [Table 45-2]

[0451] 1-((3-iodopyridine-4-yl)methyl)-1H-imidazole-4-carb Nitrile synthesis [ka] In a 16 mL THF (0°C) solution of PPh3 (1.43 g, 5.45 mmol), N2 Under atmospheric conditions, add a solution of DIAD (1.1 g, 5.45 mmol) in THF (16 mL). After adding, the mixture was stirred at 0°C until a white solid precipitate formed. To this mixture, 1H THF containing -imidazole-4-carbonitride (304 mg, 3.27 mmol) 8 mL), followed by (3-iodopyridine-4-yl)methanol (640 mg, 2.72 THF (8 mL) containing mmol was added. The resulting mixture was stirred at room temperature for 3 hours. This mixture was concentrated under reduced pressure. The residue was diluted with DCM (60 mL), and then with water and The residue was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was then siliceous. Purified by column chromatography (PE containing 50% HCl), 1-( (3-iodopyridine-4-yl)methyl)-1H-imidazole-4-carbonitrile (890 mg, yield: 53%) was obtained as a pale yellow oil. LC-MS (ESI): m / z 311 [M+H] + .

[0452] The following intermediates were synthesized using a similar experimental protocol: [Table 46]

[0453] 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile synthesis [ka] In a flask of stirred concentrated H2SO4 (25 mL), add NaNO2 (2.93 g, 42.5 mm). The solution was added in several portions at 0°C. The mixture was heated to 50°C and left at this temperature for 1 hour. The mixture was stirred. This nitrite mixture was cooled to 0°C and set aside. Separately, concentrated H2SO4(3 0.97g, 40.5 mmol) is used with 4-fluoro-2-iodoaniline (9.60g, 4 It was added to a 40 mL AcOH solution containing 0.5 mmol at room temperature. This solution was then used to create the original solution. The nitrite mixture was added dropwise at 0°C. After the addition was complete, the mixture was heated to 50°C for 1 hour. Next, the reaction mixture was prepared using ethyl 2,3-dicyanopropanoate (9.24g H2 of (60.8 mmol) and anhydrous NaOAc (49.82 g, 607.6 mmol) It was added to a 100 mL O suspension at 5°C. After stirring at 15°C for 15 hours, the reaction mixture was observed. The substance was diluted with water and extracted with DCM (250 mL). The resulting organic layer was dissolved in 30% NH4OH aqueous solution. The mixture was vigorously stirred with the liquid (150 mL) for 2 hours. The organic phase was separated and anhydrous sodium 2SO4 was used. The residue was dried in step 4, filtered, and concentrated under vacuum. Flash chromatography was performed on the residue (0 → Purified with PE containing 70% ethyl, then 5-amino-1-(4-fluoro-2-iodine) Dophenyl)-1H-pyrazole-3-carbonitrile (11g, 83%) is a brown solid. The result obtained was: LC / MS ESI (m / z): 329 [M+H] +

[0454] 5-amino-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-ka Rubonitrile (12.0g, 36.6mmol) and isopentyl nitrite (12.8g, A 110 mmol THF (150 mL) solution at 25°C is heated to 70°C and stirred for 16 hours. This reaction was then diluted with HCl. The resulting mixture was then diluted with H2O, and then with brine. Washed. The organic layer was dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted by silica gel column chromatography using PE / EA (0 → 20%). It is purified and 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carb Nitrile (6.0 g, 52% yield) was obtained as a clear oil. LC / MS ESI (m / z) : 314 [M+H] + .

[0455] 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carbaldehyde synthesis [ka] (4-Fluoro-2-iodophenyl)hydrazine (4.10 g, 16.3 mmol) [(1E)-4,4-dimethoxy-3-oxobuta- [1-en-1-yl]dimethylamine (2.82 g, 16.3 mmol) was added. The mixture was heated under reflux for 48 hours and then concentrated. The crude residue was then treated with acetone (50 ml). To the solution (L), 10 mL of 6N HCl was added. The resulting solution was stirred at room temperature for 30 minutes. Then, it was partitioned between ethyl acetate and water. This organic extract was then mixed with water and saturated sodium bicarbonate. The residue was washed with brine and then dried with anhydrous sodium sulfate. The residue was concentrated to dryness. Crude 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carb Dehyde (4.50g, yield: 88%) was obtained as black oil. LC / MS (ESI) m / z: 317 [M+H] + .

[0456] The following intermediates were synthesized using a similar experimental protocol: [Table 47]

[0457] Synthesis of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide [ka] 3,5-Difluoro-2-iodobenzoic acid (11.3g, 39.8mmol), EDC I (9.92g, 51.7mmol), HOBt (6.99g, 51.7mmol), Toxy(methyl)amine (2.92g, 47.9mmol) and DIPEA (15.40 A mixture of (g, 119.4 mmol) in DMF (40 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with EA (80 mL), and washed with saturated NaHCO3 (40 mL). (Lx3). Separate the combined organic layers, wash with brine, dry with anhydrous Na2SO4, and filter. The solution was then passed through a period of time and concentrated. The residue was then purified by silica gel flash column chromatography. 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (12g 92% was obtained as a pale yellow solid. LC-MS (ESI): m / z 328 [M+H ] + .

[0458] Synthesis of (5-cyclobutyl-1-methyl-1H-pyrazole-3-yl)methanol [ka] Ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (4 Diisobutylaluminum hydride is added to a 40 mL THF solution of 0.20 g (20.2 mmol) Add nium (33.6 mL, 50.4 mmol, 1.5 M THF solution) dropwise at -78°C. The mixture was stirred at -78°C for 1 hour. After 1 hour, the reaction mixture was EA (20 mL). Dilute with ), then add water (2 mL), NaOH aqueous solution (15%, 2 mL), and water (5 mL). The ingredients (L) were added sequentially at 0°C. After warming to room temperature, anhydrous MgSO4 was added and the mixture was stirred for 15 minutes. This was continued. The mixture was filtered, and the filtrate was concentrated in a vacuum to obtain crude (5-cyclobutyl -1-methyl-1H-pyrazole-3-yl)methanol (2.86g, 85%) yellow Obtained as oil. LC / MS ESI (m / z): 167 [M+H] + .

[0459] The following intermediates were synthesized using a similar experimental protocol: [Table 48]

[0460] 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 Amberlyst1 5 (26 mg, 83 mmol) was added. The mixture was vigorously stirred at 45°C for 6 hours. The solution was filtered, and the solvent was removed under vacuum to obtain a red residue, which was then subjected to silica gel column chromatography. Purified by Graphie (PE containing 15-30% siRNA), (3-ethyl-1,2- Oxazol-5-yl)methanol (8.05g, yield: 77%) was obtained as a pale yellow oil. Ta. LC / MS ESI (m / z): 128 [M+H] + .

[0461] The following intermediates were synthesized using a similar experimental protocol: [Table 49]

[0462] 3-(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole Synthesis of Ru [ka] (5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-yl)methano To a stirred DCM (10 mL) solution of 410 mg, 2.47 mmol of phosphorus tribromide ( A 2.00 g (7.40 mmol) solution of DCM (5 mL) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at 0°C for 2 hours, washed with saturated NaHCO3 (30 mL), and then anhydrous Na2S. The residue was dried with O4 and evaporated to dryness. The residue was then subjected to silica gel column chromatography. The solution was then eluted with PE / siRNA (9:1 → 4:1) and purified, and 3-(bromomethyl)-5- (Cyclopropylmethyl)-1-methyl-1H-pyrazole (285 mg, yield 50%) It was obtained as a yellow oil. LC / MS (ESI) (m / z): 229 [M+H] + .

[0463] 5-((2-chloropyridine-3-yl)methyl)-1-methyl-1H-pyrazole- Synthesis of 3-Carbonitrile [ka] 3-(bromomethyl)-2-chloropyridine (2.07 g, 10.1 mmol), (3 -Cyano-1-methyl-1H-pyrazole-5-yl)boronic acid (1.52g, 10.0 toluene (20 ml) of Pd(PPh3)4 (0.81 g, 0.70 mmol), Pd(PPh3)4 Add Na2CO3 (2.13g, 20.1 mmol) to the EtOH (4mL) solution. It was added. The reaction mixture was degassed three times with N2 and then stirred overnight at 100°C. This mixture The mixture was cooled to room temperature, filtered, and concentrated in a vacuum. The residue was then subjected to flash chromatography. - Purified by (PE containing 0 → 50% toluene), 5-((2-chloropyridine-3 -Il)methyl)-1-methyl-1H-pyrazole-3-carbonitrile (675mg, 29% was obtained as a yellow solid. LC / MS ESI (m / z): 233 [M+H] + .

[0464] The following intermediates were synthesized using a similar experimental protocol: [Table 50]

[0465] Synthesis of (5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methanol [ka] At -60°C, ethyl 5-bromo-1-cyclobutyl-1H-pyrazole-4-carboxy In a THF (20 mL) solution of silate (1.9 g, 7.0 mmol), add DIBAL-H ( A 1M toluene solution (20.9 mL, 20.9 mmol) was added dropwise at -60°C. Then This mixture was stirred at 0°C for 3 hours. The reaction mixture was then mixed with EA (20 mL) and water (1 mL). Dilute with (1 mL), then add 15% sodium hydroxide solution (1 mL) and water (2.5 mL) in order. Next, the following was added. After heating to room temperature, anhydrous magnesium sulfate was added and stirring continued for 15 minutes. The resulting mixture was filtered, and the filtrate was washed with saturated NH4Cl aqueous solution and brine. The residue was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was then stored in a silica gel column. Purified by chromatography (PE containing 0-10% ethyl acetate), (5-bromo-1- Cyclobutyl-1H-pyrazole-4-yl)methanol (1.6g, 15%) is pale yellow Obtained as oil. LC / MS ESI (m / z): 231 [M+H] + .

[0466] Synthesis of 3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole [ka] 3-(benzyloxy)-1-ethyl-1H-pyrazole (11.5g, 56.9mm) To a stirred THF (200 mL) solution of ol), add n-BuLi (27.3 mL, 68.3 mm A 2.5M THF solution was added under N2 conditions at -78°C. The mixture was stirred at -78°C for 1 hour. Afterward, a solution of CBr4 (22.6 g, 68.2 mmol) in THF (50 mL) was added. The reaction mixture is stirred at -78°C for a further 1.5 hours, and then saturated with NH4Cl (50 mL). The residue was quenched using ) and concentrated in a vacuum. Flash chromatography was performed (0→2 Purified by PE containing 5% alkylammonium compounds, 3-(benzyloxy)-5-bromo-1- Ethyl-1H-pyrazole (8.3g, 52% yield) was obtained as a yellow oil. LC / MS ESI (m / z): 281.0 [M+H] + .

[0467] The following intermediates were synthesized using a similar experimental protocol: [Table 51]

[0468] (3-bromo-1-methyl-1H-pyrazole-4-yl)(5-ethylisoxazo Synthesis of 0-3-yl)methanone [ka] 3-Bromo-4-iodo-1-methyl-1H-pyrazole (500 mg, 1.74 mm) In a stirred THF (10 mL) solution of ol), add i-PrMgBr (2.1 mL, 2.1 mmol) 1. A 1M THF solution was added under N2 conditions at 0°C. After stirring at 0°C for 1 hour, 5-ethyl- N-methoxy-N-methyl-1,2-oxazole-3-carboxamide (360 mg, A 1.95 mmol THF (2 mL) solution was added dropwise. This reaction mixture was then incubated at 0°C for a further 1 Stirring for a while, then quenched with saturated NH4Cl (10 mL), and extracted with toluene. (30 mL x 2). Wash the combined organic phase with brine (20 mL) and rinse with anhydrous Na2SO4. The residue was dried and concentrated. The residue was subjected to silica gel column chromatography (25% EtOA). Purified with PE containing c, 3-(3-bromo-1-methyl-1H-pyrazole-4-cal Bonyl)-5-ethyl-1,2-oxazole (400 mg, yield 77%) is used as the yellow oil. The result obtained was: LC / MS (ESI) (m / z): 284.3 [M+H] + .

[0469] 2-Bromo-3-((4-ethyl-1H-1,2,3-triazol-1-yl)methyl Synthesis of 5-fluoropyridine [ka] 1-Butine solution (approximately 0.2 M, 12 mL) to which 3-(azidomethyl)-2-bromo- 5-Fluoropyridine (350 mg, 1.52 mmol) and CuI (57 mg, 0.3 0 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then filtered through Celite. The filtrate was concentrated in a vacuum to obtain a residue, which was then subjected to silica gel column chromatography. Purified by (PE:EA=10:1~3:1), 2-bromo-3-[(4-ethyl -1H-1,2,3-triazol-1-yl)methyl]-5-fluoropyridine(13 0.0 mg (30% yield) was obtained as a white solid. LC / MS (ESI): m / z = 285 [M+H] + .

[0470] (3-bromo-1-methyl-1H-pyrazole-4-yl)(3-ethylisoxazo Synthesis of 5-yl methanol [ka] 3-Bromo-4-iodo-1-methyl-1H-pyrazole (1.43g, 4.98mg) Mix 10 mL of THF with isopropylmagnesium bromide (1 M THF solution) The solution (5.48 mL, 5.48 mmol) was slowly added under N2 conditions at 0°C. This mixture The mixture was stirred at 0°C for 1 hour. 3-ethylisoxazole-5-carb A solution of dehyde (0.62g, 5.0 mmol) in dried THF (3mL) was incubated at 0°C for 10 minutes. The mixture was added dropwise, and the resulting mixture was stirred at 0°C for a further 1 hour. The reaction mixture was then cooled with ice water. The solution was quenched and then extracted twice with toluene. The combined extract was concentrated, and the residue was saturated. Purified by licagel column chromatography (PE:EA=3:1), (3-bromo (-1-methyl-1H-pyrazole-4-yl)(3-ethylisoxazol-5-yl) Methanol (900 mg, yield: 63%) was obtained as yellow oil. LC / MS ESI ( m / z): 286 [M+H] + .

[0471] The following intermediates were synthesized using a similar experimental protocol: [Table 52-1] [Table 52-2] [Table 52-3] [Table 52-4] [Table 52-5] [Table 52-6]

[0472] 5-Bromo-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl Synthesis of isothiazole [ka] (5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol) A solution of 4-yl methanol (60 mg, 0.20 mmol) in TFA (3 mL) TES (193 mg, 1.60 mmol) was added. The mixture was heated to 70°C. The mixture was stirred for 2 hours. The reaction mixture was concentrated and diluted with a saturated NaHCO3 aqueous solution, and EtOA was added. Extracted with c. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, and filtered. The residue was concentrated. The residue was then flash-chromatographed (silica gel, 0 → 40% EA). Purified with PE, 5-bromo-4-((1-ethyl-1H-1,2,3-triaz (4-yl)methyl)isothiazole (50 mg, yield 88%) was obtained as a yellow oil. LC / MS (ESI) m / z: 273 [M+H] +

[0473] The following intermediates were synthesized using a similar experimental protocol: [Table 53-1] [Table 53-2] [Table 53-3] [Table 53-4] [Table 53-5] [Table 53-6] [Table 53-7] [Table 53-8] [Table 53-9] [Table 53-10] [Table 53-11]

[0474] 4-Bromo-5-((4-(difluoromethyl)-1H-pyrazole-1-yl)methyl Synthesis of 2-methylthiazole [ka] 1-((4-bromo-2-methylthiazole-5-yl)methyl)-1H-pyrazole A 5 mL solution of -4-carbaldehyde (580 mg, 2.03 mmol) in DAST was prepared using N 2. Stir at 30°C for 12 hours. The reaction mixture was then mixed with a saturated NaHCO3 aqueous solution (50 mL). The mixture was quenched at 0°C and then extracted with SiO2 (15 mL). The organic phase was then extracted with Na2 The residue was dried with SO4, filtered, and concentrated in vacuum. The residue was then subjected to silica gel column chromatography. Purified with Raffy (PE containing 10→25% ethyl), 4-bromo-5-((4-( Difluoromethyl)-1H-pyrazole-1-yl)methyl)-2-methylthiazole 426 mg, yield 68%, was obtained as yellow oil. LC / MS (ESI) (m / z): 308 [M+H] + .

[0475] Synthesis of 3,5-difluoro-2-iodobenzaldehyde [ka] 3,5-Difluoro-2-iodo-N-methoxy-N-methylbenzamide (8.00 In a 60 mL solution of THF (24.5 mmol) at -78°C, add DIBAL-H (36 0.7 mL, 39.7 mmol, 1.0 M was added dropwise under an N2 atmosphere. After addition, the mixture was mixed. The mixture was stirred at 0°C for 2 hours. This mixture was quenched with ice water and then extracted with DCM. (40 mL x 2). Wash the combined organic layers with brine, dry with anhydrous sodium 2SO4, and filter. The residue was then concentrated. The residue was subjected to flash column chromatography (5% DC) using silica gel. Purified with MeOH containing M, 3,5-difluoro-2-iodobenzaldehyde (6 0.0g, 92% was obtained as yellow oil. LC-MS (ESI): m / z 269 [M+ H] + .

[0476] The following intermediates were synthesized using a similar experimental protocol: [Table 54]

[0477] [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 (20mL x2) 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] + .

[0478] (5-bromo-1-methyl-1H-pyrazole-4-yl)(5-iodo-1-methyl Synthesis of -1H-pyrazole-4-yl)methanol [ka] 5-Bromo-4-iodo-1-methyl-1H-pyrazole (2.00g, 6.99mm) In a 35 mL THF solution at -70°C, add isopropylmagnesium bromide (1. A 0M THF solution (13.9 mL, 13.9 mmol) was added dropwise under an N2 atmosphere. Then, the mixture is stirred at -70°C for 30 minutes, and then 5-iodo-1-methyl-1H-p Razole-4-carbaldehyde (2.14g, 9.09mmol) in THF (15mL) The solution was added dropwise at -70°C for 10 minutes. The resulting mixture was stirred at -70°C for a further 2 hours. The mixture was then quenched with saturated NH4Cl solution (60 mL). The mixture was extracted using DCM. Dissolve (2 x 100 mL). Wash the combined extract with brine and dry with anhydrous sodium 2SO4. The residue was dried, filtered, and concentrated. The residue was subjected to silica gel column chromatography (30% E Purified with PE containing tOAc, (5-bromo-1-methyl-1H-pyrazole-4-I (5-iodo-1-methyl-1H-pyrazole-4-yl)methanol is used as a yellow oil. (785 mg, yield 29%). LC / MS ESI (m / z): 397 [M+H ] + .

[0479] The following intermediates were synthesized using a similar experimental protocol: [Table 55]

[0480] 1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-p Synthesis of rhazoles [ka] 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (3.0g, 12 1.1 mmol) of 1-methylpyrrolidine (50 mL) is mixed with copper oxide (348 mg, 2. Add 43 mmol) at room temperature, followed by 1H-pyrazole (868 mg, 12.8 mmol) l) was added. After stirring overnight at 120°C, the reaction mixture was diluted with ¼ and water. The organic layer was separated, washed three times with saturated NH4Cl aqueous solution and once with brine, and then in a vacuum. The residue was concentrated. The residue was subjected to flash chromatography of silica gel (PE:EA=10: Purified by 1-1:1 (V / V), then 1-(2-(1,3-dioxolan-2-yl) -4-fluorophenyl)-1H-pyrazole (2.0g, yield 70%) as yellow oil Obtained. TLC: R f = 0.3 (PE / EA = 5:1), LC / MS ESI (m / z): 235 [M+H] + .

[0481] The following intermediates were synthesized using a similar experimental protocol: [Table 56]

[0482] 5-Fluoro-2-(4-(hydroxymethyl)-1-methyl-1H-pyrazole-5 Synthesis of -yl benzaldehyde [ka] (5-iodo-1-methyl-1H-pyrazole-4-yl)methanol (1.6g, 6 (4-fluorocarbon) is added to a solution of 0.7 mmol) dioxane (15 mL) and H2O (5 mL). -2-Formylphenyl)boronic acid (1.69g, 10.1mmol), sodium carbonate Mu (2.14g, 20.2 mmol) and Pd(dppf)Cl2 (492mg, 0.6 70 mmol) was added. After stirring at 80°C for 2 hours, the reaction mixture was diluted with water and Et The mixture was extracted twice with OAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, dimethyl / PE=1 / 1). Prepared as 5-fluoro-2-[4-(hydroxymethyl)-1-methyl-1H-pyrazole Ru-5-yl]benzaldehyde (1.2 g, yield 76%) was obtained as a white solid. LC / MS ESI (m / z): 235 [M+H] + .

[0483] 3-Formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo Synthesis of 5-carbonitride [ka] 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-cal LiTMP is added to a THF (50 mL) solution of bonitrile (5.40 g, 24.2 mmol). MgCl2 (1.0 M THF solution, 36.3 mL, 36.3 mmol) under nitrogen, - The solution was added dropwise at 16°C. The resulting solution was stirred at -16°C for 1 hour. Then, N,N-dimethyl Add 3.7 mL of 48.4 mmol of sulfate formamide and stir the mixture for 1 hour. The reaction mixture was quenched with brine and extracted with HCl (2 x 30 mL). The residue was dried and concentrated. The residue was then flash-chromatographed (silica gel, 0-5%). Purified with petroleum ether containing ethyl acetate, 3-formyl-1-((2-(trimethyl (3.4g) 60% was obtained as a brown liquid. LC / MS (ESI) m / z: 252 [M+H]+ .

[0484] The following intermediates were synthesized using a similar experimental protocol: [Table 57]

[0485] (2-chloropyridine-3-yl)(3-ethyl-1-methyl-1H-pyrazole-5) -Il) Methanol Synthesis [ka] 2-Chloro-3-iodopyridine (1.04g, 4.34mmol) THF (17m To the solution (L), add isopropylmagnesium bromide (5.21 mL, 3.43 mmol) -5 It was added at °C. After stirring at room temperature for 0.5 hours, 3-ethyl-1-methyl-1H-pyrazole 600 mg, 4.34 mmol of ru-5-carbaldehyde was added. Stirring was performed at room temperature. Continue for 0.5 hours, then pour the mixture into water (80 mL) and extract with EA (80 mL) (x3). Wash the organic layer with saturated NaCl (60 mL x 2) and dry with anhydrous Na2SO4. The residue was filtered and concentrated in a vacuum. The residue was then subjected to silica gel column chromatography (3 Purified with PE containing 0% alkylammonium compounds, (2-chloropyridine-3-yl)(3-ethyl -1-methyl-1H-pyrazole-5-yl)methanol (850 mg, 78%) pale yellow It was obtained as a color solid. LC / MS (ESI): m / z = 252 [M+H] + .

[0486] The following intermediates were synthesized using a similar experimental protocol: [Table 58-1] [Table 58-2] [Table 58-3] [Table 58-4]

[0487] 2-Chloro-3-((1-ethyl-1H-pyrazole-4-yl)methyl)-5-meth Synthesis of xypyridine [ka] 3-(bromomethyl)-2-chloro-5-methoxypyridine (100mg, 0.423 (1-ethyl-) in a solution of (1-ethyl-) in THF (2.5 mL) and H2O (0.5 mL). 1H-pyrazole-4-yl)boronic acid (59 mg, 0.42 mmol), K3PO4 ( 269 ​​mg, 1.27 mmol), and 1,1'-bis(di-t-butylphosphino) Erocene palladium dichloride (28 mg, 0.042 mmol) was added. The substance was stirred at 70°C for 16 hours, then poured into water (80 mL), and extracted with EA (80 mL). (Lx3). Wash the combined organic layers with brine (60 mL), dry with Na2SO4, and filter. The residue was then filtered and concentrated. The residue was then subjected to silica gel column chromatography (10 → 50% Et). Purified by PE containing OAc, 2-chloro-3-[(1-ethyl-1H-pyrazole -4-yl)methyl]-5-methoxypyridine (100 mg, yield: 94%) is a white solid. The result was obtained as follows: LC / MS (ESI): m / z = 252 [M+H] + .

[0488] The following intermediates were synthesized using a similar experimental protocol: [Table 59]

[0489] 2-Chloro-3-((1-ethyl-1H-pyrazole-4-yl)methyl)-4-meth Synthesis of xypyridine [ka] (2-Chloro-4-methoxypyridine-3-yl)methanol (447 mg, 2.58 To a 20 mL solution of mmol) of DCM, add CBr4 (853 mg, 2.58 mmol) and PPh3 (675 mg, 2.58 mmol) was added at -10°C. The mixture was then subjected to -1 The mixture was stirred at 0°C for 2 hours. The reaction product was then quenched with saturated NH4Cl aqueous solution at 0°C, and D Extraction was performed using CM (30 mL). The organic layer was washed with brine and dried over anhydrous sodium 2SO4. The residue was then concentrated. The residue was subjected to silica gel column chromatography (P containing 25% EA). Purified by E), 3-(bromomethyl)-2-chloro-4-methoxypyridine (350 mg, yield: 58%, was obtained as yellow oil. LC / MS (ESI) (m / z): 23 6 [M+H] + .

[0490] 3-(bromomethyl)-2-chloro-4-methoxypyridine (250 mg, 1.06 mg) mol), 1-ethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl) )-1H-pyrazole (234 mg, 1.06 mmol), K3PO4 (179 mg, 0 0.846 mmol), and Pd(dppf)Cl2 (28 mg, 0.042 mmol) Mix the mixture with water (1 mL) and THF (5 mL) and stir at 95°C for 4 hours under an N2 atmosphere. The reaction mixture was filtered, and the filtrate was diluted with EA (50 mL). This solution was then brewed. The residue was washed with a line (20 mL), dried with anhydrous Na2SO4, and concentrated. Purified by sugar column chromatography (PE containing 0-30% alkyl group), 2- Chloro-3-((1-ethyl-1H-pyrazole-4-yl)methyl)-4-methoxyp Lysine (120 mg, yield: 45%) was obtained as a colorless oil. LC / MS (ESI) (m / z): 252 [M+H] + .

[0491] 4-Bromo-5-((1-ethyl-1H-pyrazole-4-yl)methyl)oxazo Synthesis of Ru [ka] (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazole-4-yl) In a solution of methanol (1.21 g, 4.45 mmol) in trifluoroacetic acid (12 mL), Add triethylsilane (3.60 mL, 22.2 mmol) and stir at room temperature for 1.5 hours. Next, the reaction mixture was concentrated in a vacuum to obtain a residue, which was then diluted with EA (20 mL). The solution was then basicized to pH 7 with a saturated NaHCO3 aqueous solution. The layers were separated, and the aqueous phase was treated with EA. Extracted (3 x 20 mL). Washed the combined organic phase with brine (10 mL) and anhydrous sodium. The residue was dried with 2SO4, filtered, and concentrated in a vacuum. The residue was then subjected to flash chromatography. - Purified by (PE containing 0-40% ethyl), and 4-bromo-5-((1-ethyl -1H-pyrazole-4-yl)methyl)oxazole (678 mg, yield 60%) yellow Obtained as a colored oil. LC / MS ESI (m / z): 256 [M+H] + .

[0492] The following intermediates were synthesized using a similar experimental protocol: [Table 60-1] [Table 60-2] [Table 60-3] [Table 60-4] [Table 60-5] [Table 60-6]

[0493] (3-bromo-1-methyl-1H-pyrazole-4-yl)(5-ethylisoxazo Synthesis of yl-3-yl methanol [ka] 3-(3-bromo-1-methyl-1H-pyrazole-4-carbonyl)-5-ethyl- 1,2-Oxazole (400 mg, 1.41 mmol) stirred in methanol (10 mL) NaBH4 (65 mg, 1.9 mmol) was added to the solution at 0°C. The reaction product was then converted to 0°C. The mixture was stirred for 1 hour, then concentrated to dryness. The residue was then subjected to silica gel column chromatography. - Purified with (PE:HCl=1:1, V / V), (3-bromo-1-methyl-1H- Pyrazole-4-yl)(5-ethyl-1,2-oxazol-3-yl)methanol 360 mg was obtained as a white solid with a yield of 85%. LC / MS (ESI) (m / z): 286.0 [M+H] + .

[0494] The following intermediates were synthesized using a similar experimental protocol: [Table 61-1] [Table 61-2]

[0495] 5-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)-3-eth Synthesis of Luisoxazole [ka] (3-bromo-1-methyl-1H-pyrazole-4-yl)(3-ethylisoxazo (5-yl)methanol (900 mg, 3.15 mmol) dichloromethane (8 ml) To the solution (L), add triethylsilane (4.06 mL, 25.2 mmol) and trifluorovinegar. Acid (2.34 mL, 31.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. Mixed. Remove the solvent under vacuum, and treat the residue with water and EA. Separate the organic layer and the true Concentrated in the air, 5-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl (Lu)-3-ethylisoxazole was obtained as a brown oil (680 mg, yield: 80%). LC / MS ESI (m / z): 270 [M+H] + .

[0496] The following intermediates were synthesized using a similar experimental protocol: [Table 62-1] [Table 62-2] [Table 62-3]

[0497] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(4-chloropyrimidine- Synthesis of 5-yl(methanol) [ka] 4-Chloro-5-iodopyrimidine (2.60 g, 10.8 mmol) at -78°C HF (50 mL) solution, n-BuLi (2.5 M THF solution, 8.65 under N2 atmosphere) (mL, 21.6 mmol) was added dropwise. The mixture was stirred at -78°C for 10 minutes, then 5-Bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (1.98g, 9.7 A 3 mmol THF (10 mL) solution was added dropwise at -78°C. The resulting mixture was then cooled at -78°C. The mixture was stirred at °C for 30 minutes. The reaction mixture was then quenched with saturated NH4Cl aqueous solution, followed by EA Extraction was performed (100ml x 2). The organic layer was washed with brine and dried with anhydrous Na2SO4. The residue was dried and concentrated. Column chromatography was performed on the silica gel (30% Purified with PE containing (5-bromo-1-ethyl-1H-pyrazole-4-yl)(4 -Chloropyrimidine-5-yl)methanol was obtained as yellow oil (1.4g, yield: 41%). %). LC / MS ESI (m / z): 317 [M+H] + .

[0498] 5-(hydroxy(3-iodo-1-methyl-1H-pyrazole-4-yl)methyl) Synthesis of -1-methyl-1H-pyrazole-3-carbonitrile [ka] 1-Methyl-1H-pyrazole-3-carbonitride (600 mg, 5.60 mmol) ) in a THF (20 mL) solution, lithium diisopropylamide (4.20 mL, 8.4 A 0 mmol, 2.0 M THF solution was added dropwise at -78°C for 1 hour. After 1 hour, 3-iodine was added. D-1-methyl-1H-pyrazole-4-carbaldehyde (1.98g, 8.40mmo) The THF (15 mL) solution from (1) was added dropwise, and the resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL), and then... Extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (10 mL) and then removed. The residue was dried with sodium 2SO4, filtered, and concentrated under vacuum. The residue was then flash-chromatographed. Purified by Raffy using DCM (0→5%, V / V) containing MeOH, and 5-(hydrox C(3-iodo-1-methyl-1H-pyrazole-4-yl)methyl)-1-methyl-1 H-pyrazole-3-carbonitrile (0.94 g, 82%) was obtained as a yellow solid. C / MS ESI (m / z): 344 [M+H] + .

[0499] The following intermediates were synthesized using a similar experimental protocol: [Table 63]

[0500] 3-Cyclobutyl-5-((3-iodo-1-methyl-1H-pyrazole-4-yl) Synthesis of methyl isoxazole [ka] 5-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)-3-cy Robutylisoxazole (230 mg, 0.78 mmol), methyl [2-(methyl a Mino(ethyl)amine (30 mg, 0.39 mmol) and CuI (40 mg, 0.21 mmol) Dioxane (5.0) containing a mixture of mmol, KI (1.29 g, 7.79 mmol) The mixture (mL) was stirred under N2 at 100°C for 5 hours. The mixture was diluted with water and extracted with EA. (50mL x 3). Wash the combined extract twice with brine and dry with anhydrous Na2SO4. The residue was filtered and concentrated. The residue was then subjected to flash chromatography (0-50% EA). Purified by (PE), 3-cyclobutyl-5-((3-iodo-1-methyl-1H-P Razole-4-yl)methyl)isoxazole (220 mg, yield 78%) is mixed with yellow oil. The result obtained was: LC-MS(ESI): 344 [M+H] + .

[0501] The following intermediates were synthesized using a similar experimental protocol: [Table 64]

[0502] tert-butyl2-((3-iodo-1-methyl-1H-pyrazole-4-yl)methyl Synthesis of (Chill)hydrazine-1-carboxylate [ka] 3-Iodo-1-methyl-1H-pyrazole-4-carbaldehyde (4.70g, 19 (0.9 mmol) and tert-butyl carbacate (2.63 g, 19.9 mmol) A 20 mL solution of MeOH was stirred at 25°C for 12 hours. This mixture was concentrated under reduced pressure to obtain a crude solution. tert-butyl(E)-2-((3-iodo-1-methyl-1H-pyrazole-4- (6.80g, yield 98%) hydroxy(methylene)hydrazine-1-carboxylate (yellow) Obtained as oil. LC / MS ESI (m / z): 351 [M+H] + .

[0503] tert-butyl(E)-2-((3-iodo-1-methyl-1H-pyrazole-4- Il(methylene)hydrazine-1-carboxylate (6.80g, 19.4mmol) Add NaBH3CN (1.22g, 19.4 mmol) to AcOH (20 mL) solution. The mixture was added at °C. The reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ELISA (20 mL) and washed with saturated Na2CO3 (20 mL). The residue was dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was then subjected to column chromatography on silica gel. Purified by tography (PE containing 10-30% EA), tert-butyl 2-(( 3-Iodo-1-methyl-1H-pyrazole-4-yl)methyl)hydrazine-1-cal Voxylate (5.00 g, 73% yield) was obtained as a white solid. LC / MS ESI ( m / z): 353 [M+H] + .

[0504] 5-Chloro-3-iodo-(1-methyl-1H-pyrazole-4-yl)(1-ethyl Synthesis of -1H-pyrazole-4-yl)methanol [ka] Isopropylmagnesium chloride-lithium chloride complex (1.88 mL, 2.45 mmol) (1.3M THF solution) and 1-ethyl-4-iodo-1H-pyrazole (502mg) The mixture was added dropwise to a 2.26 mmol THF (4 mL) solution at 0°C under N2. Stir for 1 hour, then add 5-chloro-3-iodo-1-methyl-1H-pyrazole-4- This mixture contains THF (1 mL) with caraldehyde (510 mg, 1.89 mmol). It was added dropwise at 0°C. The mixture was heated to room temperature and stirred under N2 for 2 hours. The mixture was poured into water (100 mL) and then extracted with EA (100 mL x 2). The cell layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was then subjected to column chromatography. Purified by matrixing (silica gel, PE containing 1-10% EA), 5-chloro-3- Iodo-(1-methyl-1H-pyrazole-4-yl)(1-ethyl-1H-pyrazole) -4-yl)methanol (420 mg, 61%) was obtained as a yellow solid. LC / MS ( ESI) m / z: 367 [M+H] + .

[0505] The following intermediates were synthesized using a similar e...

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, isothiazolylene, imidazoylene, and A five-membered heteroarylene selected from the group consisting of riazoylenes, and said five-membered hetero Arylene has 0, 1, or 2 R values. 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 is carbon, oxygen, or sulfur, R １ It is selected from the group consisting of H, methyl, and hydroxymethyl, R ２ Each example is independent of H, CN, Halo, and 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 a group consisting of 3-6 member heterocyclines, 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 bonding of X to the methylene group bonded to X and Y. He agreed, 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, isothiazolylene, imidazoylene, and A five-membered heteroarylene selected from the group consisting of riazoylenes, and said five-membered hetero Arylene has 0, 1, or 2 R values. ２ Replaced by, Y is 2 ＊ ,3-substituted furanilen, 2,3 ＊ - Substituted furanilen, 3 ＊ , 4-substituted franile Hmm, 1 ＊ , 2-substituted imidazoylene, 1 ＊ ,5-substituted imidazoylene, 1,5 ＊ - Substitution I Midazoliene, 4, 5 ＊ - Substitution 1,2,3-oxadiazoylene, 3,4 ＊ - Substitution 1, 2 -Oxazolylene, 4 ＊ ,5-substituted 1,2-oxazolylene, 4,5 ＊ -Substitution 1, 2-O Xazoliene, 4, 5 ＊ - Substituting 1,3-oxazolylene, 1 ＊ , 2-substituted phenylene, 1 , 5 ＊ - Substituted pyrazolylene, 4 ＊ ,5-substituted pyrazolylene, 3,4 ＊ - Substitute pyridazinile Hmm, 4 ＊ ,5-substituted pyridadinylene, 2,3 ＊ - Substituted pyridinylene, 3 ＊ ,4-substituted pyramidal Dinylene, 3, 4 ＊ - Substituted pyridinylene, 4,5 ＊ - Substituted pyrimidinylene, 1 ＊ ,2-position Converted pyrrolylene, 1, 2 ＊ - Substituting pyrrolylene, 2,3 ＊ - Substituting pyrrolylene, 3 ＊ ,4-substitution Pyrrolylene, 4, 5 ＊ - Substitution 1,2,3- thiadiazoylene, 3,4 ＊ -Substitution 1, 2- Azoylene, 4 ＊ ,5-substituted 1,2-thiazoylene, 4,5 ＊ - Substitution 1,2- Thiazolile Hmm, 4, 5 ＊ - Substitution 1,3-thiazoylene, 2 ＊ ,3-substituted thiophenylene, 2,3 ＊ - Substituted thiophenylene, 3 ＊ ,4-substituted thiophenylene, 4,5 ＊ -Substitutions 1, 2, 3- Azinylene, 1,5 ＊ - Substituting 1,2,3-triazolylene, and 3,4 ＊ - Substitution 1, 2, A heteroarylene selected from the group consisting of 4-triazolylene, and said heteroarylene Len is 0, 1, or 2 R ３ Replaced by, ＊ 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 heteroarylene ring atom that is beta relative to the bond site is carbon, oxygen, or sulfur. can be, R １ It is selected from the group consisting of H, methyl, and hydroxymethyl, R ２ Each example is independent of H, CN, Halo, and 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 a group consisting of 3-6 member heterocyclines, 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 bonding of X to the methylene group bonded to X and Y. He agreed, 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 These are independently H, CN, Halo, and C. １－４ Alkoxy, C １－４ Alkyl, Halo-C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and 3-6 A compound according to claim 1 or 2, selected from the group consisting of a number of heterocyclyls.

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, fluoro, CN, methyl, ethyl, and isop. Ropyr, chloro, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl Lu, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl Selected from the group consisting of chloropropyl, cyclobutyl, and oxetanyl. Bini / or (ii) R ３ Each example independently contains H, fluoro, chloro, bromo, CN, methoxy, and diphthong. Selected from the group consisting of ioromethyl, trifluoromethyl, methyl, and ethyl, The compound according to any one of claims 1 to 8.

10. It is one of the following compounds: 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 (b iloid duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, etc. Epithelial hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, bile duct cancer Selected from cholangiocarcinoma and neuroblastoma, That is, 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 the mutation, the ROS1 protein with the G2032R mutation is expressed. The pharmaceutical composition described in item 22.

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 oncogenic ALK gene fusion is one of the human ALK genes. 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 mutations, G1202R, G1202del, L1196M, L1196Q, L11 98F, G1269A, D1203N, I1171N, I1171S, I1171T, F 1174L, F1174C, V1180L, C1156Y, S1206Y, E1210K ALK tan having one or more mutations selected from the group consisting of , and R1275Q The protein is expressed, or the oncogenic ALK gene or oncogenic ALK gene fusion occurs. Due to one or more mutations in the above, G1202R and L1196M, G1269A, ALK tan having comutations with one or more mutations selected from L1198F The pharmaceutical composition according to claim 25, wherein a protein is expressed.

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. Pharmaceutical compositions used in methods to reduce ROS1 or ALK levels in cells and the compound described in 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, a MEK inhibitor, Claim 2, which is a MET inhibitor, an SHP2 inhibitor, an anti-PD-1 agent, or a RAS inhibitor. The pharmaceutical composition described in 9.

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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