Heteroaromatic macrocyclic ether chemotherapeutic agents

Abstract

To provide pharmaceutical compositions containing receptor tyrosine kinase (RTK) inhibitors, suitable for use in the treatment or prevention of cancer.SOLUTION: The present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound and / or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is incorporated herein by reference in its entirety. No. 088590, and U.S. Provisional Patent Application No. 63 / 12 filed December 15, 2020 This application claims the benefit of priority to US Pat. No. 5,733, both of which are incorporated herein by reference in their entireties. is incorporated herein. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are cell surface enzymes that determine whether cells grow and divide. and transmits these signals to the cell via kinase activity. Many RTKs are proto-oncogenes, and abnormal RTK activity is associated with cancer and related disorders. This abnormal kinase activity can be caused by mutations, For example, activating mutations in the kinase domain, fusions containing the intact kinase domain, Proteins can be produced by gene rearrangements, amplifications, and other means. RTK proto-oncogenes include ROS1 and anaplastic lymphoma kinase (ALK) ), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB), and NTRK3 (encoding TRKC) is an example.

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

[0004] ALK is a RTK proto-oncogene, and ALK rearrangements are associated with NSCLC, anaplastic large cell lung cancer, and Lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophageal Squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, thyroid breast cancer ALK activating mutations detected in head and neck cancer, Spitz nevus-like tumors, and neuroblastomas Oncogenic ALK gene fusions are detected in over 20 different cancers, including It contains the kinase domain (3' region) of ALK fused to the 5' region of a 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 These include TPN3, FBXO36, ATIC and KIF5B.

[0005] NTRK1, NTRK2, and NTRK3 are R proteins that encode TRK family kinases. NTRK1, NTRK2, and NTRK3 are proto-oncogenes, and chromosomal rearrangements are common. However, it is detected at low frequency in ROS1-positive or ALK-positive patients. Therapeutically, inhibition of TRK, particularly in the central nervous system (CNS), may reduce dizziness / ataxia / gait disturbances. It has been associated with adverse reactions including behavioral disturbances, paresthesias, weight gain, and cognitive changes.

[0006] Prior art drugs used to treat oncogenic ROS1 and ALK are substantially These defects are due to associated TRK inhibition, limited CNS activity, and resistance. This may mean one or more of the following: insufficient activity against the TRK mutation. Treatment of OS1- or ALK-positive patients may result in dizziness / ataxia / gait disturbances, especially in the CNS. It is associated with adverse reactions including behavioral disturbances, paresthesias, weight gain, and cognitive changes. 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 G, L2155S, L2032K, and L2086F, individually or in combination CNS-penetrating and TRK-sparing inhibitors of ROS1 with resulting acquired resistance mutations Similarly, CNS-penetrating agents of ALK with acquired resistance mutations and TRK receptor agonists are needed. Various ALK drug-resistant strains, occurring individually or in combination, are needed. The following mutations have been reported: G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206 Y, E1210K, 1151Tins, F1174C, G1202del, D1203N , S1206Y, S1206C, L1152R, L1196Q, L1198P, L119 8F, R1275Q, L1152P, C1156T, and F1245V. Summary of the Invention

[0007] An embodiment disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof : [ka] During the ceremony, Q is CH or N; Z is CR5 or N; X is a 5-membered heteroatom containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. heteroarylene, wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 R2. It is replaced, Y is 1,2 * -substituted imidazolylene, 4 * ,5-substituted imidazolylene, 4 * ,5-substitution 1,2,3-Oxadiazolylene, 3 * ,4-substituted 1,2,5-oxadiazolylene, 3 * ,4-substituted 1,2-oxazolylene, 4 * ,5-substituted 1,3-oxazolylene, 2 * , 3-substituted pyrazinylene, 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazolylene, 3 * ,4-substituted pyridazinylene, 2 * ,3-substituted pyridinylene, 4 * ,5-substituted pyrimidinyl Ren, 2 * ,3-substituted pyrrolylene, 5 * ,6-substituted 1,2,3,4-tetrazinylene, 1 * ,5-substituted 1,2,3,4-tetrazolylene, 1,5 * -substituted 1,2,3,4-tetra Zorylene, 4 * ,5-substituted 1,2,3-thiadiazolylene, 3 * ,4-substitution 1,2,5- Thiadiazolylene, 3 * ,4-substituted 1,2-thiazolylene, 4 * ,5-substituted 1,3-thia Zorylene, 4 * ,5-substituted 1,2,3-triazinylene, 5 * ,6-substituted 1,2,4-thiazol-1,2,4-diol Riazinylene, 5,6 * -substituted 1,2,4-triazinylene, 1 * ,5-substitution 1,2,3 -triazolylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5-substitution 1,2 ,4-triazolylene, 1,5 * -substituted 1,2,4-triazolylenes, and 3 * ,4-position substituted 1,2,4-triazolylene, The teroarylene is substituted with 0, 1, or 2 R3; *indicates the point of attachment of X or Y to the methylene group bonded to X and Y, In Y, the bond to the aromatic ring containing Z is alpha to the point of attachment to the methylene group. the heteroarylene ring atom beta to the point is nitrogen; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each 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 heterocycloalkyl; R3 is H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0008] In certain embodiments, the present disclosure is suitable for use in treating or preventing cancer in a subject. and a pharmaceutical composition comprising an effective amount of any of the compounds described herein. (e.g., a compound of the present disclosure, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) In certain embodiments, the pharmaceutical composition comprises a medicament containing a medicament salt, and one or more pharmaceutically acceptable excipients. The product may be for use in the treatment or prevention of a condition or disease described herein. do.

[0009] Embodiments of the present disclosure include a method for treating rhesus mastitis characterized by one or more mutations in the ROS1 or ALK gene. The present invention relates to a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein. A compound (e.g., a compound of formula (I) or any of its embodiments disclosed herein) In certain embodiments, the compound is an inhibitor of ROS1. In other embodiments, the compound is an inhibitor of ALK, and in further embodiments, the compound is The compound is an inhibitor of ROS1 and ALK. In certain embodiments, a human subject is treated with such a treatment. He needs treatment.

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

[0011] In some embodiments, the method of treating or preventing cancer comprises administering one or more compounds of formula (I): This may include administering it in conjunction with other chemotherapeutic agent(s) listed above. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition Unless otherwise defined, all technical and scientific terms used herein are defined by the principles of the present disclosure. The terms "antibody" and "antibody" have the meanings commonly understood by one of ordinary skill in the art. The following references are used in this disclosure: For those skilled in the art, general definitions of many of the terms used are 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). The following terms have the meanings ascribed to them unless otherwise specified:

[0013] In some embodiments, the chemical structures are disclosed along with the corresponding chemical names. In such cases, the chemical structure, not the chemical name, controls the meaning.

[0014] In this disclosure, "comprises," "comprising," "," "containing," and "having" are used in U.S. patent law. and "includes," "inclusive," etc. It can mean "consisting essentially of" or "including" or "consisting essentially of". "essentially of" or "consists essen "(tially)" similarly has the meaning ascribed to it in U.S. patent law, and such term is intended to be an open-ended and the basic or novel characteristics of the recited things are obtained by the existence of other things than those recited. Other than those listed are permitted as long as they are not substantially different, but prior art embodiments are is excluded.

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

[0016] The term "acyl" is art-recognized and refers to a group having the general formula hydrocarbyl C( It refers to a group represented by alkylC(O)—, preferably alkylC(O)—.

[0017] The term "acylamino" is art-recognized and refers to a group substituted with an acyl group. It refers to an amino group which may be represented, for example, by the formula hydrocarbylC(O)NH—.

[0018] The term "acyloxy" is art-recognized and refers to a group having the general formula: hydrocarbyl It refers to a group represented by alkylC(O)O—, preferably alkylC(O)O—.

[0019] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tetraeth ... 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" refers to an alkyl group containing at least one double bond. It refers to an aliphatic group containing aryl, arylsulfonic acid ... The latter is an alkenyl group having a substituent replacing a hydrogen atom on one or more carbon atoms of the alkenyl group. Such substituents may or may not be contained within one or more double bonds. Furthermore, such substituents may be present on one or more carbon atoms except where this would inhibit stability. The term "alkyl" includes all of the contemplated alkyl groups described below, for example, one or more by alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups of Substitution of alkenyl groups is contemplated.

[0022] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched, non-aromatic hydrocarbon. Typically, a linear or branched alkyl group contains 1 to about 20 alkyl groups, unless otherwise defined. Preferably, the alkyl group has from 1 to about 10 carbon atoms. Examples of linear and branched alkyl groups include: Methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl Examples include t-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight chain Branched alkyl groups are also referred to as "lower alkyl" groups.

[0023] Additionally, as used throughout the specification, examples, and claims, "alkyl" ( The term "unsubstituted alkyl" or "lower alkyl" applies to both "unsubstituted alkyl" and "substituted alkyl." The latter is intended to include substitutions in place of hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, include, for example, halo. aryl, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl, formyl, or or acyl, etc.), thiocarbonyl (thioester, thioacetate, or thioformate, etc.), phosphate, etc.), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, Amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkyl Thio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, It may contain terecyclyl, aralkyl, or aromatic or heteroaromatic moieties. It is understood that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, the substituents of substituted alkyl may include substituted and unsubstituted amino, azido, iodo, and methyl. Amino, Amido, Phosphoryl (including Phosphonates and Phosphinates), Sulfonyl (including Sulfonyl) sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups, as well as ether, alkylthio, carbonyl (ketone, aldehyde, carboxyle Exemplary substituted alkyls include -C, ... Cycloalkyl is an alkyl, alkenyl, alkoxy, alkylthio, etc. , aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc. .

[0024] "C x-y The term "" includes acyl, acyloxy, alkyl, alkenyl, alkynyl, When used in conjunction with chemical moieties such as alkyl, alkoxy, or alkyl groups containing x to y carbon atoms in the chain, For example, "C x-y The term "alkyl" refers to the group consisting of x to y atoms in the chain. Substituted or unsubstituted saturated hydrocarbons, including straight and branched chain alkyl groups containing 10 carbon atoms. It refers to the halogen atom, and haloalkyl such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl refers to hydrogen when the group is in a terminal position and hydrogen when the group is in an internal position. Indicates a bond. 2-y alkenyl" and "C 2-y The term "alkynyl" refers to the above group. They are similar in length and possible substitutions to alkyl, but each has at least one double bond. refers to a substituted or unsubstituted unsaturated aliphatic group containing a double or triple bond.

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

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

[0027] As used herein, the term "alkynyl" refers to an alkynyl group containing at least one triple bond. It refers to an aliphatic group containing alkynyl, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl." The latter is an alkynyl group having a substituent replacing a hydrogen atom on one or more carbon atoms of the alkynyl group. Such substituents may or may not be contained within one or more triple bonds. It may be present on one or more carbon atoms. Furthermore, such substituents are not permitted unless they inhibit stability. For example, one or more alkyl groups may be present in the alkyl group. alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups Substitution of the quinyl group is contemplated.

[0028] As used herein, the term "amide" refers to the group [ka] where each R 30 independently represent hydrogen or a hydrocarbyl group; There are two R 30 However, together with the N atom to which they are attached, the ring structure contains 4 to 8 atoms. Completes a heterocycle with a child.

[0029] The terms "amine" and "amino" are art-recognized and include unsubstituted and Both substituted amines, as well as salts thereof, e.g., [ka] where each R 31 are independently hydrogen or hydroca represents a methyl group or two R 31 together with the N atoms to which they are bonded As used herein, "a" refers to a heterocyclic ring having 4 to 8 atoms in the ring structure. The term "aminoalkyl" 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. It refers to the aryl group.

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

[0032] The term "carbamate" is art-recognized and refers to a group [ka] where each R 32 and R 33 are independently hydrogen or a hydrocarbyl group, e.g. For example, it represents an alkyl group, or R 32 and R 33 together with the intervening atom(s). This completes a heterocycle having 4 to 8 atoms in the ring structure.

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

[0034] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic rings in which one, two, three or more atoms are shared between the two rings The term "fused carbocyclic ring" refers to a ring in which each ring is connected to the other by two adjacent atoms. Each ring in a fused carbocycle can be a saturated ring, an unsaturated ring, or an aromatic ring. In an exemplary embodiment, the aromatic ring, e.g., phenyl, may be selected from a saturated or unsaturated ring. Can be fused to a saturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, may be used in combination with carbocyclic rings. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclohexane, and cyclohexane. Cyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetramethylcyclohexyl Hydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adaman Exemplary fused carbocycles include decalin, naphthalene, 1,2,3, 4-Tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydronaphthalene Examples include dihydro-1H-indene and bicyclo[4.1.0]hept-3-ene. A "carbocycle" can be substituted at any one or more positions that can have a hydrogen atom.

[0035] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. Typically, monocyclic cycloalkyl groups are substituted with aryl groups, as defined elsewhere. Unless otherwise specified, they have from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms. The second ring of the formula cycloalkyl may be selected from saturated, unsaturated, and aromatic rings. Alkyl has one, two, three or more atoms shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic molecule in which each ring is fused to the other ring. Refers to bicyclic cycloalkyls that share two adjacent atoms. The second ring in the "cycloalkenyl" group may be selected from saturated, unsaturated, and aromatic rings. is a cyclic hydrocarbon containing one or more double bonds.

[0036] As used herein, the term "carbocyclylalkyl" refers to a carbocyclic group substituted with a It refers to an alkyl group.

[0037] As used herein, "C 3-4 The term "cycloalkylmethyl" refers to a group consisting of 3 to 4 alkyl groups. It refers to a methyl group substituted with a carbocyclic group containing carbon atoms.

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

[0039] As used herein, the term "carboxy" is represented by the formula -COH Refers to the base.

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

[0041] As used herein, the term "ether" refers to a bond between an oxygen atom and another hydrocarbyl refers to a hydrocarbyl group bonded to a group. Thus, an ether substituent on a hydrocarbyl group is , hydrocarbyl-O-. The ether may be symmetrical or asymmetrical. Examples include heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which have the general formula It can be represented by alkyl-O-alkyl.

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

[0043] As used herein, the terms "hetaralkyl" and "heteroaralkyl" mean a hetero It refers to an alkyl group substituted with a tharyl group.

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

[0045] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring The ring structure preferably includes a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, has at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably , containing one or two heteroatoms. The terms "heteroaryl" and "hetaryl" are used interchangeably. The term refers to a polycyclic ring with two or more cyclic rings in which two or more carbons are common to two adjacent rings. Also included are cyclic ring systems in which at least one of the rings is heteroaromatic, e.g., Other cyclic rings include cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, cyclohexyl ... Heteroaryl groups can be, for example, Pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole , pyridine, pyrazine, pyridazine, and pyrimidine, etc.

[0046] The asterisk ( * ) notation, as shown in the example below, indicates the ring atom of the part bonded to the methylene group between X and Y. Identify: [ka] For example, "1" for Y * ,5-substituted imidazolylene" is substituted: [ka] means.

[0047] As mentioned above, the IUPAC numbering rules for heteroarylene rings specify the positions of the ring atoms. In this example, the 1-position of the imidazolylene is methylene. The asterisk notation indicates that the X and Y. Here, the 5-membered heteroarylene group is used in both the name and structure of the heteroarylene group. The ring atom at position 1 is not marked because it is attached to a phenyl group with variable R4. It has not been done.

[0048] Exemplary rings for X include the "1,5" ring shown below. * -substituted imidazolylene". [ka] The ring atom attached to the methylene group (position 5 in this example) is the heteroarylene name and The ring atoms attached to the aromatic ring bearing Q are marked. It has not been installed.

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

[0050] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted heterocyclic rings. It refers to a substituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, These ring structures contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 to 4 heteroatoms. More preferably, it contains one or two heteroatoms. The term "formula" refers to two or more cyclic rings in which two or more carbons are common to two adjacent rings. Also included are polycyclic ring systems having rings, at least one of which is heterocyclic; For example, other cyclic rings include cycloalkyl, cycloalkenyl, cycloalkynyl, acycloalkyl, cycloalkenyl, cycloalkyn ... The heterocyclyl group may be aryl, heteroaryl, and / or heterocyclyl. Examples of suitable amines include piperidine, piperazine, pyrrolidine, morpholine, lactones, lactones, and the like. Examples include Mu.

[0051] As used herein, the term "heterocyclylalkyl" refers to a heterocyclic group substituted with a heterocyclic group. refers to an alkyl group formed by

[0052] As used herein, the term "hydrocarbyl" refers to both =O and =S substituents. bonded through carbon atoms that do not have a carbon-hydrogen bond, usually at least one carbon-hydrogen bond and primarily It refers to a group that has a basic skeleton and may optionally contain heteroatoms. Groups such as dimethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrochlorides for the purposes of this application. Although considered to be carbyl, acetyl (having an =O substituent on the linking carbon atom) and Substituents such as ethoxy (linked through an oxygen rather than a carbon) are considered hydrocarbyls. Hydrocarbyl groups include aryl, heteroaryl, carbocyclic, heterocyclic, and cyclic rings. alkyl, alkenyl, alkynyl, and combinations thereof. But not limited to these.

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

[0054] Chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or When used in conjunction with alkoxy, the term "lower" means that the substituent has 10 or fewer alkyl groups. "Lower alkyl" means a group containing, preferably, six or fewer non-hydrogen atoms. " refers, for example, to alkyl groups containing 10 or fewer carbon atoms, preferably 6 or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkoxy, or hydroxyl groups are as defined herein. The aryl, alkynyl, or alkoxy substituents may occur alone or in combination with other substituents. In combination with substituents, for example, in the recitation of hydroxyalkyl and aralkyl (this For example, atoms in an aryl group are not counted when counting carbon atoms in an alkyl substituent. lower acyl, lower acyloxy, and lower alkoxy, respectively, regardless of whether they appear together (not shown). The alkyl is lower alkenyl, lower alkynyl, or lower alkoxy.

[0055] The terms "polycyclyl," "polycyclic," and "polycyclic" refer to a ring structure in which two or more atoms join together. Two or more rings (e.g., cycloaliphatic rings) that are common to adjacent rings, e.g., the rings are "fused rings" alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or Each ring of the polycycle may be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains 3 to 10 atoms, preferably Or contains 5 to 7.

[0056] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0057] The term "substituted" refers to having substituents replacing a hydrogen on one or more carbons of the backbone. "Substituted" or "substituted with" refers to a moiety in which such substitution occurs on the substituted atom and and the allowed valence of the substituents, and the substitution is such that the compound is stable, e.g., spontaneously It includes the implicit condition that a stable compound is produced that is not subject to transformation by rearrangement, cyclization, elimination, etc. It will be understood that, as used herein, the term "substituted" refers to the All permissible substituents are contemplated. In a broad aspect, the permissible substituents are Groups include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic groups of organic compounds; The permissible substituents are defined for appropriate organic compounds and include aromatic and nonaromatic substituents. For the purposes of this disclosure, heteroatoms such as nitrogen are The heteroatoms may be hydrogen substituents and / or substituted groups as described herein to satisfy the valence of the heteroatoms. The organic compounds may have any permissible substituents. The substituents may be any of the substituents described herein. Groups such as halogen, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl aryl, formyl, or acyl), thiocarbonyl (thioester, thioacetate, or or thioformate, etc.), alkoxy, phosphoryl, phosphate, phosphonate, phosphatase, Sulfonate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl Doryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide , sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties It will be understood by those skilled in the art that substituents can themselves be substituted, where appropriate. Unless specifically stated as "unsubstituted," references herein to chemical moieties include substituted. For example, the term "aryl" refers to an "aryl" group or moiety. Reference implicitly includes both substituted and unsubstituted variants.

[0058] The term "sulfate" is art-recognized and refers to the group -OSO3H, or or a pharmaceutically acceptable salt thereof.

[0059] The term "sulfonamide" is art-recognized and can be represented by the general formula [ka] wherein each R 36 and R 37 are independently hydrogen or hydride represents a hydroxyl group, e.g., alkyl, or R 36 and R 37 but the intervening atom(s) ) together to complete a heterocycle having 4 to 8 atoms in the ring structure.

[0060] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 3 8 refers to R 38 represents a hydrocarbyl.

[0061] The term "sulfonate" is art-recognized and refers to the group SO3H, or It refers to a pharmaceutically acceptable salt thereof.

[0062] The term “sulfone” is art-recognized and refers to the group —S(O)—R 39 refers to R 39 represents a hydrocarbyl.

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

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

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

[0066] The term "urea" is art-recognized and has the general formula [ka] where each R 41 and R 42 are independently hydrogen or hydride represents alkyl, or R 41 Either of these is R 42 and intervention Together with the atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure .

[0067] The term "protecting group" refers to a group that, when attached to a reactive functional group in a molecule, prevents the reactivity of that functional group. Protecting groups refer to a group of atoms that mask, reduce, or block a desired activity during synthesis. Examples of protecting groups are described in Greene and Wuts, Protective Groups 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 & Representative nitrogen protecting groups include formyl, acetyl, and methyl. trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tetrafluoroacetyl rt-Butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl Methylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyl Oxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro -veratryloxycarbonyl ("NVOC"), and the like. Typical hydroxyl protecting groups are those that protect the hydroxyl group from acylation (esterification) or are alkylated, e.g., benzyl and trityl ethers, and alkyl ethers. ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol These include, but are not limited to, glycol derivatives and allyl ethers.

[0068] In certain embodiments, the compounds of the present disclosure may be racemates. In embodiments, the compounds of the present disclosure may be enriched in one enantiomer. For example, The compounds have an ee of greater than about 30%, about 40%, about 50%, about 60%, about 70% ee, about 80% ee, about 90% ee, or even about 95% ee or In certain embodiments, compounds of the present disclosure may have multiple ee's. In certain such embodiments, the compounds of the present disclosure may have one or more dimeric For example, compounds of the present disclosure may be enriched in stereoisomers, such as greater than about 30% de, about 40% de de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% or even about 95% or more of de.

[0069] In certain embodiments, the pharmaceutical agent is a compound that primarily comprises one enzyme of the compound (e.g., of formula (I)). The enantiomerically enriched mixture can be prepared by, for example, For example, at least about 60 mole percent of one enantiomer, more preferably at least about 60 mole percent of one enantiomer. It may comprise at least about 75, about 90, about 95, or even about 99 mole percent. In certain embodiments, a compound enriched in one enantiomer may be enriched in the other enantiomer. Here, "substantially free" means that the substance in question is, for example, in the composition. less than about 10% of the amount of the other enantiomer in a substance or mixture of compounds , or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or For example, if a composition or mixture of compounds contains less than about 98 grams of rum containing the first enantiomer and about 2 grams of the second enantiomer, Contains about 1 mole percent of the first enantiomer and only about 2% of the second enantiomer It is said that...

[0070] In certain embodiments, the pharmaceutical agent is primarily a dimer of one compound (e.g., of formula (I)). The diastereomerically enriched mixture can be , e.g., at least about 60 mole percent of one diastereomer, more preferably , may comprise at least about 75, about 90, about 95, or even about 99 mole percent .

[0071] In some embodiments, moieties of the compounds exist as a mixture of tautomers. A "convertible isomer" is a structural isomer of a moiety or compound that is readily interconvertible with another structural isomer. For example, the pyrazole ring has two tautomers: [ka] They differ in the position of the pi bond and hydrogen atoms. Unless otherwise specified, the moiety or compound A single tautomer diagram of encompasses all possible tautomers.

[0072] The term "subject" to which administration is contemplated includes humans (i.e., males or females of any age). may be administered to women, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults) adult, middle-aged adult, or elderly adult) and / or other primates (e.g., cynomolgus monkeys, mammals, including commercially important mammals, e.g., cattle, pigs, horses, sheep, animals, including geese, goats, cats, and / or dogs, and / or birds, including commercially important birds, e.g. For example, chickens, ducks, geese, quail, and / or turkeys. The preferred subject is a human.

[0073] As used herein, a medication that "prevents" a disorder or condition is a medication that, in a statistical sample, and the disorder or condition is detected in the treated sample compared to the untreated control sample. or a reduction in the occurrence of said disorder or condition compared to an untreated control sample. It refers to a compound that delays the onset or reduces the severity of one or more symptoms. These effects are also referred to as "prophylactic" effects. Therefore, as used herein, unless otherwise specified, Unless otherwise specified, the terms "prevention" and "preventing" include, but are not limited to, a preventative effect. Refers to an approach to obtain beneficial or desired results that are not readily apparent. For patients at risk of developing a certain disease or who report one or more physiological symptoms of the disease Patients with this condition may not have been diagnosed with the disease, but In one embodiment, for a prophylactic effect, an undesirable condition (e.g., The drug is administered prior to clinical symptoms of a disease or other condition that is undesirable for the subject. (e.g., it protects the subject from developing an undesirable condition).

[0074] As used herein, unless otherwise specified, "treatment" or "treating" The term refers to a curative or palliative measure. A beneficial or desired clinical outcome is , whether detectable or undetectable, associated with a disease or disorder or condition The total or partial relief of symptoms, reduction in the extent of the disease, or stable (i.e., no worsening) B) Slowing or slowing the progression of a disease, or improving a disease condition (e.g., one or more symptoms of the disease) or palliation, and remission (whether partial or complete). "Treatment" also refers to the improvement in survival compared with the expected survival if no treatment is given. In one embodiment, "treatment" refers to the treatment of an undesirable condition. This includes administering a medication after the onset of a pre-existing undesirable condition or its side effects. (intended to reduce, improve, or stabilize

[0075] The term "prodrug" refers to a drug that, under physiological conditions, produces a therapeutically active agent (e.g., For example, compounds of formula (I) are intended to include compounds that are converted into prodrugs. A common method for making hydroxybenzoates is to hydrolyze them under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is a compound that includes one or more selected moieties. The target enzyme activity converts the ester to a carbonate, e.g., an ester or carbonate (e.g., Esters or carbonates of alcohols or carboxylic acids are preferred processes of the present disclosure. In certain embodiments, in the formulations depicted above, the compound of formula (I) Part or all of the compounds can be replaced with the corresponding suitable prodrugs, e.g. , where the hydroxyl of the parent compound is presented as an ester, carbonate, or carboxylic acid. will be done.

[0076] As used herein, an "effective amount" refers to an amount sufficient to achieve a desired biological effect. As used herein, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired biological effect. For example, a therapeutically effective amount refers to an amount sufficient to ameliorate at least one sign or symptom of cancer. It can refer to a quantity sufficient to

[0077] A "response" to a treatment regimen may include, among other things, a reduction or improvement in negative symptoms, a decrease in the severity of the disease or is a reduction in the progression of symptoms, an increase in beneficial symptoms or an improvement in clinical outcome, a reduction in side effects, a reduction in the severity of the disease, These include stabilization of the disease, partial or complete cure of the disease.

[0078] As used herein, unless otherwise indicated, the term "relapse" refers to a recurrence of a disease following a previous treatment. refers to a disorder, disease, or condition that has progressed after responding to treatment (e.g., achieving complete remission). The prior treatment may include more than one treatment.

[0079] As used herein, unless otherwise indicated, the term "refractory" refers to a condition that has progressed beyond the primary stage. Treatment with steroids or other anti-inflammatory drugs (ASDs) refers to a disorder, disease, or condition that has not responded to previous treatments, which may include the above treatments.

[0080] compound In one aspect, provided herein is a compound of formula (I), or an enantiomer thereof: a mer, a mixture of enantiomers, or tautomers, or a pharmaceutically acceptable salt thereof is: [ka] During the ceremony, Q is CH or N; Z is CR5 or N; X is a 5-membered heteroatom containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. heteroarylene, wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 R2. It is replaced, Y is a 5- or 6-membered alkyl group 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, or is substituted with two R3, In Y, the bond to the methylene group bonded to X and Y and the bond to the aromatic ring containing Z The points are on adjacent atoms alpha to the point of attachment to the methylene group, including Z. The ring atom of the 5- to 6-membered heteroarylene that is beta to the point of attachment to the aromatic ring is It is raw, R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each R2 is independently H, halo, CN, C 1-4 Alkoxy, C 1-4 Alkyl, halo- C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6Cycloalkyl and C3 -6 heterocycloalkyl; Each R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F, X is 3 * ,4-substituted pyrazolylene, * is the bond to the methylene group bonded to X and Y. Indicates the point of attachment of X or Y.

[0081] In one aspect, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof: be: [ka] During the ceremony, Q is CH or N; Z is CR5 or N; X is a 5-membered heteroatom containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. heteroarylene, wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 R2. It is replaced, Y is 1,2 * -substituted imidazolylene, 4 * ,5-substituted imidazolylene, 4 * ,5-substitution 1,2,3-Oxadiazolylene, 3 * ,4-substituted 1,2,5-oxadiazolylene, 3 * ,4-substituted 1,2-oxazolylene, 4 * ,5-substituted 1,3-oxazolylene, 2 * , 3-substituted pyrazinylene, 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazolylene, 3 * ,4-substituted pyridazinylene, 2 * ,3-substituted pyridinylene, 4 * ,5-substituted pyrimidinyl Ren, 2 * ,3-substituted pyrrolylene, 5 * ,6-substituted 1,2,3,4-tetrazinylene, 1 * ,5-substituted 1,2,3,4-tetrazolylene, 1,5 * -substituted 1,2,3,4-tetra Zorylene, 4 * ,5-substituted 1,2,3-thiadiazolylene, 3 * ,4-substitution 1,2,5- Thiadiazolylene, 3 * ,4-substituted 1,2-thiazolylene, 4 * ,5-substituted 1,3-thia Zorylene, 4 * ,5-substituted 1,2,3-triazinylene, 5 * ,6-substituted 1,2,4-thiazol-1,2,4-diol Riazinylene, 5,6 * -substituted 1,2,4-triazinylene, 1 * ,5-substitution 1,2,3 -triazolylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5-substitution 1,2 ,4-triazolylene, 1,5 * -substituted 1,2,4-triazolylenes, and 3 * ,4-position substituted 1,2,4-triazolylene, The teroarylene is substituted with 0, 1, or 2 R3; * indicates the point of attachment of X or Y to the methylene group bonded to X and Y, In Y, the bond to the aromatic ring containing Z is alpha to the point of attachment to the methylene group. the heteroarylene ring atom beta to the point is nitrogen; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each 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 heterocycloalkyl; Each R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0082] In one aspect, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof: be: [ka] During the ceremony, Q is CH or N; Z is CR5 or N; X is a 5-membered heteroatom containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. heteroarylene, wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 R2. It is replaced, Y is 1,2 * -substituted imidazolylene, 4 * ,5-substituted imidazolylene, 4,5 * -replacement Imidazolylene, 4 * ,5-substituted 1,2,3-oxadiazolylene, 3 * ,4-substitution 1, 2,5-Oxadiazolylene, 3 * ,4-substituted 1,2-oxazolylene, 4 * ,5-substitution 1,3-oxazolylene, 2 * ,3-substituted pyrazinylene, 1 *,5-substituted pyrazolylene, 3 * ,4-substituted pyrazolylene, 3 * ,4-substituted pyridazinylene, 2 * ,3-substituted pyridinyl Ren, 4 * ,5-substituted pyrimidinylene, 2 * ,3-substituted pyrrolylene, 5 * ,6-substitution 1, 2,3,4-Tetrazine, 1 * ,5-substituted 1,2,3,4-tetrazolylene, 1,5 * -substituted 1,2,3,4-tetrazolylene, 4 * ,5-substituted 1,2,3-thiadiazolylene N, 3 * ,4-substituted 1,2,5-thiadiazolylene, 3 * ,4-substituted 1,2-thiazol-1 N, 4 * ,5-substituted 1,3-thiazolylene, 4 * ,5-substituted 1,2,3-triazinylene , 5 * ,6-substituted 1,2,4-triazinylene, 5,6 * -substituted 1,2,4-triazinylidene Ren, 1 * ,5-substituted 1,2,3-triazolylene, 4 * ,5-substituted 1,2,3-thiazol-1 Zorylene, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -substituted 1,2,4- Riazolylene, and 3 * , 4-substituted 1,2,4-triazolylenes and the heteroarylene is substituted with 0, 1, or 2 R3. R, * indicates the point of attachment of X or Y to the methylene group bonded to X and Y, In Y, the bond to the aromatic ring containing Z is alpha to the point of attachment to the methylene group. the heteroarylene ring atom beta to the point is nitrogen; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each 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 heterocycloalkyl; Each R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0083] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene. a 5-membered heteroaryl selected from the group consisting of benzophenone, imidazolylene, and triazolylene; In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is a 5-membered heteroarylene selected from the group * ,5-substituted pyrazolylene, 4,5 * -substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 3 * ,4-substituted isoxazolylene, 3 * ,4-position Substituted isothiazolylene, 4 * ,5-substituted isothiazolylene, 4 * ,5-substituted imidazolylene , 1 * ,5-substituted imidazolylene, 1 * ,5-substituted triazolylenes, and 4* ,5-substitution and a 5-membered heteroarylene selected from the group consisting of triazolylene.

[0084] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene. a 5-membered heteroaryl selected from the group consisting of benzophenone, imidazolylene, and triazolylene; In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is a 5-membered heteroarylene selected from the group * ,5-substituted pyrazolylene, 4,5 * -substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 4,5 * -substituted isoxazolylene, 3 * ,4-position Substituted isoxazolylene, 3 * ,4-substituted isothiazolylene, 4 * ,5-substituted isothiazolidine Ren, 4,5 * -substituted isothiazolylene, 4 * ,5-substituted imidazolylene, 1 * ,5-position Substituted imidazolylene, 1 * ,5-substituted triazolylenes, and 4 * ,5-substituted triazolylene and a 5-membered heteroarylene selected from the group consisting of:

[0085] In certain embodiments, X is a 5-membered heteroaryl selected from the group consisting of: It is: [ka] In one embodiment, X is pyrazolylene. In one embodiment, X is 3 * , In one embodiment, X is not a 4-substituted pyrazolylene. [ka] In one embodiment, X is not [ka] In another embodiment, X is not 3 * , 4-substituted pyrazolylene. So, X is 4 * In another embodiment, X is a 4,5-substituted pyrazolylene. * - In another embodiment, X is 1 * , 5-substituted pyrazolylene In one embodiment, X is [ka] In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0086] In one embodiment, X is isoxazolylene. In one embodiment, X is 4 * In one embodiment, X is a 4,5-substituted isoxazolylene. * -replacement In one embodiment, X is 3 * ,4-substituted isoxazolidinyl In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0087] In one embodiment, X is isothiazolylene. In one embodiment, X is 3 * In one embodiment, X is 4,4-substituted isothiazolylene. * ,5-substituted iso In one embodiment, X is 4,5 * -substituted isothiazolylene In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0088] In one embodiment, X is imidazolylene. In one embodiment, X is 4 * In one embodiment, X is 1,5-substituted imidazolylene. * ,5-substituted imidazo In one embodiment, X is [ka] is.

[0089] In one embodiment, X is triazolylene. In one embodiment, X is 1 * In one embodiment, X is 4,5-substituted triazolylene. * ,5-substituted triazo In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0090] In one embodiment, X is substituted with 0 R2 (i.e., all vacant positions on X are In one embodiment, X is substituted with one R2 that is not H. In this embodiment, X is substituted with two R2 that are not H.

[0091] R2 is independently H, halo, CN, C 1-4 Alkoxy, C 1-4 Alkyl, halo- C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C3 -6 In one embodiment, R2 is selected from the group consisting of: In one embodiment, R2 is not C 1-4 In one embodiment, , R2 is methyl. In one embodiment, R2 is ethyl. In one embodiment, R2 is isopropyl. In one embodiment, R2 is cyclopropyl. In one embodiment, R2 is cyclobutyl. In one embodiment, R2 is In one embodiment, R2 is -CHF2. In one embodiment, R2 is -CH2CHF2. In one embodiment, R2 is halo. In one embodiment, R2 is fluoro. In one embodiment, R2 is chlorine. In one embodiment, R2 is CN. In one embodiment, R2 is It is methoxy.

[0092] In certain embodiments, X is a 5-membered heteroaryl selected from the group consisting of: It is: [ka] In some embodiments, Y is 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazo Lilen, 1, 2 * -substituted imidazolylene, 4 * ,5-substituted imidazolylene, 1 * ,5-position Substituted 1,2,3-triazolylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5 -substituted 1,2,4-triazolylene, 1,5 * -substituted 1,2,4-triazolylene, 4 * ,5-substituted 1,3-thiazolylene, 2 * ,3-substituted pyridinylene, 4 * ,5-substituted pyrimidinyl Dinylene, and 2 * , 3-substituted pyrazinylene; is.

[0093] In some embodiments, Y is 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazo Lilen, 1, 2 * -substituted imidazolylene, 4 * ,5-substituted imidazolylene, 4,5 * -Place Substituted imidazolylene, 1 * ,5-substituted 1,2,3-triazolylene, 4 * ,5-substitution 1,2 ,3-triazolylene, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -replacement 1 ,2,4-triazolylene, 4 * ,5-substituted 1,3-thiazolylene, 2* ,3-substituted pyridinium Ginylene, 4 * ,5-substituted pyrimidinylene, and 2 * ,3-substituted pyrazinylenes is a heteroarylene selected from:

[0094] In certain embodiments, Y is a heteroarylene selected from the group consisting of: the law of nature: [ka] * indicates the point of attachment of Y to the methylene groups attached to X and Y, R3 is H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 alkyl.

[0095] In one embodiment, Y is a 5-membered heteroarylene. In one embodiment, Y is 1,5 * -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] is.

[0096] In one embodiment, Y is imidazolylene. In one embodiment, Y is 1, 2* In one embodiment, Y is 4-substituted imidazolylene. * ,5-substituted imidazo In one embodiment, Y is 4,5 * -substituted imidazolylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] is.

[0097] In one embodiment, Y is triazolylene. In one embodiment, Y is 1 * In one embodiment, Y is 4,5-substituted 1,2,3-triazolylene. * ,5- In one embodiment, Y is a substituted 1,2,3-triazolylene. * ,5-substitution 1 In one embodiment, Y is 1,5,2,4-triazolylene. * -replacement 1,2, In one embodiment, Y is 4-triazolylene. [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] is.

[0098] In one embodiment, Y is thiazolylene. In one embodiment, Y is 4 * , In one embodiment, Y is a 5-substituted 1,3-thiazolylene. [ka] is.

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

[0100] In one embodiment, Y is pyrimidinylene. In one embodiment, Y is 4 * ,5-substituted pyrimidinylene. In one embodiment, Y is [ka] is.

[0101] In one embodiment, Y is pyrazinylene. In one embodiment, Y is 2 * , In one embodiment, Y is 3-substituted pyrazinylene. [ka] is.

[0102] In one embodiment, Y is substituted with 0 R3 (i.e., all vacant positions on Y are substituted with 0 R3). In one embodiment, Y is substituted with one R that is not H. In this embodiment, Y is substituted with two R3 that are not H.

[0103] In one embodiment, R3 is H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 In one embodiment, R3 is selected from the group consisting of alkyl. is not H. In one embodiment, R3 is C 1-4 alkyl. In one embodiment, R3 is methyl. In one embodiment, R3 is ethyl. In embodiments, R3 is halo. In one embodiment, R3 is fluoro. In one embodiment, R3 is chloro. In one embodiment, R3 is CN.

[0104] In one embodiment, X is a pyrazolylene as provided herein (e.g., a pyrazolylene as provided herein). Provide 4 * , 5-substituted pyrazolylene), and Y is a pyrazolylene as provided herein. In another embodiment, Y is an imidazolylene as provided herein. In one embodiment, Y is a triazolylene as provided herein. In another embodiment, Y is a thiazolylene as provided herein. In another embodiment, Y is pyrimidinylene, as provided herein. In another embodiment, Y is a pyrazinylene as provided herein.

[0105] In one embodiment, X is an isoxazolylene as provided herein and Y is In another embodiment, Y is a pyrazolylene as provided herein. In another embodiment, Y is a triazolylene as provided herein. In another embodiment, Y is a thiazolylene as provided herein. In another embodiment, Y is pyridinylene as provided herein. In another embodiment, Y is a pyrimidinylene as provided herein. This is Niren.

[0106] In one embodiment, X is an isothiazolylene as provided herein and Y is an isothiazolylene as provided herein. In another embodiment, Y is an imido group as provided herein. In another embodiment, Y is a triazolylene as provided herein. In another embodiment, Y is a thiazolylene as provided herein. and Y is pyridinylene as provided herein. In another embodiment, Y is In another embodiment, Y is a pyrimidinylene as provided herein. It's Ren.

[0107] In one embodiment, X is an imidazolylene as provided herein and Y is an imidazolylene as provided herein. In another embodiment, Y is an imidazoline group as provided herein. In another embodiment, Y is a triazolylene as provided herein. In another embodiment, Y is a thiazolylene as provided herein. In another embodiment, Y is a pyridinylene as provided herein. In another embodiment, Y is a pyrimidinylene as provided herein. It is.

[0108] In one embodiment, X is a triazolylene as provided herein and Y is a triazolylene as provided herein. In another embodiment, Y is an imidazoline group as provided herein. In another embodiment, Y is a triazolylene as provided herein. In another embodiment, Y is a thiazolylene as provided herein. In another embodiment, Y is a pyridinylene as provided herein. In another embodiment, Y is a pyrimidinylene as provided herein. It is.

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

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

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

[0112] In some embodiments, the compound of formula (I) has the structure (IA): [ka] In other embodiments, the compound of formula (I) has the structure (IB): [ka] In one embodiment, the compound is a compound of any one of the following formulae, or an enamel thereof: enantiomer, mixture of enantiomers, or tautomers, or pharmaceutically acceptable salts thereof It is a salt that can be used: [ka] In some embodiments, each R2 is independently H, CN, methyl, ethyl, isobutyl, or methyl. methyl, methoxy, chloro, trifluoromethyl, cyclopropyl, cyclopropylmethyl , 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, cyclobutyl, and oxetanyl.

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

[0114] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0118] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0119] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0120] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0122] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is: [ka] is.

[0124] In certain embodiments, the compound is: [ka] is.

[0125] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, the compound is selected from the group consisting of: [ka] or an enantiomer, mixture of enantiomers, or tautomer thereof isomer, or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the compound is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt thereof.

[0128] In one embodiment, provided herein is a compound of Table 1: [Table 1] TIFF0007815341000073.tif226165TIFF0007815341000074.tif221165TIFF0007815341000075.tif231165TIFF0007815341000076.tif231165TIFF0007815341000077.tif236165TIFF0007815341000078.tif208165 or a pharmaceutically acceptable salt thereof.

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

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

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

[0132] In certain embodiments, the pharmaceutically acceptable salt is prepared from a solution of water, methanol, ethanol, and Dimethylformamide.

[0133] In certain embodiments, the compound may be administered in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier or excipient. It is a pharmaceutical composition.

[0134] In certain embodiments, the composition is in the form of a tablet, capsule, granule, lyophilisate for reconstitution, powder, or the like. powders, solutions, syrups, suppositories, injections, transdermal delivery systems, and solutions suitable for topical administration. It is a form selected from the group consisting of:

[0135] How to use Provided herein are compounds of the present disclosure, e.g., compounds of formula (I), or derivatives thereof. an anantiomer, a mixture of enantiomers, or tautomers, or a pharmaceutically acceptable salt thereof and administering a salt thereof to a patient in need thereof.

[0136] Cancer is a disease of uncontrolled cell growth caused by alterations in certain genes. Some of these changes are mediated by extracellular signals to promote cell survival, growth, and proliferation. Receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit Abnormal RTK activation occurs in the genes that encode them. This leads to excessive cell proliferation and ultimately to cancer. Generally, RTKs consist of an N-terminal domain that binds to extracellular ligands, It contains a transmembrane domain and a C-terminal kinase domain that catalyzes intracellular signaling.

[0137] In some embodiments, the compounds of Formula (I) are inhibitors of human ROS1. 1 is a RTK encoded by the ROS1 gene. Its biological function is unknown, but its homologs in several other species act as extracellular ligands. It has been shown to bind to ROS1 and stimulate cell differentiation. ROS1 is essential for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are sufficient It is a well-documented cause of cancer, accounting for 1-2% of non-small cell lung cancer (NSCLC) and many These rearrangements involve the C-terminus of ROS1 and various parts of the ROS1 gene. This results in a fusion to the N-terminus of a host protein, the most common of which is CD7. 4. ROS1 fusion mediates MAPK, PI3K, and JAK / STAT signaling. It has constitutive kinase activity that promotes tumor growth through a small molecule tyrosine kinase inhibitor. TKIs, including crizotinib and entrectinib, have been shown to inhibit ROS1 in cancer. Crizotinib has been used to target ROS1 fusions. It is the first TKI approved by the FDA for the treatment of rheumatoid arthritis, with an overall response rate of 60-80% and no progression-free survival. The median duration of progression is 9 to 19 months. Despite initial responses, most patients continue to receive crizotinib. Resistance to tinib is acquired, resulting in relapse. The main mechanism of resistance is solvent f The G2032R mutation in ront dramatically reduced the affinity of crizotinib. Inhibitors with activity against the ROS1-G2032R fusion are FDA approved. This demonstrates a need in the art.

[0138] In some embodiments, the compound of formula (I) inhibits human anaplastic lymphoma kinase (ALK) ALK, also known as cluster of differentiation 246 (CD246), is an inhibitor of AL ALK and ROS1 are evolutionarily related. Both belong to the insulin receptor superfamily, and their kinase domains are , which share approximately 80% sequence similarity. Pleiotrophin and midkine growth factors Several ALK ligands have been identified in humans, including ALK in humans. Although the role of ALK remains uncertain, mounting evidence from mouse studies supports its role in the regulation of the nervous system. Similar to ROS1, ALK chromosomal rearrangements are , oncogenic traits via MAPK, JAK / STAT, or other signaling pathways ALK rearrangements also lead to constitutively active fusion proteins that promote transformation of NSCs. It accounts for 3-5% of LC, about half of anaplastic large cell lymphoma (ALCL), and many other cancers. The main fusions in this subset were EML4-ALK in NSCLC and NPM1 in ALCL. -ALK. Oncogenic point mutations in ALK occur much less frequently than translocations. and amplification have also been observed. and lorlatinib are indicated for first-line or prior treatment of ALK-positive NSCLC and other cancers. For example, crizotinib is a TKI approved by the FDA for post-treatment use in patients with 60-69 years of age. The overall response rate was 80% and the median progression-free interval was 8-11 months. Despite the initial response, the activity of the aforementioned FDA-approved TKIs is comparable to that of the FDA-approved TKIs in CLC. Many resistance mutations have emerged against HIV. Some of these mutations, e.g., L11 Combination of 96M gatekeeper and G1202R solvent front mutation The combination of these drugs is resistant to all approved drugs. New treatments are needed in the art.

[0139] In a further embodiment, the compound of formula (I) inhibits human tropomyosin receptor kinase (T The TRK family consists of receptor tyrosine kinases TRKA, TRK B, and TRKC, which contain NTRK1, NTRK2, and NTRK3, respectively. Each TRK is encoded by a distinct but overlapping set of neurotrophins. All T are activated by ligands such as NGF, BDNF, and NT-3. RKs exhibit sequence convergence in the ligand-binding domain rather than convergence in the kinase domain. Consistent with their divergence, TRK regulates similar downstream signaling pathways (90% similarity). They regulate processes such as memory, movement, pain, and proprioception during development and in adult mammals. NTRK rearrangements play important roles in the mammalian nervous system. Similar to ROS1 and ALK, NTRK rearrangements Resulting in a constitutively active TRK fusion, which is expressed via MAPK, PI3K, and other pathways TRK fusions are found in many cancers, including secretory breast cancer and mammary-like secretory breast cancer. It accounts for over 80% of cases of carcinoma, infantile fibrosarcoma, and congenital mesoblastic nephroma. Inhibition of TRK fusions is beneficial for the treatment of cancers that express TRK fusions.

[0140] Many ROS1 and ALK inhibitors in the prior art also inhibit the potency of naturally occurring non-oncogenic TRKs. Native TRKs play important roles in the nervous system and the inadvertent activation of native TRKs is a key factor in the development of inflammatory cytokines. Inhibition may result in adverse reactions including dizziness, ataxia, gait disturbances, paresthesias, weight gain, and cognitive changes. This is a substantial drawback, as it is associated with the non-mutated and / or mutated R New therapies that selectively target OS1 and / or ALK while sparing TRK are emerging. , there is a need in the art.

[0141] In one embodiment, provided herein are methods for detecting intracellular ROS1 or ALK levels. The method is a method for reducing the risk of developing a steroid hormone, the method comprising administering to a subject a compound or pharmaceutical composition provided herein or In embodiments, such contacting involves contacting the cells with a combination of pharmaceutical agents. In embodiments, such contacting occurs within a cell of a cancer, e.g., a human. It occurs in the cells of human patients with

[0142] In one embodiment, the compounds provided herein selectively inhibit ROS1. In one embodiment, the compound selectively inhibits ROS1 over ALK. As such, the selectivity ratio is a measure of selectivity, especially the IC 50 Measured by the ratio of values If the amount can be increased, it is more than about 1.5 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, more than about 10 times, It may be more than about 20-fold, more than about 30-fold, more than about 50-fold, or more than about 100-fold. So, the selectivity of ROS1 for ALK is related to the IC 50 values ​​and ROS1 IC 50 It is measured by the ratio of

[0143] In one embodiment, the compound inhibits TRK (e.g., TRKA, TRKB, and / or selectively inhibits ROS1 over TRBCs. Selectivity is one of several measures, especially IC 50 more than about 5 times, as can be measured by the ratio of values 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, About It may be greater than 10,000-fold, or greater than about 20,000-fold. The selectivity of ROS1 for TRK is 50 values ​​and IC against ROS1 50 value It is measured by the ratio of

[0144] In one embodiment, the compounds provided herein selectively inhibit ALK. In certain embodiments, the compounds selectively inhibit ALK over ROS1. The selectivity ratio is a measure of selectivity, among other things, the IC 50 It is measured by the ratio of If possible, more than about 1.5 times, more than about 2 times, more than about 3 times, more than about 4 times, more than about 5 times, or more than about 10 times In one embodiment, the selectivity of ALK for ROS1 can be IC 50 value and IC for ALK 50 It is measured by the ratio of

[0145] In one embodiment, the compound inhibits TRK (e.g., TRKA, TRKB, and / or selectively inhibits ALK over TRBCs. As a non-limiting example, the selectivity ratio can be expressed as Sex is one of several measures, especially IC 50 More than about 5 times, if it can be measured by the ratio of values 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 More than 800 times, more than about 1000 times, more than about 1500 times, more than about 2000 times, more than about 5000 times, and In one embodiment, the selectivity of ALK over TRK can be greater than about 10,000-fold. is the IC for TRK 50 value and IC for ALK 50 It is measured by the ratio of

[0146] In one embodiment, the compound inhibits TRK (e.g., TRKA, TRKB, and / or selectively inhibits ROS1 and ALK over TRBCs. The ratio of selectivity is a measure of selectivity, especially IC 50 If it can be measured by the ratio of the 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 The ratio may be greater than about 0, greater than about 10,000, or greater than about 20,000. The selectivity of ROS1 and ALK over TRK was 50 Values ​​and ROS IC against 1 and ALK 50 It is measured by the ratio of

[0147] In one embodiment, provided herein are antibodies that selectively inhibit ROS1 over ALK. In one embodiment, the method comprises: The purpose of this study was to select ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC). In one embodiment, the method selectively inhibits the expression of a protein, wherein the inhibition occurs intracellularly. comprises contacting ROS1 with an effective amount of a compound provided herein. In embodiments, such contacting occurs intracellularly. In embodiments, such contacting occurs intracellularly in a mammal, e.g., In embodiments, such contacting occurs within a cell of a human having a cancer as described herein. It occurs within the patient's cells.

[0148] In one embodiment, provided herein are antibodies that selectively inhibit ROS1 over ALK. The method comprises administering to a subject suffering from cancer, the method comprising administering to the subject a therapeutically effective amount of the inhibitory agent. This includes administering to the patient an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods for treating a patient suffering from a ROS1-associated cancer. A method of treating a subject having a rheumatoid arthritis, the method comprising administering to the subject an amount of a compound provided herein. and selectively inhibiting ROS1 over ALK by administering a compound or pharmaceutical composition. wherein the amount is sufficient to selectively inhibit ROS1 over ALK.

[0149] In one embodiment, provided herein is a method for detecting TRK (e.g., TRKA, TRKB and / or TRBCs), wherein the inhibition is The method is carried out in a subject suffering from a rheumatoid arthritis, and the method comprises administering to the subject an effective amount of a compound provided herein. In certain embodiments, the method includes administering a compound or pharmaceutical composition according to the present invention. Provided herein is a method for treating a subject suffering from a cancer associated with ROS1, the method comprising: The method comprises administering to the subject an amount of a compound or pharmaceutical composition provided herein. This allows TRK (e.g., TRKA, TRKB, and / or TRBC) to differentiate into ROS. 1, wherein the amount selectively inhibits TRK (e.g., TRKA, TRKB, and and / or TRBCs) is sufficient to selectively inhibit ROS1.

[0150] In one embodiment, provided herein are antibodies that selectively inhibit ALK over ROS1. In one embodiment, the method comprises: select ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) In one embodiment, the method comprises: In some embodiments, the method includes contacting ALK with an effective amount of a compound provided herein. In embodiments, such contacting occurs intracellularly. In embodiments, such contacting occurs intracellularly. In embodiments, such contacting occurs within a cell of a human patient having a cancer as described herein. occurs within the cells of

[0151] In one embodiment, provided herein are antibodies that selectively inhibit ALK over ROS1. The method comprises administering to a subject suffering from cancer, the method comprising administering to the subject a therapeutically effective amount of the inhibitory agent. This includes administering to the patient an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods for treating a patient suffering from an ALK-associated cancer. A method of treating a subject, the method comprising administering to the subject an amount of a compound provided herein. Alternatively, the pharmaceutical composition may be administered to selectively inhibit ALK over ROS1. wherein the amount is sufficient to selectively inhibit ALK over ROS1.

[0152] In one embodiment, provided herein is a method for detecting TRK (e.g., TRKA, TRKB and / or TRBCs), wherein the inhibition is The method is carried out in an affected subject, and comprises administering to the subject an effective amount of a compound provided herein. In certain embodiments, the method of the present invention includes administering a compound or pharmaceutical composition comprising administering to a subject a therapeutically effective amount of the compound or pharmaceutical composition described herein. Provided herein is a method for treating a subject suffering from an ALK-associated cancer, the method comprising: administering to said subject an amount of a compound or pharmaceutical composition provided herein. Select ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) by and wherein the amount is selected from the group consisting of TRK (e.g., TRKA, TRKB, and / or is sufficient to selectively inhibit ALK over TRBC.

[0153] As used herein, unless otherwise specified, inhibition of ROS1 includes inhibition of wild-type ROS1. Inhibition of ALK includes inhibition of wild-type ALK or its mutants. Inhibition of TRK includes inhibition of wild-type TRK or its mutants. Inhibition is included.

[0154] Cancers that may be treated by the methods of the present disclosure include lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumors, ovarian cancer, e.g., serous ovarian cancer, melanoma, e.g., Spitz nevus melanoma chromatidoma, glioblastoma, bile duct cancer, e.g., cholangiocarcinoma (c holangiocarcinoma), gastric cancer, colorectal cancer, angiosarcoma, undifferentiated large cell lung cancer lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer, e.g. esophageal squamous cell carcinoma, kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple myeloma Gative breast cancer, thyroid cancer, e.g., papillary thyroid carcinoma, neuroblastoma, epithelioid hemangioendothelioma, These include, but are not limited to, colon cancer and Spitz nevus-like tumors.

[0155] Cancers that may be treated by the methods of the present disclosure include those that involve ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by the methods of the present disclosure include those involving ROS1, ALK, The present invention aims to detect one or more oncogenic proteins selected from the group consisting of TRKA, TRKB, and TRKC. This includes cancers that are resistant to targeted treatment.

[0156] In one embodiment, the cancer in the methods provided herein is anaplastic lymphoma kinase. As used herein, unless otherwise specified, "ALK" refers to a condition in which the patient is ALK-positive. ALK-positive (ALK+) cancers, diseases, or disorders are caused by inappropriately high expression and / or repression of the ALK gene. or refers to a cancer, disease, or disorder characterized by the presence of a mutation in the ALK gene In one embodiment, the mutation abrogates the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a "mutation" or or "mutant" refers to the amino acid or nucleotide sequence of ALK, or a fragment thereof. This includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the fragments. As used herein, unless otherwise specified, an ALK "rearrangement" refers to an ALK fusion gene. and / or genetic translocations involving the ALK gene that can result in ALK fusion proteins The ALK fusion also refers to one or more mutants of the ALK family, as long as the mutant retains kinase phosphorylation activity. It may include any of the above deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, or fragments thereof.

[0157] In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, the cancer treated by the methods of the present disclosure is a cancer characterized by a kinase In one embodiment, the one or more ALK point mutations are L1152, C1156, I1171, F1174, V1180, L1196, L1 198, G1202, D1203, S1206, E1210, F1245, G1269, and a point mutation at R1275. In one embodiment, the one or more AL The point mutations in K are 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 ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is G1202R and L11 and co-mutation with one or more mutations selected from 96M, G1269A, and L1198F. In one embodiment, the ALK mutation is G1202R / L1196M In one embodiment, the ALK mutation is a double mutation of G1202R / G In one embodiment, the ALK mutation is a double mutation at G12 It is a double mutation of 02R / L1198F.

[0158] In one embodiment, the ALK mutation is one or more ALK rearrangements (in one embodiment In one embodiment, the ALK mutation comprises one or more In some embodiments, the present invention comprises an ALK fusion (in one embodiment, one fusion). The cancers treated by the disclosed methods include ALK fusions. K fusions include EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, 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; In one embodiment, the ALK mutation is EML4-ALK, i.e., The echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase EML4-ALK has a different breakpoint junction. There are many variants associated with this condition, with variant 1 (v1) and variant 3 (v3) being the most clinically relevant. is also common.

[0159] In one embodiment, the ALK mutation comprises one ALK rearrangement and one or more ALK mutations. In one embodiment, the ALK mutation comprises a point mutation at EML4-ALK. In one embodiment, the ALK mutation is EML4 - ALK G1202R (variant 1). In one embodiment, the ALK mutation is The mutation is EML4-ALK L1196M / G1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269 In one embodiment, the ALK mutation is EML4-A (variant 1). LK G1202R / L1198F (Variant 1).

[0160] In one embodiment, the ALK+ cancer is identified by an FDA-approved test or a method known in the art. Tests that may be used include, for example, the Foundat ionOne CDx™ (F1CDx) (324 gene substitutions, insertions, and Deletion alterations (indels), copy number alterations (CNAs), and selected genes Reconstruction of the offspring, as well as microsatellite instability (MSI) and tumor mutation burden (T Genomic signatures, including MB, were analyzed using formalin-fixed paraffin-embedded (FFPE) tumor tissue samples. Sequencing-based in vitro diagnostics for detection using DNA isolated from the (Blocking device), VENTANA ALK (D5F3) CDx assay (BenchMark Formalin-fixed plates stained on an XT or BenchMark ULTRA automated stainer Anaplastic lymphoma kinase in FFPE non-small cell lung cancer (NSCLC) tissue ALK Break (qualitative detection of ALK protein) and Vysis ALK Break Apart FISH Probe Kit Test (Formalin-Fixed Paraffin-Embedded (FF) Fluorescence in situ hybridization in non-small cell lung cancer (NSCLC) tissue specimens A qualitative test to detect rearrangements involving the ALK gene via FISH (Fish-Induced Staining) is one example. In one embodiment, the test is performed by fluorescence in situ hybridization (F ISH) test, e.g., Vysis ALK Break Apart FISH Pro For more information on FDA-approved tests, see, for example, ttps: / / www.fda.gov / MedicalDevices / Produc tsandMedicalProcedures / InVitroDiagnostic Further Vysis ALK B information can be found at: s / ucm303030.htm Break Apart FISH Probe Kit is available at, for example, https: / / w www.molecular.abbott / us / en / products / oncol ogy / vysis-alk-break-apart-fish-probe-kit and IEEE Transactions on Applied Physics, Vol. 1, No. 1, pp. 111-114, 2003, the entire contents of which are incorporated herein by reference.

[0161] Also provided are methods of treating a subject with cancer (e.g., ALK-positive cancer). The method includes using a sample obtained from a subject who has cancer and who has previously been administered a first ALK inhibitor. Identify whether cancer cells in the pool harbor one or more ALK inhibitor resistance mutations and if the subject has cancer cells with one or more ALK inhibitor-resistant mutations, In this case, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be administered as monotherapy. This includes administering to the subject either as a single agent or in combination with another anti-cancer agent. In some embodiments, the one or more ALK inhibitor resistance mutations are resistant to the first ALK inhibitor. In some embodiments, the cancer cells or tumors are resistant to treatment with the compound. wherein the one or more ALK inhibitor resistance mutations are one or more ALK inhibitor resistance mutations For example, the one or more ALK inhibitor resistance mutations include those at amino acid positions 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219 196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1 151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1 152, 1156, and 1245, e.g., 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 In some embodiments, the other anti-cancer agent may comprise a substitution with one or more of: The other anti-cancer agent may be any anti-cancer agent known in the art. For example, the other anti-cancer agent may be another ALK inhibitor (e.g., For example, a second ALK inhibitor.

[0162] In one embodiment, the cancer in the methods provided herein is ROS1 positive (ROS 1+). As used herein, unless otherwise specified, "ROS1 positive" ( ROS1+) cancers, diseases, or disorders are characterized by inappropriately high expression of the ROS1 gene and / or Refers to a cancer, disease, or disorder characterized by the presence of a mutation in the ROS1 gene.1 In one embodiment, the mutation alters the biological activity of the ROS1 nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a "mutation" or or "mutants" refer to the amino acid or nucleotide sequence of ROS1, or It includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the fragment. As used herein, unless otherwise specified, a "reconstitution" of ROS1 refers to a ROS1 fusion. Genes involving the ROS1 gene that may result in ROS1 fusion proteins and / or ROS1 fusion proteins The ROS1 fusion also indicates that the mutant retains kinase phosphorylation activity. As long as the fragment contains one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, It may include.

[0163] In one embodiment, the ROS1 mutation comprises one or more ROS1 point mutations. In some embodiments, the cancer treated by the methods of the present disclosure is a cancer characterized by ROS1 kinase. In one embodiment, the one or more ROS1 mutations The mutations are E1935, L1947, L1951, G1971, E1974, and L1982. , S1986, F2004, E2020, L2026, G2032, D2033, C20 60, F2075, L2086, V2089, V2098, G2101, D2113, and and a point mutation at L2155. In one embodiment, the one or more ROS The single point mutations were 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 In one embodiment, the ROS1 is selected from the group consisting of ROS1G, ... In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1 mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. In one embodiment, the ROS1 mutation is D2033N. In one embodiment, the ROS1 mutation is L2086F. 2004C. In one embodiment, the ROS1 mutation is F2004V. In one embodiment, the ROS1 mutation is G2101A. In one embodiment, the ROS1 mutation is L1982F. The mutations were G2032R, S1986F, S1986Y, F2004C, and F200 Co-mutation with one or more of 4V, L2026M, or D2033N.

[0164] In one embodiment, the ROS1 mutation is one or more ROS1 rearrangements (one embodiment). In one embodiment, the ROS1 mutation comprises one rearrangement. In some embodiments, the ROS1 fusion comprises one or more ROS1 fusions (in one embodiment, one fusion). In one embodiment, the cancer treated by the methods of the present disclosure comprises a ROS1 fusion. The ROS1 fusion protein is involved in the expression of SLC34A2, CD74, TPM3, SDC4, EZR, and LR. IG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., 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 In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is an SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is an EZR-ROS1 fusion. The ROS1 fusion is an SLC34A2-ROS1 fusion. In one embodiment, the ROS 1 fusions, such as GOPC-ROS1 fusions (e.g., GOPC-ROS1-S ... In one embodiment, the ROS1 fusion is a CEP85L-ROS1 fusion. It is a combination.

[0165] In one embodiment, the ROS1 mutation comprises one ROS1 rearrangement and one or more R In one embodiment, the ROS1 mutation comprises a CD74-R ROS1 point mutation. OS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1 one or more ROS1 rearrangements, as well as F2004C, F2004V, and G2032R In one embodiment, the ROS1 The mutations are CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1 and a G2101A ROS1 point mutation.

[0166] In one embodiment, the ROS1 mutation is CD74-ROS1 F2004C. In one embodiment, the ROS1 mutation is CD74-ROS1 F2004 In one embodiment, the ROS1 mutation is CD74-ROS1 G21 In one embodiment, the ROS1 mutation is CD74-ROS1 G In one embodiment, the ROS1 mutation is CD74-ROS1 In one embodiment, the ROS1 mutation is CD74-ROS1. In one embodiment, the ROS1 mutation is CD74- In one embodiment, the ROS1 mutation is ROS1 D2033N. -ROS1 F2004C. In one embodiment, the ROS1 mutation is EZ In one embodiment, the ROS1 mutation is R-ROS1 F2004V. In one embodiment, the ROS1 mutation is ZR-ROS1 G2101A. EZR-ROS1 G2032R. In one embodiment, the ROS1 mutation is , SLC34A2-ROS1 F2004C. In one embodiment, the ROS1 The mutation is SLC34A2-ROS1 F2004V. The ROS1 mutation is SLC34A2-ROS1 G2101A. In some embodiments, the ROS1 mutation is SLC34A2-ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004C (e.g., For example, GOPC-ROS1-S F2004C, GOPC-ROS1-L F2004C) In one embodiment, the ROS1 mutation is GOPC-ROS1 F200 4V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2 In one embodiment, the ROS1 mutation is GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1 In one embodiment, the ROS1 mutation is CEP8 5L-ROS1 F2004C. In one embodiment, the ROS1 mutation is: In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004V. The mutation is CEP85L-ROS1 G2032R. In one embodiment, the ROS The mutation in 1 is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). The ROS1 mutation is CD74-ROS1 L1982F.

[0167] In one embodiment, the ROS1+ cancer is identified by an FDA-approved test or a method known in the art. It is determined by other tests known in the art. Tests that can be used include, for example, Thermo Oncomine™ Dx Targ by Fisher Scientific et Test (Qualitative in vitro diagnostic test, targeted high-throughput parallel sequencing) Formalin-fixed paraffin from patients with non-small cell lung cancer (NSCLC) using a ligation technique DNA and RNA isolated from FFPE tissue samples were analyzed for 23 genes. Vysis R, which detects sequence variants associated with genomic DNA using the Ion PGM Dx system OS1 Break Apart FISH Probe Kit (formalin-fixed parasites) Fluorescence in situ imaging in FFPE non-small cell lung cancer (NSCLC) tissue specimens Involves ROS1 gene rearrangement at 6q22 via hybridization (FISH) RT real-time polymerase chain reaction (a qualitative test to detect rearrangements) or via local diagnostic testing Examples include reverse transcription-polymerase chain reaction (RT-PCR) or next generation sequencing (NGS).

[0168] Also provided are methods of treating a subject with cancer (e.g., a ROS1-positive cancer). The method includes obtaining a tumor suppressor antibody from a subject who has cancer and who has previously been administered a first ROS1 inhibitor. Identify whether cancer cells in a sample harbor one or more ROS1 inhibitor resistance mutations. and determining whether the subject has cancer cells with one or more ROS1 inhibitor-resistant mutations. wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is This includes administering to the subject either as a monotherapy or in conjunction with another anti-cancer agent. In some embodiments, the one or more ROS1 inhibitor resistance mutations are mutated by the first ROS1 inhibitor. Increases the resistance of cancer cells or tumors to treatment with toxic agents. In embodiments, the one or more ROS1 inhibitor-resistant mutations are one or more ROS1 inhibitor-resistant mutations. For example, one or more ROS1 inhibitor-resistant mutations may be present 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, e.g., 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 In some embodiments, the other anti-cancer agent may comprise one or more substitutions thereof. The other anti-cancer agent may be any anti-cancer agent known in the art. For example, the other anti-cancer agent may be another ROS1 inhibitor (e.g., For example, a second ROS1 inhibitor).

[0169] In one embodiment, the compounds provided herein are CNS-penetrating compounds. In embodiments, administration of an effective amount of a compound provided herein (e.g., orally or intravenously) ), the compound is able to penetrate the CNS (e.g., the blood-brain barrier) and Inhibiting (e.g., selectively inhibiting) ROS1 and / or ALK in the brain A sufficient concentration can still be achieved.

[0170] In one embodiment, provided herein is a method of treating CNS metastasis of cancer, comprising: The method comprises administering to a subject in need thereof an effective amount of a compound described herein, e.g., A compound of formula (I) or its enantiomer, mixture of enantiomers, or tautomer In one embodiment, the method comprises administering a medicament containing a compound of formula (I) or a medicament containing a compound of formula (I), ... The CNS metastasis is a brain metastasis. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is an ALK+ cancer.

[0171] In some embodiments, the compound is selected from the group consisting of human tropomyosin receptor kinase A, B, or or C. In certain embodiments, mutant or non-mutant ROS IC of the compound for inhibition of 1 or ALK 50 is a wild-type tropomyosin receptor kinase The IC of the compound for inhibition of enzymes A, B, or C 50 This is less than one-fifth of the TRK Inhibition of steroids, especially in the central nervous system (CNS), can cause dizziness / ataxia / gait disturbances, paresthesias, and weight gain. It has been associated with adverse reactions including steroid use and cognitive changes.

[0172] In some embodiments, provided are cancer (e.g., ROS1-positive cancer or AL cancer). A method for minimizing adverse events in a subject requiring treatment for a cancer (K-positive cancer), The method includes administering a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I), its enamel enantiomer, mixture of enantiomers, or tautomers, or pharmaceutically acceptable salts thereof and administering to the subject a salt thereof, wherein the method is for preventing or reducing adverse events associated with a TRK inhibitor. In some embodiments, the cancer is a ROS1-associated cancer or an ALK-associated cancer. In some embodiments, the adverse event is a TRK-related (or ALK+) cancer. There are a number of CNS adverse events.

[0173] As used herein, "minimizing" adverse events refers to the use of TRK inhibitors (e.g., For example, entrectinib, repotrectinib, or lorlatinib compared with the serial incidence of adverse events in subjects or patient populations receiving rituximab (i.e., rituximab) It also refers to a reduction in the incidence of adverse events in a subject or patient population. Adverse event incidence is the frequency or prevalence of a particular adverse event for a subject or patient population. In some embodiments, the incidence of adverse events refers to the percentage of adverse events experienced by an individual subject. In some embodiments, minimizing adverse events refers to the total number of adverse events experienced. refers to minimizing TRK-related CNS adverse events. So, minimizing TRK-related CNS adverse events means treating less than 40% of the patient population. In some embodiments, T Minimizing RK-related CNS adverse events means that the incidence is less than 35% and 30% of the patient population. Less than, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% are TRK-related In some embodiments, the TRK-related CNS adverse events are Minimizing adverse events in patients with SI means that less than 12% of the patient population will experience multiple TRK-related SIs. In some embodiments, the term "TRK-related CNS" refers to a condition in which a patient has a CNS adverse event. Minimizing adverse events means occurring in less than 11%, less than 10%, less than 9%, or <8% <7% <6% <5% <4% or <3% multiple TRK-related This means having CNS adverse events.

[0174] In some embodiments, the TRK-related CNS adverse event is one or more of the following: Refers to: dizziness, ataxia, gait disturbance, paresthesia, weight gain, hyperphagia, 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 lability, personality changes, mood swings, emotional disorders, aggression , agitation, mood changes, depressed mood, euphoria, or mania), and cognitive impairment (e.g., memory impairment, Disability, cognitive impairment, memory loss, confusion, attention disorder, delirium, psychosis, attention deficit / hyperactivity disorder , dementia, or reading disability).

[0175] In one embodiment, provided herein are methods for treating TRK-associated CNs in the treatment of cancer. A method for preventing or limiting side effects or adverse events of S, said method comprising: A subject in need thereof is administered an effective amount of a compound provided herein, e.g., a compound of formula (I) or its enantiomer, mixture of enantiomers, or tautomer, or In one embodiment, the method comprises administering a pharmaceutically acceptable salt of In one embodiment, the method prevents the occurrence of a TRK-related CNS adverse event. In one embodiment, the method comprises: In one embodiment, provided herein are therapeutic agents for treating TRK 1. A method for treating CNS metastases of cancer with reduced associated side effects, said method comprising administering to a patient in need thereof administering to a subject an effective amount of a compound provided herein, e.g., a compound of formula (I), or or its enantiomers, mixtures of enantiomers, or tautomers, or its pharmaceutical In one embodiment, the CNS side effects or The reduction / limitation / prevention of adverse events is due to the presence of ROS1+ and / or A in a statistical sample. Standard treatments for LK+ cancers, such as approved ROS1 and / or ALK inhibitors ( (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib) and In one embodiment, the TRK-related side effect is a TRKB-related C In one embodiment, the TRK-related CNS side effect or adverse event. Elephants may experience dizziness, ataxia, gait disturbances, paresthesias, weight gain, cognitive impairment, mood disorders, or sleepiness. It is a sleep disorder.

[0176] In one embodiment, provided herein is a method for treating cancer, the method comprising: A subject in need thereof is administered a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) ) or its enantiomer, mixture of enantiomers, or tautomer or a pharmaceutically acceptable salt thereof. is a ROS1-associated cancer. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is an ALK-associated cancer. , ALK+ cancer. In one embodiment, the cancer is identified as ROS1+ In one embodiment, the cancer is identified as ALK+.

[0177] In one embodiment, provided herein is a method for treating a ROS1+ cancer, the method comprising: The method includes administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., For example, a compound of formula (I) or an enantiomer thereof, a mixture of enantiomers, or This includes administering a tautomer, or a pharmaceutically acceptable salt thereof.

[0178] In one embodiment, provided herein is a method for treating ALK+ cancer, the method comprising: The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., , a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, or an alternating This includes administering the mutant, or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, provided herein is a method of treating cancer in a subject, comprising: The method includes (i) identifying the cancer in the subject as ROS1+; and i) a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I), or an enzyme thereof; an anantiomer, a mixture of enantiomers, or tautomers, or a pharmaceutically acceptable salt thereof The method includes administering to the subject a salt obtained by the method.

[0180] In one embodiment, provided herein is a method of treating cancer in a subject, comprising: The method includes (i) identifying the cancer in the subject as ALK+; and (ii) ) a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I), or an enamel thereof enantiomer, mixture of enantiomers, or tautomers, or pharmaceutically acceptable salts thereof The method includes administering to the subject a salt thereof.

[0181] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) Cancer) includes lung cancer, e.g., non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic leukemia, and cystic tumor (IMT), bile duct cancer (bile duct cancer), e.g. holangiocarcinoma), ovarian cancer, e.g., serous ovarian cancer, gastric cancer, colorectal cancer Intestinal cancer, angiosarcoma, melanoma, e.g., Spitz nevus melanoma, epithelioid hemangioendothelioma, esophageal cancer esophageal squamous cell carcinoma (ESCC), kidney cancer, such as renal medullary carcinoma or renal cell carcinoma, Breast cancer, e.g., triple-negative breast cancer, colon cancer, thyroid cancer, e.g., papillary thyroid cancer, sarcoma, Pitts nevus-like tumor or neuroblastoma.

[0182] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In embodiments, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is recurrent or refractory non-small cell lung cancer. is refractory ROS1+ non-small cell lung cancer. In one embodiment, the cancer is recurrent or In one embodiment, the cancer is a newly diagnosed ALK+ non-small cell lung cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ALK+ non-small cell lung cancer. It's cancer.

[0183] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is In one embodiment, the cancer is an ALK+ glioblastoma. In one embodiment, the cancer is recurrent or refractory glioblastoma. In one embodiment, the cancer is recurrent or refractory ROS1+ glioblastoma. In one embodiment, the cancer is recurrent or refractory ALK+ glioblastoma. The cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is a newly diagnosed ROS1+ glioblastoma. The patient had ALK+ glioblastoma.

[0184] In one embodiment, the cancer is IMT. In one embodiment, the cancer is RO In one embodiment, the cancer is ALK+ IMT. In embodiments, the cancer is relapsed or refractory IMT. is relapsed or refractory ROS1+ IMT. In one embodiment, the cancer is relapsed In one embodiment, the cancer is newly diagnosed or refractory ALK+ IMT. In one embodiment, the cancer is a newly diagnosed ROS1+ IMT. In one embodiment, the cancer is newly diagnosed ALK+ IMT.

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

[0186] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is an S1+ ovarian cancer. In one embodiment, the cancer is an ALK+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ovarian cancer. is recurrent or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is recurrent In one embodiment, the cancer is newly diagnosed or refractory ALK+ ovarian cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In embodiments, the ovarian cancer is serous ovarian cancer. Malignant serous ovarian cancer.

[0187] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS 1+ gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is recurrent or refractory gastric cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ gastric cancer. In one embodiment, the cancer is a newly diagnosed ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer. In some embodiments, the cancer is newly diagnosed ALK+ gastric cancer.

[0188] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory colorectal cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colorectal cancer. The cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ colorectal cancer. The patient had ALK+ colorectal cancer.

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

[0190] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is spinal cord injury. In one embodiment, the cancer is a Spitz nevus-like tumor. In one embodiment, the cancer is ROS1+ Spitzoid melanoma. In one embodiment, the cancer is ALK+ Spitz nevoid melanoma. is recurrent or refractory Spitz nevoid melanoma. In one embodiment, the cancer is In one embodiment, the tumor is a recurrent or refractory ROS1+ Spitz nevoid melanoma. The cancer is recurrent or refractory ALK+ Spitzoid melanoma. The cancer is newly diagnosed Spitz nevoid melanoma. In one embodiment, the cancer is a newly diagnosed ROS1+ Spitz nevoid melanoma. In one embodiment, the The cancer is a newly diagnosed ALK+ Spitz nevoid melanoma.

[0191] In one embodiment, the cancer is 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. In one embodiment, the cancer is recurrent or refractory ROS1+ hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory ALK hemangioendothelioma. + epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ROS1+ hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ALK+ epithelial hemangioendothelioma. It is a superficial hemangioendothelioma.

[0192] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ROS1+ ESCC. In one embodiment, the cancer is ALK+ ESCC. In one embodiment, the cancer is recurrent or In one embodiment, the cancer is recurrent or refractory ESCC. In one embodiment, the cancer is recurrent or refractory ALK+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ROS1+ ESCC. In this case, the cancer is newly diagnosed ALK+ ESCC.

[0193] In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is renal medullary cancer. In one embodiment, the cancer is a ROS1+ renal medullary cancer. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is recurrent or In one embodiment, the cancer is recurrent or refractory renal medullary cancer. 1+ renal medullary cancer. In one embodiment, the cancer is relapsed or refractory ALK+ renal medullary cancer. In one embodiment, the cancer is newly diagnosed renal medullary cancer. In one embodiment, the cancer is newly diagnosed ROS1+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. 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 relapsed or refractory ROS1+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal cell carcinoma. In an embodiment, the cancer is newly diagnosed ALK+ renal cell carcinoma.

[0194] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS 1+ breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is recurrent or refractory breast cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ breast cancer. In one embodiment, the cancer is a newly diagnosed ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. The cancer is triple-negative breast cancer.

[0195] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is RO In one embodiment, the cancer is S1+ colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In embodiments, the cancer is recurrent or refractory colon cancer. is recurrent or refractory ROS1+ colon cancer. In one embodiment, the cancer is recurrent In one embodiment, the cancer is newly diagnosed or refractory ALK+ colon cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.

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

[0197] In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory neuroblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ neuroblastoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. The cancer is newly diagnosed ROS1+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed ALK+ neuroblastoma.

[0198] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) In one embodiment, the lymphoma is a non-Hodgkin's lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large cell lymphoma (LDLC), or diffuse large cell lymphoma (LVLC). Large B-cell lymphoma (DLBCL), also known as large B-cell lymphoma, is a type of blood cancer. and methods for treating other hematological disorders or hematological malignancies that are ROS1+ or ALK+. are also provided herein.

[0199] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is R In one embodiment, the cancer is OS1+ ALCL. In one embodiment, the cancer is ALK+ ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ROS1+ ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALK+ ALCL. It's CL.

[0200] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is In one embodiment, the cancer is ROS1+ DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ROS1+ DLBCL. In one embodiment, the cancer is relapsed or refractory ALK+ DLBCL. The cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed In one embodiment, the cancer is a newly diagnosed ROS1+ DLBCL. The patient had ALK+ DLBCL.

[0201] In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ROS1+ large B-cell lymphoma. In one embodiment, the cancer is recurrent or ALK+ large B-cell lymphoma. In one embodiment, the cancer is recurrent or refractory large B-cell lymphoma. In one embodiment, the cancer is refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is recurrent or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is a newly diagnosed ROS1+ large B-cell lymphoma. is a newly diagnosed ALK+ large B-cell lymphoma.

[0202] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is a novel In one embodiment, the cancer (or ROS1+ cancer, or ALK + cancer) has not been previously treated.

[0203] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is In one embodiment, the cancer is recurrent or refractory. In some cases, the cancer (or ROS1+ cancer, or ALK+ cancer) is refractory to treatment.

[0204] In one embodiment, the subject has not received prior treatment. The subject is treatment-naive to tyrosine kinase inhibitor (TKI) therapy. In embodiments, the subject has undergone one or more prior lines of therapy. The subject has received a second or more line of therapy. In one embodiment, the subject has received a first or more line of therapy. In one embodiment, the prior treatment is a tyrosine kinase inhibitor. In one embodiment, the prior treatment includes crizotinib, ceritinib, or a TKI. alectinib, brigatinib, lorlatinib, entrectinib, and repotrectinib , cabozantinib, foretinib, taretrectinib, merestinib, masitinib, and In one embodiment, the prior treatment comprises one or more of: In one embodiment, the one or more chemotherapies are in addition to the TKI therapy. can be.

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

[0206] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is TKI-resistant non-small cell lung cancer. In one embodiment, the cancer is TKI-resistant ROS1+ non-small cell lung cancer. In embodiments, the cancer is TKI-resistant ALK+ non-small cell lung cancer.

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

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

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

[0210] In one embodiment, provided herein is a method for treating metastatic ALK+ non-small cell lung cancer (NSC) A method of treating a patient with LC, the method comprising administering to the patient a therapeutically effective amount of any of the compounds provided herein. The compound, for example, a compound of formula (I), or an enantiomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. .

[0211] In one embodiment, provided herein is a method for treating metastatic ROS1+ non-small cell lung cancer (NSCLC). A method of treating a patient with CLC, comprising administering to the patient a therapeutically effective amount of a compound according to the present invention. The compounds provided herein, for example, compounds of formula (I), or their enantiomers, administering a mixture of tautomers, or tautomers, or pharmaceutically acceptable salts thereof; Includes.

[0212] In one embodiment, the patient is an adult patient. In one embodiment, the patient is a pediatric patient. He is a child patient.

[0213] In one embodiment, provided herein is a method for treating adult patients with metastatic ROS1+ NSCLC. The method comprises administering to said patient a therapeutically effective amount of a compound provided herein. A compound, for example a compound of formula (I), or an enantiomer thereof, or a mixture of enantiomers thereof This includes administering the compound, or a tautomer, or a pharmaceutically acceptable salt thereof.

[0214] In one embodiment, provided herein is a method for treating adult patients with metastatic ROS1+ NSCLC. The method comprises administering to said patient a therapeutically effective amount of a compound provided herein. A compound, for example a compound of formula (I), or an enantiomer thereof, or a mixture of enantiomers thereof administering to the patient a compound, or a tautomer, or a pharmaceutically acceptable salt thereof; Patients must have progressed to or been successfully treated with at least one prior TKI therapy. Intolerant.

[0215] In one embodiment, provided herein are solvent front mutations. 1. A method of treating adult patients with ROS1+ metastatic NSCLC harboring G2032R, comprising: The method comprises administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I): or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient is administered at least one of the following: Have progressed on or are intolerant to prior TKI therapy.

[0216] In one embodiment, provided herein is a method for detecting ROS1-associated (or ROS1+) The present invention relates to a method for treating cancer in a subject in need thereof, wherein the cancer is caused by a tyrosine kinase inhibitor. The subject has acquired resistance to a tyrosine kinase inhibitor (TKI), and the method comprises administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor (TKI). The compounds provided herein, e.g., compounds of formula (I), or their enantiomers, Administering a mixture of anti- and anti-cancer drugs, or tautomers, or pharmaceutically acceptable salts thereof This includes:

[0217] In one embodiment, provided herein is a method for detecting ROS1-associated (or ROS1+) The present invention relates to a method for treating cancer in a subject in need thereof, wherein the cancer is caused by a tyrosine kinase inhibitor. The cancer has acquired resistance to one or more ROS1 inhibitors (TKIs), and the subject is identified as having a mutation, and the method comprises administering to the subject a therapeutically effective amount of a compound of the invention described herein. Compounds provided herein include, for example, compounds of formula (I), or enantiomers thereof, Administering a mixture of tautomers, or tautomers, or pharmaceutically acceptable salts thereof In one embodiment, the one or more ROS1 inhibitor-resistant mutations are one or more amino acids at amino acid positions selected from 004, 2026, 2032, and 2033 In one embodiment, the one or more ROS1 inhibitor-resistant mutations include: S1986F, S1986Y, F2004C, F2004V, L2026M, G2032 one or more amino acids selected from R, D2033N, L2086F, and G2101A In one embodiment, the one or more ROS1 inhibitor-resistant mutations include a G20 In one embodiment, the one or more ROS1 inhibitor-resistant mutations are G2 032R, S1986F, S1986Y, F2004C, F2004V, L2026M , D2033N, or G2101A. The ROS1 inhibitor resistance mutation is L2086F.

[0218] In one embodiment, provided herein are methods for treating ALK-associated (or ALK+) cancers. 1. A method of treating cancer in a subject in need thereof, wherein the cancer is treated with a tyrosine kinase inhibitor The subject has acquired resistance to a TKI, and the method comprises administering to the subject a therapeutically effective amount of a TKI according to the present invention. The compounds provided herein, for example, compounds of formula (I), or their enantiomers, Administering a mixture of thiomers, or tautomers, or pharmaceutically acceptable salts thereof Includes:

[0219] In one embodiment, provided herein are methods for treating ALK-associated (or ALK+) cancers. 1. A method of treating cancer in a subject in need thereof, wherein the cancer is treated with a tyrosine kinase inhibitor The cancer has acquired resistance to one or more ALK inhibitor-resistant mutations. The subject is identified as having a mutation, and the method comprises administering to the subject a therapeutically effective amount of a compound provided herein. a compound of formula (I) or an enantiomer thereof, This includes administering a mixture, or a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations are 1196, 1198, 1202, and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations are L1196M, L11 containing one or more amino acid substitutions selected from 98F, G1202R, and G1269A In one embodiment, the one or more ALK inhibitor resistance mutations is G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations are G1202R and L Contains one or more of 1196M, L1198F, and G1269A.

[0220] In one embodiment, provided herein is an ALK gene having the mutation G1202R. a method of treating an adult patient with metastatic NSCLC of at least 100 mg / kg, said method comprising administering to said patient a therapeutically effective amount of A therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, or tautomers, or pharmaceutically acceptable salts thereof and administering a salt thereof to the patient, wherein the patient has progressed to at least one prior TKI therapy. have or are intolerant of

[0221] In one embodiment, provided herein are methods for treating ALK-associated (or ALK+) cancers. 1. A method of treating cancer in a subject in need thereof, wherein the cancer is treated with a tyrosine kinase inhibitor The subject has acquired resistance to a TKI, and the method comprises administering to the subject a therapeutically effective amount of a TKI according to the present invention. The compounds provided herein, for example, compounds of formula (I), or their enantiomers, Administering a mixture of thiomers, or tautomers, or pharmaceutically acceptable salts thereof Includes:

[0222] In one embodiment, the TKI is a ROS1 inhibitor. The TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, or cefotaxime. Nib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib cabozantinib, foretinib, merestinib, taretrectinib, masitinib, or or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.

[0223] In certain embodiments, the subject has a recurrence of the cancer after first-line treatment. In some cases, the subject has a recurrence of the cancer after second-line treatment.

[0224] In one embodiment, the cancer or disease is present in a pediatric patient (including an infant patient). In one embodiment, the cancer is ALK+ in pediatric patients 1 year of age and older and in young adults. In another embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL). ALK+ relapsed or refractory systemic anaplastic large cell carcinoma in older pediatric patients and young adults In one embodiment, the cancer is a pediatric patient aged 1 year or older, and ROS1+ systemic anaplastic large cell lymphoma (ALCL) in young adults. In this embodiment, the cancer is a ROS1+ recurrence in pediatric patients 1 year of age and older, and in young adults. recurrent or refractory systemic anaplastic large cell lymphoma (ALCL).

[0225] In certain embodiments, the cancer treatment or prevention method includes one or more responses, e.g., Increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, microvascular density as evidenced by a reduction in tumor size, a reduction in angiogenesis, an inhibition of tumor metastasis, tumor regression, and an increase in the survival of the subject. It can be done.

[0226] Combination therapy In some embodiments, the method of treating or preventing cancer comprises administering one or more compounds of formula (I): This may include administering it in conjunction with other chemotherapeutic agent(s) listed above.

[0227] As used herein, unless otherwise specified, "in association with" or "in combination with" "In combination" means that the other drug and the compound of formula (I) must be administered at the same time; This does not imply that the compounds must be formulated together for delivery, but These delivery methods are within the scope of the present disclosure. The compounds provided herein may be administered in combination with one or more other It may be administered simultaneously with or before a drug (e.g., one or more other additional drugs). (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours) , 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 It may be administered before (e.g., 5, 15, or 16 weeks) or after (e.g., 5, 15, or 16 weeks). 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 In general, each therapeutic agent should be administered at a dose determined for that particular agent. The other therapeutic agent may be administered at a dose and / or time schedule as provided herein. The compound may be administered in a single composition or separately in different compositions. Triple drug combinations are also contemplated herein.

[0228] Chemotherapeutic agents that may be conjointly administered with the compounds of the present disclosure include 1-amino-4-phenylindole, arylamino-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 1-amino-4-[2-anthracenylamino]-9,10- Dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, Af Atinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole Zol, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP(A OPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin cerebrospinal fluid, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, Lorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetin riboflavin, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacaine Rubadin, dactinomycin, daunorubicin, demethoxyviridine, dexamethasone, Dichloroacetic acid, dienestrol, diethylstilbestrol, docetaxel, doxoxo Rubicin, epirubicin, eribulin, erlotinib, estradiol, estramus tin, etoposide, everolimus, exemestane, filgrastim, fludarabine, Fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib Nib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea Rhea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, Ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamizole ol, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megest rol, melphalan, mercaptopurine, mesna, metformin, methotrexate, Miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, Mutama Isin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF2 79, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin Platinum, paclitaxel, pamidronate, pazopanib, pemex etred), pentostatin, perifosine, PF-04691502, plicamycin Pomalidomide, porfimer, PPADS, procarbazine, quercetin, ralti Trexed, ramucirumab, Reactive Blue 2, rituximab, rolofylline, romidine Depsin, rucaparib, selumetinib, sirolimus, 2,4-dinitrobenzenesulfone sodium benzoate, sorafenib, streptozocin, sunitinib, suramin, talazoparib , tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, saline domide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, Trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine These include vindesine, vinorelbine, and vorinostat (SAHA). In embodiments of the present disclosure, chemotherapeutic agents that may be conjointly administered with compounds of the present disclosure include ABT- 263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsi In other embodiments, compounds of the present disclosure include benzodiazepines, benzodiazepines, and vorinostat (SAHA). Chemotherapeutic agents that may 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 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydriodide Anthracene-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-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, Quercetin, Reactive Blue 2, Lolophili , sodium 2,4-dinitrobenzenesulfonate, smarin, and tonapophilin Examples include:

[0229] Many combination therapies are being developed for the treatment of cancer. The compounds (e.g., compounds of Formula (I)) may be administered in conjunction with one or more combination therapies. Examples of combination therapies that can be conjointly administered with compounds of the present disclosure are listed in Table 2. [Table 2] TIFF0007815341000080.tif235165TIFF0007815341000081.tif242165TIFF0007815341000082.tif22916 5TIFF0007815341000083.tif211165TIFF0007815341000084.tif241165TIFF0007815341000085.tif96165

[0230] In certain embodiments, the co-therapy of the present disclosure may be administered in combination with other types of chemotherapeutic agents, e.g. This includes co-administration with cancer immunotherapeutics. Cancer cells often have a specific structure that cannot be recognized by the immune system. Therefore, cancer immunotherapeutic agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and cause cell death. Immunotherapeutic agents are agents that suppress tumor-mediated inhibition of the natural immune response or inhibit the immune response. Activation of the antibody can facilitate tumor recognition by the immune system. Immunotherapeutic agents include abagovomab, adecatumumab, afutuzumab, alemtuzumab, Anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559 , catumaxomab, durvalumab, epacadostat, epratuzumab, indoximo inotuzumab ozogamicin, intelmumab, ipilimumab, isatuximab, la Ambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab , ocaratulumab, ofatumumab, oratumumab, pembrolizumab, pidilizumab , rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody cancer immunotherapeutic is an anti-CD73 monoclonal antibody. Clonal antibodies (mAb), anti-CD39 mAb, anti-PD-1 mAb, and anti-CTLA4m Ab. Thus, in some embodiments, the methods of the present disclosure comprise one or more Co-administration of cancer immunotherapeutic agents, such as the agents listed above, is also included.

[0231] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I) and SH2 inhibitors, such as CGP78850, CPG85793, C90, and C126. This involves the co-administration of G7-18NATE, G7-B1, and NSC642056.

[0232] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I) and MEK inhibitors, such as trametinib, cobimetinib, binimetinib, and selumetinib. , including the co-administration of PD-325901, CI-1040, and TAK-733.

[0233] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I) and JNJ-38877605, PF-04217903, foretinib, and AMG458. , tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride and co-administration of a MET inhibitor selected from savolitinib.

[0234] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of Formula (I), and a compound of Formula (TN Select from O-155, RMC-4630, JAB-3068, or RLY-1971 This includes co-administration of an SHP2 inhibitor.

[0235] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I) and aliskiren, captopril, losartan, irbesartan, olmesartan, and cannone. Desartan, valsartan, fimasartan, azilsartan, telmisartan, epro Sartan, benazepril, enalapril, lisinopril, perindopril, quinapril, This includes co-administration of a RAS inhibitor selected from ramipril and trandolapril.

[0236] In some embodiments, the combination therapy comprises a compound provided herein, e.g., a compound of Formula (I In one embodiment, the TKI is In one embodiment, the TKI is an OS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In an embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, or roxadrib. Ruratinib, entrectinib, repotrectinib, cabozantinib, foretinib, Restinib, taretrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib.

[0237] In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I) and an anti-PD-1 therapy. In certain embodiments, the combination therapy comprises a Other embodiments include co-administration of a compound of formula (I), such as a compound of formula (I), with oxaliplatin. In some embodiments, the combination therapy comprises a compound of the present disclosure, e.g., a compound of formula (I), and doxorubicin. This includes co-administration of

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

[0239] In certain embodiments, compounds of the present disclosure may be used in combination with one or more other compounds of the present disclosure. Additionally, such combinations may be administered in combination with other therapeutic agents, such as those for cancer, immune disorders, or or other drugs suitable for the treatment of neurological disorders, e.g., administered in conjunction with the drugs identified above. In certain embodiments, the compounds of the present disclosure are administered in combination with one or more additional chemotherapeutic agents. In certain embodiments, administering one or more Concomitant administration of additional chemotherapeutic agents results in an additive effect.

[0240] Pharmaceutical Composition In certain embodiments, the present disclosure provides a pharmaceutical agent suitable for use in a human patient, The drug may be any of the compounds described above (e.g., a compound of the present disclosure, e.g., a compound of formula (I), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical , may be for use in the treatment or prevention of a condition or disease described herein. Any of the compounds of the present disclosure may be used as a pharmaceutical agent for the treatment of any of the diseases or conditions disclosed herein. It can be used in the manufacture of

[0241] The compositions and methods of the present disclosure can be used to treat a subject in need of treatment. In certain embodiments, the subject is a mammal, eg, a human, or a non-human mammal. When administered to a subject, e.g., a human, the composition or compound preferably has a cytotoxic activity, e.g., It is administered as a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. Acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or saline. Buffered saline or other solvents or vehicles, such as glycols, glycerol, oils, e.g. Examples include olive oil, or injectable organic esters. The compositions are intended for administration to humans, particularly those intended for administration via invasive routes (i.e., transport across epithelial barriers). route that avoids delivery or diffusion (e.g., injection or implantation), and the aqueous solution is The excipients are, for example, pyrogen-free or substantially pyrogen-free. or selectively targeting one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form, for example, a tablet, capsule (s including prinkle capsules and gelatin capsules), granules, lyophilisates for reconstitution, powders The composition may be included in a transdermal delivery system, e.g., a solution, syrup, suppository, injection, etc. The composition may also be contained in a solution suitable for topical administration, for example, eye drops. It is possible.

[0242] Pharmaceutically acceptable carriers may be used, for example, to stabilize compounds such as those disclosed herein. , which acts to increase its solubility or to increase its absorption Such physiologically acceptable agents may include, for example, carbohydrates. an antioxidant, such as glucose, sucrose or dextran; an antioxidant, such as aspartame; Corbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers may also be used. Pharmaceutically acceptable carriers, including physiologically acceptable drugs, are also suitable. The selection depends, for example, on the route of administration of the composition. It can be a self-microemulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical compositions (formulations) can be, for example, pharmaceutical compositions containing the compounds of the present disclosure. The matrix may be a liposome or other polymer matrix, e.g., a phospholipid or other lipid Liposomes containing the liposomes are non-toxic, physiologically acceptable and metabolizable carriers, and are relatively It is simple to make and administer.

[0243] The term "pharmaceutically acceptable" is used herein to mean that, within the scope of sound medical judgment, and target tissue without undue toxicity, irritation, allergic reaction, or other problems or complications. compounds, materials, and compositions suitable for use in contact with, and commensurate with a reasonable benefit / risk ratio; and / or used to refer to dosage forms.

[0244] As used herein, the phrase "pharmaceutically acceptable carrier" means a a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or Each carrier must be compatible with the other ingredients of the formulation and not harmful to the subject. It must be "acceptable" in the sense that it is not capable of functioning as a pharmaceutically acceptable carrier. Some examples of suitable materials include: (1) sugars, such as lactose, glucose, and sugars; (2) starches, such as cornstarch and potato starch; (3) cells cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) ) talc, (8) excipients such as cocoa butter and suppository waxes, (9) oils such as Peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, ( 10) Glycols, for example, propylene glycol; (11) Polyols, for example, glycols; Serine, sorbitol, mannitol and polyethylene glycol, (12) esters, For example, ethyl oleate and ethyl laurate, (13) agar, (14) buffers, e.g. For example, magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrophosphate, Genfrey's water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol (20) phosphate buffers, and (21) other non-toxic compatible substances used in pharmaceutical formulations. Examples include:

[0245] The pharmaceutical composition (preparation) can be administered to a subject, for example, orally (e.g., in an aqueous or non-aqueous form). Drenches, tablets, capsules (sprinkle capsules and gelatin capsules) in liquid or suspension form (including cells), bolus, powder, granules, paste for application to the tongue), through the oral mucosa absorption (e.g., sublingually), anally, rectally, or vaginally (e.g., with a pessary, cream, or fluid) as a foam), parenterally (intramuscular, intravenous, subcutaneous or intrathecal, e.g., as a sterile solution or as a suspension), intranasal, intraperitoneal, subcutaneous, transdermal (e.g., a patch applied to the skin), and topical (e.g., creams, ointments, or sprays applied to the skin, or eye drops) The compounds can be administered by any of a number of routes, including via inhalation. In certain embodiments, the compounds may be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found in, for example, U.S. Pat. No. 0,973, No. 5,763,493, No. 5,731,000, No. 5,541,23 Nos. 1, 5,427,798, 5,358,970 and 4,172,896, and in the patents cited therein.

[0246] The formulations may conveniently be presented in unit dosage form and may be prepared in any convenient manner well known in the art of pharmacy. can be prepared by the methods of combining with a carrier material to produce a single dosage form. The amount of active ingredient that can be administered will vary depending on the subject being treated and the particular method of administration. The amount of active ingredient that can be combined with a carrier material to produce a therapeutic effect will generally vary. Generally, out of 100 percent, this amount is about 1 percent. 10 to about 99 percent active ingredient, preferably about 5 to about 70 percent, most preferably about 10 to about 99 percent More preferably, it ranges from about 10 percent to about 30 percent.

[0247] Methods for preparing these formulations or compositions include dissolving an active compound, such as a compound of the present disclosure, in a carrier and optionally one or more accessory ingredients. Generally, the formulations comprise a composition comprising the compounds of the present disclosure. The compound is uniformly and intimately mixed with a liquid carrier, or a finely divided solid carrier, or both. The product is prepared by bringing into association and then, if necessary, shaping the product.

[0248] Formulations of the present disclosure suitable for oral administration each contain a predetermined amount of a compound of the present disclosure as the active ingredient. Capsules (including sprinkle capsules and gelatin capsules), cachets, pills, Tablets, lozenges (flavored base, usually sucrose and acacia or tragacanth) in the form of a lyophilisate, powder, granules or in a solution in an aqueous or non-aqueous liquid. or suspension, or oil-in-water or water-in-oil liquid emulsion, or elixir or syrup, or pastilles (gelatin and glycerin, or sucrose) and acacia) and / or may be included in mouthwashes, etc. The composition or compound may also be administered as a bolus, electuary or paste.

[0249] Solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules) ), tablets, pills, dragees, powders, granules, etc., the active compound is a pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate, and / or mixed with any of the following: (1) a filler or extender, e.g., starch; , lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) Combinations, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone (3) humectants, such as glycerol; (4) Disintegrants, such as agar, calcium carbonate, potato starch, or tapioca (5) Dissolution retarders, e.g., sodium carbonate, alginic acid, certain silicates, and sodium carbonate. (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents. agents, e.g., cetyl alcohol and glycerol monostearate, etc.; (8) absorbents, e.g., (9) lubricants, such as talc, stearic acid, etc. Calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate thorium, and mixtures thereof; (10) complexing agents, such as modified cyclodextrins and Unmodified cyclodextrin, and (11) colorant. Capsules (sprinkle capsules) In the case of tablets and pills, including gelatin capsules, the pharmaceutical composition may contain a buffering agent. Solid compositions of a similar type also may contain lactose or milk sugar and high molecular weight polyethylene. It is used as a filler for soft and hard gelatin capsules with excipients such as ethylene glycol. It is possible.

[0250] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, agents, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or crosslinking agents), cross-linked carboxymethylcellulose sodium), surfactants or dispersants Molded tablets may be made in a suitable machine by mixing the powdered compound moistened with an inert liquid diluent. It can be made by shaping.

[0251] The pharmaceutical composition may be used in tablets and other solid dosage forms, such as dragees, capsules (sprinkle capsules), and the like. The pharmaceutical preparations, including capsules and gelatin capsules, pills and granules may optionally be scored or Coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation arts, They may also be prepared with coatings, for example, to provide a desired release profile. Hydroxypropyl methylcellulose in various proportions to form a matrix of other polymers , liposomes and / or microspheres for sustained release of the active ingredient contained therein. or may be formulated to provide controlled release. They may be, for example, formulated using bacteria-retaining filters. by filtering through a syringe or by dissolving in sterile water or other sterile injectable 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 opacifying agents and may be used to deliver the desired ointment or ointment to only certain portions of the gastrointestinal tract. or preferentially, optionally, in a delayed manner, release the active ingredient(s). Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. It may be in the form of

[0252] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, frozen solutions for reconstitution, and the like. Examples include lyophilized concentrates, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain, for example, water or other solvent, cyclodextrin, alcohol and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol Recall: 1,3-butylene glycol, oils (specifically cottonseed oil, peanut oil, corn oil) Koshi oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran fatty acid esters of furyl alcohol, polyethylene glycol and sorbitan, and Mixtures of these and other inert diluents commonly used in the art may also be included.

[0253] Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying agents and Suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives may also be included.

[0254] Suspensions may contain, in addition to the active compound, suspending agents, such as ethoxylated isostearyl alcohols. sorbitol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, The gel may also include stonite, agar and tragacanth, and mixtures thereof.

[0255] Formulations of the pharmaceutical composition for rectal, vaginal, or urethral administration may be included as a suppository; It contains one or more active compounds in a range of aqueous solutions, such as cocoa butter, polyethylene glycol, sesquioleate, sorbitan stearate ... mixed with one or more suitable non-irritating excipients or carriers, including pharmaceutical waxes, or salicylates and is solid at room temperature but liquid at body temperature. It melts in the rectum or vaginal cavity to release the active compound.

[0256] Formulations of pharmaceutical compositions for oral administration may be prepared as mouthwashes, or oral sprays, or It may be provided as a mouth ointment.

[0257] Alternatively or additionally, the composition may be applied to a catheter, stent, wire, or other intraluminal cavity. Delivery via such devices may be via the bladder, urethra, ureters, or rectum. It may be particularly useful for delivery to the intestine or to the intestine.

[0258] Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, Also included are foam or spray formulations containing carriers known in the art to be suitable. do.

[0259] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, and These include creams, lotions, gels, solutions, patches and inhalants. and any preservatives, buffers, or propellants that may be required, together with sterile conditions. The mixture may be mixed as follows.

[0260] The ointments, pastes, creams and gels contain, in addition to the active compound, animal and vegetable fats. , oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or The composition may contain excipients such as a mixture of

[0261] Powders and sprays may contain, in addition to the active compound, lactose, talc, silicic acid, aluminum hydroxide, etc. Excipients such as aluminum, calcium silicate and polyamide powder, or mixtures of these substances Sprays may further contain conventional propellants, e.g., chlorofluorocarbons. It may include hydrogen and volatile unsubstituted hydrocarbons such as butane and propane.

[0262] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of flow can be controlled by providing a rate-limiting membrane or by incorporating the compound into a polymer matrix or gel. The amount of the ions can be controlled by dispersing the ions in the pores.

[0263] Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this disclosure. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 005 Nos. 9744, 2005 / 0031697 and 2005 / 004074, and U.S. No. 6,583,124, the contents of which are incorporated herein by reference. Optionally, the liquid ophthalmic preparation may contain similar properties to those of tears, aqueous humor, or vitreous humor. The preferred route of administration is topical administration (e.g., These are administered locally as eye drops or via implants.

[0264] As used herein, the terms "parenteral administration" and "parenterally administered" refer to administration via the It refers to a method of administration other than enteral or topical administration, usually by injection, including intravenous, intramuscular, intraarterial, Intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular Intrathecal, intrathecal, intrathecal and intrasternal injections and infusions.

[0265] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in one or more pharmaceutically acceptable carriers. sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or In combination with sterile powders that can be reconstituted immediately before use into sterile solutions or dispersions for injection. This includes antioxidants, buffers, bacteriostats, and agents that render the formulation isotonic with the blood of the intended recipient. The formulation may contain a suitable solute or a suspending or thickening agent.

[0266] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, and the like. alcohols, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) ), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters. Suitable fluidity may be achieved, for example, by coating. The use of materials such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of boundary conditions can also contribute to the prevention of granular buildup. This can be maintained by the use of surfactants.

[0267] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can include various antibacterial and antifungal agents, for example, parabens, chlorhexidine glucans ... This may be ensured by including isotonicity agents such as propylbutanol, phenol sorbic acid, etc. It may also be desirable to include additives such as sugars, sodium chloride, and the like in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be achieved by the use of agents delaying absorption, for example, aluminum. This may also be achieved by including monostearate and gelatin.

[0268] In some cases, the drug is inhaled from a subcutaneous or intramuscular injection to prolong its effect. This is because the liquid phase of crystalline or amorphous materials with poor water solubility is desirable. This can be achieved by the use of a suspension. The rate of absorption of the drug is in turn dependent upon its rate of dissolution. This may depend on the crystal size and morphology. Alternatively, parenterally administered drug forms Delayed absorption of is accomplished by dissolving or suspending the drug in an oil vehicle.

[0269] Injectable depot forms may be made in biodegradable polymers such as polylactide-polyglycolide. It is made by forming a matrix of microencapsulated compounds of interest. Depending on the drug to polymer ratio and the nature of the particular polymer used, the drug release rate can be controlled. Other examples of biodegradable polymers include poly(orthoesters) and Depot injectable formulations also include liposomes or other formulations that are compatible with body tissue. Alternatively, they may be prepared by encapsulating drugs in microemulsions.

[0270] For use in the methods of the present disclosure, the active compound may be administered per se or For example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient is used as a pharmaceutical. It may also be administered as a pharmaceutical composition in combination with an acceptable carrier.

[0271] The method of introduction may also be via a rechargeable or biodegradable device. , various sustained release polymeric devices for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of polymers, including both biodegradable and non-degradable polymers, have been developed and tested in vivo. Various biocompatible polymers (including hydrogels) can be used to slowly deliver compounds to specific target sites. The implant can be formed to release the

[0272] Actual dosage levels of the active ingredients contained in pharmaceutical compositions will vary depending on the particular patient, composition, and administration. an active ingredient effective to achieve the therapeutic response required for the administration regimen without being toxic to the patient; The amounts of the ingredients may be varied to obtain the desired results.

[0273] The dosage level selected will depend on the particular compound or combination of compounds used, or its esters, salts, or amides, their activity, route of administration, time of administration, and the specific The excretion rate of the compound(s), the duration of treatment, and the specific compound(s) used in combination other drugs, compounds, and / or materials used in combination with the treatment, the age, sex, including weight, condition, general condition and previous medical history, and similar factors well known in the medical arts. It depends on various factors including:

[0274] A physician or veterinarian having ordinary skill in the art will be able to administer the required pharmaceutical composition. A therapeutically effective amount can be readily determined and prescribed, for example, by a physician or veterinarian, to determine the desired treatment. Administration of pharmaceutical compositions or compounds at levels lower than those required to achieve a therapeutic effect The dosage may be gradually increased until the desired effect is achieved. "Effective amount" means the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of will vary depending on the weight, sex, age, and medical history of the subject. Other factors that may affect the effective amount include the severity of the subject's condition, the disorder being treated, , stability of the compound, and, if necessary, other types of drugs administered in conjunction with the compounds of the present disclosure. These may include, but are not limited to, the following therapeutic agents: It may be delivered in multiple doses. Methods for determining efficacy and dosage are known to those skilled in the art. It is known that s Principles of Internal Medicine 13 ed. , 1814-1882, incorporated herein by reference).

[0275] In general, a suitable daily dose of the active compounds used in the compositions and methods of the present disclosure will be sufficient to provide a therapeutic effect. Such an effective dose is generally determined by the above. It depends on the following factors:

[0276] If desired, the effective daily dose of the active compound may be administered at appropriate intervals throughout the day, optionally in small doses. 1, 2, 3, 4, 5, 6, or more subdoses administered separately in unit dosage forms In certain embodiments of the present disclosure, the active compound may be administered twice daily or It may be administered three times a day. In a preferred embodiment, the active compound is administered once a day.

[0277] In certain embodiments, the compounds of the present disclosure may be used alone or in combination with other compounds. As used herein, "co-administration" refers to the administration of a compound or compound of formula I or II in combination with another compound or compound of formula I or II. The phrase "administered to a subject" refers to any form of administration of two or more different therapeutic compounds, wherein the second compound is administered while the previously administered therapeutic compound is still active in the body (e.g., 2 The two compounds are simultaneously effective in a subject, which may involve a synergistic effect of the two compounds. For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations. In certain embodiments, the different therapeutic agents may be administered simultaneously or sequentially. The therapeutic compounds were incubated with each other for 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or The subject receiving such treatment may be administered a number of different therapeutic compounds within one week of each other. can benefit from the combined effects of

[0278] In certain embodiments, a compound of the present disclosure and one or more additional therapeutic agent(s) (e.g., For example, the compounds of the present disclosure ( For example, a compound of Formula I or Ia) or the one or more additional therapeutic agent(s) individually In certain such embodiments, the co-administration provides improved efficacy compared to administration of: Here, the additive effect is the combination of the compound of the present disclosure and the one or more further Refers to the sum of the effects of each of the individual administrations of the therapeutic agent(s).

[0279] The present disclosure provides for the use of pharmaceutically acceptable salts of the compounds of the present disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the present disclosure include alkyl, di-, alkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present disclosure include L-arginine, Benentamine, benzathine, betaine, calcium hydroxide, Phosphorus, diethanolamine, diethylamine, 2-(diethylamino)ethanol Nol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl) (I)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium These include, but are not limited to, thorium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present disclosure include Na, Ca, K , Mg, Zn or other metal salts.

[0280] Pharmaceutically acceptable acid addition salts may be prepared in various solvates, for example, with water, methanol, ethanol, or the like. Mixtures of such solvates may also exist as acetaldehyde, dimethylformamide, etc. The source of such solvates may be from the solvent of crystallization or , may be inherent in the preparation or crystallization solvent or may be adventitious to such solvent.

[0281] Pharmaceutically acceptable anionic salts include acetate, aspartate, and benzenesulfonate. Phosphate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate Salt, chloride, citrate, decanoate, edetate, esylate, fumarate, glucept Salts include butyrate, gluconate, glutamate, glycolate, hexanoate, and hydroxybenzoate. Phthoate, iodide, isethionate, lactate, lactobionate, malate, maleate nitrate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate , octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturon Phosphate, propionate, salicylate, stearate, acetate, succinate, sulfate , tartrate, octyl, and tosylate salts.

[0282] Wetting agents, emulsifying agents and lubricating agents such as sodium lauryl sulfate and magnesium stearate sodium, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and Antioxidants and antioxidants may also be included in the composition.

[0283] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, Acid, Cysteine ​​Hydrochloride, Sodium Bisulfate, Sodium Metabisulfite, Sodium Sulfite (2) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxybenzoates, etc. Cyanisol (BHA), butylated hydroxytoluene (BHT), lecithin, gallic acid propyl, alpha-tocopherol, etc., and (3) metal chelating agents, e.g., citric acid , ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. .

[0284] Although the present disclosure has been generally described herein, descriptions of certain specific aspects and embodiments of the disclosure are not intended to be limiting. By reference to the following examples, which are included for purposes of illustration only and are not intended to limit the disclosure. This will be more easily understood.

[0285] General synthetic procedure Starting materials and reagents used in preparing these compounds were obtained from commercial suppliers, e.g. For example, it is available from Aldrich Chemical Co., Bachem, etc. or by methods well known in the art. are merely illustrative of some of the ways in which the compounds disclosed herein may be synthesized; Various modifications to these schemes may be made and will be apparent to those skilled in the art having reference to this disclosure. The starting materials, intermediates and final products of the reaction may be filtered, evaporated, or otherwise treated, if necessary. using conventional techniques, including but not limited to, distillation, crystallization, chromatography, etc. can be isolated and purified and obtained using conventional methods, including physical constants and spectral data. In some cases, the reaction may produce multiple regioisomeric products. In these cases, chromatography may be used to separate the isomers, and NOE or NOESY NMR spectroscopy may be used to assist in structural assignment.

[0286] Unless otherwise specified, reactions described herein are carried out at temperatures ranging from about -78°C to about 150°C. The process is carried out at atmospheric pressure.

[0287] [Table 3] TIFF0007815341000087.tif243165TIFF0007815341000088.tif30165

[0288] The compounds of the present invention can be prepared by a variety of synthetic methods, as further described and exemplified herein. Those skilled in the art will recognize that the following general synthetic methods are representative and not intended to be limiting. It is understood that the racemic compound is not intended to be a chiral, preparative, SFC, or can be enantiomerically enriched by HPLC separation. Variable A can be at a carbon, nitrogen or or sulfur atom, which may be the same as or different from other examples of variable A. Variable X may be a salt. represents a nitrogen, bromine, or iodine atom, which may be the same as or different from other instances of variable X. The element Z represents a nitrogen atom or a CH or CF group, and is the same as other examples of the variable Z. But it may be different.

[0289] Method A [ka] Polyhalide I was coupled with stannane II using Stille coupling conditions. To facilitate this reaction, LiCl or Cu may be added to obtain Type III compounds. A variety of additives may optionally be used, including, but not limited to, polyhalides. Intramolecular ring closure of III was carried out using two-step one-pot borylation / Suzuki cross-coupling conditions. This may be achieved using a cyclohexanediamine to give compounds of type IV.

[0290] Method B [ka] Halide V was coupled with stannane II using Stille coupling conditions to give stannane II. To facilitate this reaction, LiCl or CuI may be added to the solution to give compounds of type VI. A variety of additives may optionally be used, including but not limited to: Intramolecular ring closure is achieved using C-H insertion cross-coupling conditions to give compounds of type IV. Potassium acetate or potassium pivalate are effective for this macrocyclization step. It is a base.

[0291] Method C [ka] Nitropyridine VII was reduced using Fe metal conditions to give aminopyridines of type VIII. If the substrate contains an isoxazole moiety, SnCl2 conditions may be used instead to obtain lysine. The yield can be improved by using the following: Achieve this using one-pot borylation / Suzuki cross-coupling conditions to give Type IX compounds may be obtained.

[0292] Method D [ka] Nitropyridine X is reduced using Fe metal conditions to give aminopyridines of type XI. If the substrate contains an isoxazole moiety, SnCl2 conditions may be used instead. The yield can be improved by carrying out the intramolecular ring closure of XI through C-H insertion cross coupling. This may be achieved using potassium acetate or pyridine dimerization conditions to give compounds of type IX. Potassium valerate is an effective base for this macrocyclization step.

[0293] Method E [ka] Alcohol XII was coupled with chloropyrazine XIII using SNAr conditions. The intramolecular ring closure of XIV can be carried out in a two-step one-step reaction. This is achieved using thioboration / Suzuki cross-coupling conditions to give compounds of type XV. That's fine.

[0294] Method F [ka] Alcohol XVI was coupled with chloropyrazine XIII using SNAr conditions. The intramolecular ring closure of XVII may be carried out by C—H insertion. Cross-coupling conditions may be used to provide compounds of type XV. Potassium pivalate or potassium pivalate are effective bases for this macrocyclization step.

[0295] Method G [ka] Aminopyridine XVIII may be brominated with a suitable brominating reagent to give bromide XIX. Desilylation of XIX using a suitable fluoride ion source was followed by a two-step one-step synthesis. Intramolecular ring closure using bromination / Suzuki cross-coupling conditions affords the type XX chemistry. A mixture may be obtained.

[0296] Method H [ka] Nitropyridines XXI were reduced using Fe metal conditions to give aminopyridines of type XXII. If the substrate contains an isoxazole moiety, SnCl2 conditions may be used instead to obtain lysine. The yield can be improved by using the CH insertion cross-coupling conditions. Following intramolecular cyclization of the used XXII, TBAF desilylation afforded the type XX Potassium acetate or potassium pivalate is effective for this macrocyclization step. It is a base.

[0297] Method I [ka] Nitropyridine XXIII was reacted with an appropriate bromination reagent following reduction using Fe metal conditions. Bromination with an amine may be used to convert to compound XI. Intramolecular ring closure of XI can be achieved by C-H insertion. This may be accomplished using cross-coupling conditions to give compounds of type IX. Potassium pivalate or potassium pivalate are effective bases for this macrocyclization step.

[0298] Method J [ka] Compounds of type XXIV are treated in solution with a suitable acid (e.g., TFA or HCl). The protecting groups suitable for this method are: Examples include methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyridine, Examples include, but are not limited to, p-methoxybenzyl, and p-methoxybenzyl groups.

[0299] Method K [ka] Nitropyridines XXV were reduced using Fe metal conditions to give aminopyridines of type XI. If the substrate contains an isoxazole moiety, SnCl2 conditions can be used instead. The yield can be improved by using the same. This may be achieved using potassium acetate or other suitable coupling conditions to give compounds of type IX. Potassium pivalate is an effective base for this macrocyclization step.

[0300] Method L [ka] Nitropyridine X was reduced using iron metal and then brominated with NBS to give type XX If the substrate contains an isoxazole moiety, the iron may be replaced by The yield can be improved by using SnCl2 reduction conditions. Intramolecular ring closure was achieved using two-step one-pot borylation / Suzuki cross-coupling conditions. to give compounds of type IX.

[0301] Method M [ka] Compounds of type XXVII were first hydrogenated using palladium on carbon under a hydrogen atmosphere. Deprotection by decomposition, followed by conversion of the resulting hydroxyl group to an alkyl halide (e.g., iodine). The compound may be alkylated with methyl fluoride to give compounds of type XXVIII. Suitable protecting groups include, but are not limited to, benzyl and p-methoxybenzyl groups. It will not be done.

[0302] Method N [ka] Nitropyridines XXIX are reduced using Fe metal conditions to give aminopyridines of type XXX. If the substrate contains an isoxazole moiety, SnCl2 conditions may be used instead to obtain lysine. The yield can be improved by using the intramolecular ring closure of XXX. This may be accomplished using Ross coupling conditions to give ketones of type XXXI. Sodium or potassium pivalate are effective bases for this macrocyclization step. Reduction of XXXI to alcohols of type XXXII was carried out using sodium borohydride. Finally, deoxygenation can be achieved using triethylsilane and trifluoroacetic acid. Alternatively, compounds of type IX may be obtained.

[0303] Those skilled in the art will appreciate that it is possible to produce compounds encompassed by this disclosure, as demonstrated by the examples below. In order to achieve this, the starting materials and reaction conditions may be varied, and the order of the reactions may be altered. It will be appreciated that further steps may be used in certain cases. Protection of reactive functional groups may be necessary to achieve some of the above transformations. Generally, the need for such protecting groups, and the conditions necessary to attach and remove such groups, will be determined by economical methods. All articles referred to in this application, including patents, are hereby incorporated by reference as if fully set forth herein. and the disclosures of the references are incorporated herein by reference.

[0304] The preparation of the compounds of the present disclosure is further illustrated by the following examples, which are provided to illustrate, but are not to be construed as limiting the scope of the present disclosure. shall not be construed to limit the scope or spirit of the disclosures to the specific procedures and compounds described therein. It shouldn't be.

[0305] Analysis method LCMS data was collected using one of the following methods: [Table 4] TIFF0007815341000104.tif220165TIFF0007815341000105.tif178165

[0306] Synthesis Example Synthesis of 3-chloro-5-iodo-1H-pyrazole Intermediates [ka] Under a nitrogen atmosphere, 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide A solution of 1.90 g (9.06 mmol) of methyl acrylate in 40 mL of THF was treated with n-butyllithium nitrate. (4.35 mL, 10.9 mmol) was added dropwise at -78°C. A thick viscous precipitate formed. The solution was stirred for 30 minutes after the addition. To this stirred suspension was added 1-iodopyrrolidine-2,5 A solution of 2.24 g (9.97 mmol) of α-dione in 10 mL of THF was added dropwise at −78°C. After 1 h, the resulting clear solution was warmed to room temperature. The reaction was diluted with saturated NH4Cl The mixture was quenched at 0°C and extracted with DCM (3 x 50 mL). The organic layer was separated and The residue was washed with water, dried over anhydrous Na2SO4, and concentrated. Purification by chromatography (30% EtOAc in PE) gave 3-chloro-5-iodo 1H-pyrazole-1-sulfonamide (3.0 g, yield: 8%) 9%) as a white solid. LC / MS (ESI): m / z = 336 [M+ H] + . In a round-bottom flask equipped with a magnetic stirrer, 3-chloro-5-iodo-N,N- Dimethyl-1H-pyrazole-1-sulfonamide (3.00 g, 8.94 mmol) The mixture was cooled to 0°C in DCM (8 mL) and reacted with TFA (8.0 mL, 108 mmol). The mixture was stirred for 1.5 h. The reaction was quenched with saturated NaHCO3. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting mixture was concentrated to give 3-chloro-5-iodo-1H-pyrazole (2.1 g, yield: 100%) in a yellow liquid. Obtained as a solid. LC / MS (ESI): m / z = 229 [M+H] + .

[0307] Synthesis of (nitromethyl)cyclobutane [ka] (Nitromethylidene)cyclobutane (9.8 g, 86.63 mmol) in MeOH (5 To the solution of 100 mL of NaBH4 (4.94 g, 130 mmol) was added at 0 °C, and the resulting mixture was stirred for 6 h at 0 °C. The reaction was stirred for 10 minutes. The reaction was quenched by adding cold water and filtered. The solution was dissolved in EtOAc, washed once with water and once with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated to give a residue which was purified by flash chromatography (0 → 5% MeOH in DCM) to give (nitromethyl)cyclobutane (4.4 g, The compound was obtained as a colorless oil in a 44% yield. LC / MS ESI (m / z): 116 [M+ H]+ .

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

[0309] Synthesis of 5-chloro-3-iodo-1-methyl-1H-pyrazole [ka] 5-chloro-3-iodo-1H-pyrazole (100 mg, 0.440 mmol) and A mixture of K2CO3 (121 mg, 0.880 mmol) in DMF (8 mL) was Methyl fluoride (0.03 mL, 0.5 mmol) was added at 25° C. The mixture was then The reaction mixture was stirred at room temperature for 30 minutes, quenched with ice water, extracted twice with EA, and Wash with HCl, dry over anhydrous Na2SO4, filter, and concentrate to give crude 5-chloro-3-iodo 100 mg (94% yield) of 1H-methyl-1H-pyrazole was obtained as a yellow liquid. This material can be used as is or further purified by flash chromatography, high pressure chromatography, or Purify by chromatography or supercritical fluid chromatography to isolate any possible regioselective The isomers may be separated. LC / MS (ESI) m / z: 243 [M+H] + .

[0310] The following intermediates were synthesized using similar experimental protocols: [Table 5] TIFF0007815341000111.tif67165

[0311] Synthesis of 1-ethyl-1H-pyrrole-3-carbaldehyde [ka] 1H-Pyrrole-3H-carbaldehyde (5.00 g, 52.6 mmol) in DMF ( 30 mL) solution was added with K2CO3 (12.4 g, 89.4 mmol) and iodoethane (5 0.0 mL, 63 mmol) was added at 0° C. The mixture was stirred at room temperature for 16 hours and filtered. The filtrate was diluted with ethyl acetate (30 mL). The solution was washed with brine (50 mL). The residue was washed, dried over anhydrous Na2SO4, and concentrated. Purified by PE containing EA (0% → 35% EA) and 1-ethyl-1H-pyrrole-3-carboxylate Rubaldehyde (4.0 g, 62% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 124.1 [M+H] + .

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

[0313] Synthesis of 3-ethylisoxazole-5-carbaldehyde [ka] (3-ethylisoxazol-5-yl)methanol (4.00 g, 31.5 mmol) l) in DCM (100 mL) and DMP (16.01 g, 37.75 mmol) The mixture was stirred at room temperature for 1 hour (to completely separate the substrates containing multiple alcohol groups). (An additional equivalent of oxidizing agent may be added to ensure complete oxidation.) The mixture is then heated to a saturated Wash with Na2S2O3 (100 mL) and saturated NaHCO3 (100 mL), and add anhydrous Na The residue was purified by flash chromatography on silica gel. Purify with PE (20% EtOAc) to obtain 3-ethylisoxazole-5-carbamoyl The aldehyde (3.37 g, yield: 86%) was obtained as a yellow oil. LC / MS (ESI): m / z = 126 [M+H] + .

[0314] Synthesis of (1-ethyl-1H-pyrazol-4-yl)methanol [ka] 1-Ethyl-1H-pyrazole-4-carbaldehyde (2.10 g, 16.9 mmol) ) in THF (10 mL), 0.3 mmol) was added at -78 °C (this protocol converts the ester completely to alcohol). by increasing the number of equivalents of reducing agent so that The mixture was stirred at -78°C for 0.5 h and then warmed to 25°C for 1 h. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and then washed with EtOAc. The combined organic layers were washed with brine (15 mL) and anhydrous Na The residue was purified by flash chromatography (50 → 100% EtOAc in PE) and purified to give (1-ethyl-1H-pyrazole-4- (480 mg, 23% yield) methanol was obtained as a pale yellow oil. I) m / z: 127 [M+H] + .

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

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

[0317] Synthesis of 5-(chloromethyl)-3-ethylisoxazole [ka] (3-ethyl-1,2-oxazol-5-yl)methanol (4.10 g, 32.3 To a stirred solution of 10 mmol of triethylamine (5.8 mL, 42 thionyl chloride (2.8 mL, 39 mmol) was added, followed by thionyl chloride (2.8 mL, 39 mmol) at 0°C for 10 min. After the addition, the reaction mixture was stirred under N2 at room temperature for 5.0 hours. The reaction mixture was cooled to 0°C and quenched with 10% aqueous NaCl solution. Extracted twice with DCM, and the combined extracts were washed with saturated aqueous NaHCO3 and anhydrous Na2S The residue was purified by silica gel column chromatography ( Purification was carried out using PE containing 10% EA (30%) and 5-(chloromethyl)-3-ethyl-1, 2-Oxazole (4.20 g, yield: 90%) was obtained as a yellow oil. LC / MS ES I (m / z): 146 [M+H] + .

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

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

[0320] Synthesis of 5-bromo-2-methylthiazole-4-carbaldehyde [ka] Ethyl 5-bromo-2-methylthiazole-4-carboxylate (4.13 g, 16 A solution of 1.5 mmol of diisobutylaluminum hydride (16 0.5 mL, 24.8 mmol, 1.5 M THF solution) was added dropwise at -78 °C. The mixture was stirred for 3 h at −78° C. After 3 h, the reaction mixture was successively , water (1.0 mL), aqueous NaOH (15%, 1.0 mL), and then water (10 mL ) at 0°C. After warming to room temperature, the mixture was stirred for 15 minutes. SO4 was added and stirring was continued for 15 minutes, then the mixture was filtered to remove solids. The filtrate was concentrated in vacuo to give crude 5-bromo-2-methylthiazole-4-carbaldehyde. (2.59 g, 76%) was obtained as a yellow solid. LC / MS ESI (m / z): 2 06 [M+H] + .

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

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

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

[0324] Synthesis of (5-iodo-1-methyl-1H-pyrazol-4-yl)methanol [ka] 5-Iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00 g, 8. A mixture of NaBH4 (84 mg, 2 0.5 mmol) was added. The mixture was stirred at 20°C for 1 hour. The mixture was then cooled to 0.5 mmol with saturated N It was quenched with HCl (10 mL) and extracted with EA (60 mL×3). The residue was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by chromatography (5% MeOH in DCM) and (5-iodo-1-methyl-1H (-pyrazol-4-yl)methanol was obtained as a pale yellow solid (840 mg, yield: 41 %). LC / MS ESI (m / z): 239 [M+H] + .

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

[0326] Synthesis of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol [ka] 3-Iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00 g, 8. A solution of DIBAL-H (1.0 M in toluene) in dry THF (20 mL) was solution, 12 mL, 12 mmol) was added dropwise at -70 °C (if multiple hydrogen transfers were required, (An additional equivalent of reducing agent may be used.) The mixture was stirred at -70°C for 2 hours and then added to saturated The mixture was quenched with aqueous NH4Cl, filtered, and the filter cake was washed with THF. The combined filtrate was concentrated under reduced pressure and the residue was diluted with DCM and washed with water and brine. The residue was washed, dried over anhydrous Na2SO4, and concentrated. The product was purified by chromatography (0→20% EA in PE) and purified as follows: (3-iodo-1-methyl-1 H-pyrazol-4-yl)methanol (1.6 g, 79% yield) was obtained as a yellow oil. LC / MS ESI (m / z): 239 [M+H] + .

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

[0328] (5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanol Synthesis of [ka] 5-Iodo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (1 To a mixture of NaBH4 (0.15 g, 4.40 mmol) in MeOH (5 mL), (4.4 mmol) was added and stirred at 0°C for 1 hour. The mixture was dissolved in saturated aqueous NH4Cl solution. The mixture was quenched with ethyl acetate (30 mL) at 0° C. and extracted with EA (50 mL×3). The layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography. The product was purified by chromatography (PE:EA = 1:1, V / V) and purified with (5-iodo-2-methyl (2H-1,2,3-triazol-4-yl)methanol (960 mg, 91%) Obtained as a pale yellow solid. LC / MS (ESI) m / z: 240 [M+H] + .

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

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

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

[0332] Synthesis of 5-bromo-1-ethyl-4-iodo-1H-pyrazole [ka] 1-Ethyl-4-iodo-1H-pyrazole (105.0 g, 425.6 mmol) To a solution of LDA (2.0 M in heptane / THF / ethyl acetate) in THF (900 mL) at -78 °C benzene solution, 212.8 mL, 425.6 mmol) was added dropwise over 1 hour under N2 atmosphere. After the addition, the mixture was stirred at −78° C. for 0.5 h, and then tetrabromomethane A solution of (148.0 g, 445.0 mmol) in THF (50 mL) was added dropwise over 0.5 h. The resulting mixture was stirred at -78°C for an additional hour. The reaction flask was placed in an ice bath. The mixture was quenched with saturated aqueous NH4Cl (200 mL). The combined organic layer was washed with brine and extracted twice with CM (250 mL x 2). The mixture was dried over 2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel. The desired product was obtained as a brown solid (9 0g, yield: 70%). LC / MS ESI (m / z): 301 [M+H] + .

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

[0334] Synthesis of 2-ethyl-4,5-diiodo-2H-1,2,3-triazole [ka] 4,5-Diiodo-2H-1,2,3-triazole (50 mg, 0.18 mmol) In a solution of 14 mg of NaH in 5 mL of THF, was added at 0° C. Then iodoethane (2.94 g, 0.890 mmol) was added, The mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O (5 mL) at 0 °C. The combined organic layer was washed with brine (15 mL) and then extracted with EtOAc (15 mL × 3). 5 mL), dried over anhydrous Na2SO4, and then concentrated. Purification by chromatography (silica gel, 0→25% EtOAc in PE) gave 2 -ethyl-4,5-diiodo-2H-1,2,3-triazole (1.47 g, yield: 6 8%) as a white solid. LC / MS (ESI) m / z: 350 [M+H] + .

[0335] Synthesis of 1-(cyclopropylmethyl)-3-methyl-1H-pyrazole [ka] 3-Methyl-1H-pyrazole (5.90 mL, 73.1 mmol), (bromomethyl ) cyclopropane (7.90 mL, 80.4 mmol) and K2CO3 (20.20 g, A mixture of 146.2 mmol) in DMF (100 mL) was stirred at 80°C for 16 hours. The reaction mixture was added to water and extracted with EtOAc. The organic layer was washed with brine. The residue was purified by flash column chromatography. Purification by HPLC yielded 1-(cyclopropylmethyl)-3-methyl-1H-pyrazoline. The product (6.00 g, 60%) was obtained as a yellow solid. LC / MS (ESI) m / z: 137 [M+H] + .

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

[0337] Synthesis of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde [ka] 5-Bromo-1-ethyl-1H-pyrazole (100 g, 571 mmol) at 0°C In a solution of FA (700 mL), 1,3,5,7-tetraazaadamantane (120 g, 85 7 mmol) was added. The resulting mixture was stirred at 90°C for 16 hours. After cooling to room temperature, After that, the mixture was concentrated under reduced pressure to remove most of the TFA. The residue was dissolved in DCM ( 600 mL), washed with saturated NaHCO3 and brine, and dried over anhydrous Na2SO4 The residue was purified by column chromatography on silica gel (10% E Purified with PE containing 5-bromo-1-ethyl-1H-pyrazole-4-carboxylate. The aldehyde was obtained as a white solid (60 g, yield: 52%). LC / MS ESI (m / z): 203 [M+H] + .

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

[0339] 1-(5-bromo-1,3-thiazol-4-yl)prop-2-yn-1-ol synthesis [ka] 5-Bromo-1,3-thiazole-4-carbaldehyde (1.80 g, 9.37 mmol) To a solution of ethynylmagnesium bromide (28.1 mL, 14.1 mL) in THF (20 mL), The mixture was stirred at room temperature overnight and then quenched with water. The mixture was extracted twice with EA (100 mL). The combined organic layers were concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography to isolate PE (0 → 3 0%) and purified by 1-(5-bromo-1,3-thiazol-4-yl)propanol. 2-yn-1-ol (1.50 g, 73%) was obtained as a colorless oil. LC / MS (ES I): m / z = 218 [M+H] + .

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

[0341] Synthesis of (4-bromo-3-ethylisothiazol-5-yl)methanol [ka] 5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-yn-2-ol amine (5.00 g, 25.5 mmol) and (aminooxy)sulfonic acid (3.20 g, 2 The resulting mixture was stirred at 0 °C in 100 mL of H2O containing 5.1 mmol of HCl. The mixture was stirred at ambient temperature for 4 hours. Then, NaHCO3 (2.40 g, 28.1 mmol) and The resulting mixture was added with sodium hydrosulfide (2.20 g, 38.3 mmol). The mixture was stirred at 0° C. for 16 hours, and the filtrate was extracted with ethyl acetate, washed with brine, and The residue was dried over O4 and concentrated in vacuo. Purification by (0→20% ethyl acetate in petroleum ether) (5-phenyl-1-methyl-2 ...

[0342] (3-ethylisothiazol-5-yl)methanol (1.80 g, 12.6 mmol ), dibromine (7.00 g, 44.1 mmol) and potassium acetate (1.96 g, 20 A mixture of 1.0 mmol) in AcOH (40 mL) was stirred at ambient temperature for 16 h. The resulting mixture was quenched with Na2S2O3. The solution was basified with NaHCO3. The mixture was extracted with DCM, dried over Na2SO4, and concentrated in vacuo. The residue was filtered and washed with 100 ml of silica gel. Purification by rush phase chromatography (0→15% ethyl acetate in petroleum ether) (4-bromo-3-ethylisothiazol-5-yl)methanol (2.04 g, yield The product was obtained as a yellow oil in a 73% yield. LC-MS (ESI) m / z: 222 [M+H ] + .

[0343] Synthesis of 4-fluoro-2-iodobenzonitrile [ka] 4-Fluoro-2-iodobenzamide (4.00 g, 15.1 mmol) thiochloride The mixture was stirred at 90° C. for 16 hours. The mixture was concentrated to give 4-fluorouracil. Fluoro-2-iodobenzonitrile (2.40 g, 64% yield) was obtained as a yellow oil. C / MS (ESI) m / z: 248 [M+H] + .

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

[0345] Synthesis of (4-fluoro-2-iodophenyl)hydrazine [ka] A of 4-fluoro-2-iodoaniline (5.0 g, 21 mmol) with mechanical stirring To the cOH (10 mL) solution, concentrated HCl (40 mL) was added slowly. A thick suspension quickly formed. The reaction was then cooled to 0°C in an ice bath and sodium nitrite was added. A solution of (1.63 g, 23.6 mmol) in water (8 mL) was slowly added dropwise to the reaction mixture. The reaction was stirred for 1 h and then concentrated SnCl2 (8.46 g, 44.5 mmol) was added. A solution of HCl (8 mL) was added slowly and the reaction was allowed to warm to room temperature over 2 hours. The suspension was filtered, washed with water, dried under vacuum, and the crude (4-fluoro-2-iodo) (Hydrophenyl)hydrazine hydrochloride (4.1 g, yield: 77%) was obtained as a gray solid. C / MS (ESI) m / z: 253 [M+H] + .

[0346] Synthesis of 5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole [ka] (5-bromo-1-ethyl-1H-pyrazol-4-yl)methanol (4.00 g, A mixture of triphenylphosphine (6.14 g, 23.4 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) was To a stirred solution of dry DCM (50 mL) was added tetrabromomethane (7.76 g, 23.4 mmol) ) in DCM was added dropwise at 0° C. After the addition, the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel ( Purification by eluent: PE / EtOAc 50 / 1 to 10 / 1 gave 5-bromo-4-(bromo- (bromomethyl)-1-ethyl-1H-pyrazole (3.0 g, 57% yield) was obtained as a white solid. LC / MS ESI (m / z): 267 [M+H] + .

[0347] Synthesis of (3-cyano-1-methyl-1H-pyrazol-5-yl)boronic acid [ka] 1-Methyl-1H-pyrazole-3-carbonitrile (1.0 g, 9.3 mmol) A solution of LDA (2 M in THF, 4 mL) was added to a THF (15 mL) solution at -78 °C under a N2 atmosphere. After stirring at -78°C for 0.5 hours, the mixture was cooled to -78°C and then cooled to -78°C for 0.5 hours. A solution of 1.9 g (19 mmol) of ethyl acetate in 2 mL of THF was added dropwise. The mixture was then heated at -78 °C for 1 h. After stirring, the reaction was quenched with saturated aqueous ammonium chloride. The organic layer was diluted with tOAc and washed first with HO and then with brine. The mixture was dried over 2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. Purification by filtration (0→80% EtOAc in PE) was carried out to obtain (3-cyano-1-methyl- 1H-pyrazol-5-yl)boronic acid (800 mg, 57% yield) was obtained as a yellow oil. LC / MS ESI (m / z): 152 [M+H] + .

[0348] Synthesis of 3-cyclobutyl-1,2-oxazole-5-carbaldehyde [ka] (3-cyclobutyl-1,2-oxazol-5-yl)methanol (500 mg, 3 To a solution of MnO2 (2.80 g, 32.64 m mol) was added. The mixture was stirred at room temperature overnight and then filtered. The filtrate was evaporated under reduced pressure. Concentrate the extract and perform flash column chromatography (eluting with PE containing 0 → 15% EA). Purify by silica gel and obtain 3-cyclobutyl-1,2-oxazole-5-carbazone. The hydrochloride (260 mg, 53%) was obtained as a colorless oil. LC / MS (ESI): m / z = 152 [M+H] + .

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

[0350] Synthesis of 3-(cyclopropylmethyl)isoxazole-5-carbaldehyde [ka] [3-(cyclopropylmethyl)-1,2-oxazol-5-yl]methanol (1 A solution of 1000 mg of 10-chloro-2,4-di ... Dinane (3.65 g, 8.62 mmol) was added at 0° C. After stirring at 0° C. for 2 hours, The reaction mixture was diluted with saturated aqueous Na2CO3 (20 mL) and DCM (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, and Filtration and concentration in vacuo gave a residue which was purified by column chromatography on silica gel (0 → PE containing 25% EA (V / V) was used to purify the 3-(cyclopropylmethyl)-1 ,2-oxazole-5-carbaldehyde (0.90 g, 83%) was obtained as a yellow oil. LC / MS ESI (m / z): 152 [M+H] + .

[0351] Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile [ka] 5-Bromo-4-(chloromethyl)-1-ethyl-1H-pyrazole (5.00 g, 2 To a solution of NaCN (2.20 g, 44 After stirring at 25°C for 2 hours, the mixture was diluted with EtOAc and H The organic layer was separated, washed with brine, dried over anhydrous NaSO, and The residue was purified by silica gel column chromatography (20% EtOAc). Purified with 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl) ) Acetonitrile (4.5 g, yield: 94%) was obtained as a pale yellow oil. LC / MS ES I (m / z): 214 [M+H] + .

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

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

[0354] 3-Bromo-5-fluoro-N-methoxy-N-methylpicolinic acid cooled to -20°C A solution of magnesium methyl bromide (3.50 g, 13.3 mmol) in THF (5 mL) was added to To this mixture was added ethanol (4.43 mL, 13.3 mmol, 3 M in THF). The mixture was stirred at -20°C for 2 hours and then quenched with ice water. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0→30% EtOAc Purified by PE containing 1-(3-bromo-5-fluoropyridin-2-yl)ethoxybenzoate 2.6 g (90% yield) of benzophenone-1-one was obtained as a white solid. LC / MS ESI ( m / z): 218 [M+H] + .

[0355] Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole [ka] 3-Iodo-1-methyl-1H-pyrazole-5-carbaldehyde (2.3g, 9.7 To a stirred solution of 0.5 mmol of cyclopropylmagnesium bromide (0.5 mmol) in THF (40 mL) A hexane solution of M (20.5 mL, 10.3 mmol) was added at 0°C under N2. The reaction was stirred at 0° C. for 1.5 h, then quenched with saturated NH 4 Cl (5 mL) and concentrated. The residue was purified by flash chromatography (0-50% EtOAc in PE ) and purified by cyclopropyl(3-iodo-1-methyl-1H-pyrazol-5-yl) (I)methanol (1.6 g, 19% yield) was obtained as a yellow solid. LC / MS (ESI ) (m / z): 279 [M+H] + .

[0356] Cyclopropyl(3-iodo-1-methyl-1H-pyrazol-5-yl)methanol To a stirred solution of (1.0 g, 3.6 mmol) in DCM (18 mL), TES (4.20 g, 36.0 mmol) and TFA (2.7 mL, 36 mmol) were added at 0°C. The reaction was stirred at room temperature overnight. The reaction was concentrated to dryness. The residue was purified by flash chromatography. Purification by chromatography (0→10% EtOAc in PE) gave 5-(cyclopropylmethyl)methyl (ethyl)-3-iodo-1-methyl-1H-pyrazole (0.60 g, 51% yield) was obtained as a yellow Obtained as a solid. LC / MS (ESI) (m / z): 263 [M+H] + .

[0357] Synthesis of 4-fluoro-2-iodobenzamide [ka] 4-Fluoro-2-iodobenzoic acid (5.00 g, 18.8 mmol) in DCM (10 To the solution (2.0 mL) was added oxalyl chloride (5.00 g, 39.4 mmol), followed by D MF (0.07 mL, 0.9 mmol) was added at 0° C. After the addition, the resulting mixture was The mixture was stirred for 2 hours at 5° C. The mixture was concentrated to dryness in vacuo to give crude 4-fluoro-2-chloride. The iodobenzoyl was obtained as a yellow oil.

[0358] 4-Fluoro-2-iodobenzoyl chloride dissolved in dry DCM (50 mL) cooled to 0 °C Add 14 mL of pre-cooled NH3 water (370 mmol, 28% in H2O) to the solution. The mixture was added dropwise over 10 minutes. The internal temperature was maintained below 5°C during the addition. The white solid residue was triturated with water and PE, then The desired product, 4-fluoro-2-iodobenzamide, was obtained by drying in a vacuum oven at RT. (11 g, 92% yield over two steps) was obtained as a white solid. LC / MS (ESI): m / z = ​​266 [M+H] + .

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

[0360] Synthesis of ethyl 5-ethylisothiazole-3-carboxylate [ka] Butan-2-one (10.0 g, 139 mmol) and diethyl oxalate (20.3 g To a mixture of sodium ethoxide (3.0 M in EtOH, 57 0.6 mL, 166 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by adding saturated aqueous NH4Cl (50 mL). The mixture was cooled, acidified to pH 3 with 1.0 M HCl, and concentrated in vacuo to remove the EtOH. The residue was extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with saturated N Wash with aqueous H4Cl (20 mL) and brine, dry over anhydrous Na2SO4, and filter. The residue was purified by flash chromatography using hexanes containing EtOAc. The product was purified with PE (0→75%, V / V) to give ethyl 2,4-dioxohexanoate (19 0.0g, 80%) as an orange oil. LC / MS (ESI) (m / z): 173 [M+H] + . Ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) in toluene (30 mL) and acetic acid (3 mL) solution, ammonium acetate (3.36 g, 43.6 mm ol) was added at 0°C. The resulting mixture was then stirred at 80°C overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in saturated aqueous NaHCO3 solution. The mixture was then basified to pH 7 and extracted with EtOAc (3 x 20 mL). The organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) and then diluted with anhydrous N The residue was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography using PE containing EtOAc (0→30%, V / V). , ethyl 4-amino-2-oxohex-3-enoate (19.0 g, 80%) in a yellow The product was obtained as a solid. The product was a mixture of (Z)- and (E)-olefins. C / MS (ESI) (m / z): 172 [M+H] + .

[0361] Ethyl 4-amino-2-oxohex-3-enoate (1.30 g, 7.59 mmol) l) in THF (15 mL) at room temperature. After addition, the resulting mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and then in 30% aqueous H2O2 ( 6 mL) was added at 0° C. and stirred for 10 min at 0° C. After 10 min, the reaction mixture was The combined organic phase was then extracted with saturated aqueous NH4Cl (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo The residue was purified by flash column chromatography on silica with EtOAc. Purify with PE (0→30%, V / V) containing c and ethyl 5-ethylisothiazol-3- The carboxylate (0.72 g, 51%) was obtained as a yellow oil. LC / MS (ESI) (m / z): 186 [M+H] + .

[0362] Synthesis of 5-bromo-1-cyclobutyl-1H-pyrazole-4-carbaldehyde [ka] 5-Bromo-1-cyclobutyl-4-iodo-1H-pyrazole (11.0 g, 33. 6 mmol) in THF (60 mL) HF solution (31.0 mL, 40.4 mmol) was added at -5°C to -10°C. After stirring at rt for 15 min, anhydrous DMF (3.38 mL, 43.7 mmol) was added. The solution was stirred at -10°C for 30 minutes and then slowly poured into stirred ice water. Extract with ethyl acetate (100 mL x 2), then wash with brine (50 mL x 2), and The residue was dried over Na2SO4 and concentrated. Purification by ethanol (0→10% ethyl acetate in petroleum ether) and 5-bromo-1-cyclohexanediamine Butyl-1H-pyrazole-4-carbaldehyde (6.0 g, 78%) as a yellow solid Got it. LC / MS ESI (m / z): 229 [M+H] + .

[0363] Synthesis of 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyrazole [ka] 5-Bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole (1.0 g, 3. To a solution of NaN3 (728 mg, 89.5 mmol) in DMF (50 mL), was added at 0° C. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with EtOAc. The final organic layer was dried over anhydrous Na2SO4 and filtered. The residue was purified by silica gel column chromatography (20% EtOAc Purified by PE (containing 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyrazol-2-yl). The sol was obtained as a yellow oil (750 mg, yield: 87%). LC / MS (ESI) m / z: 230 [M+H] +

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

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

[0366] Synthesis of methyl 3-bromo-5-fluoropicolinate [ka] 3-Bromo-5-fluoropyridine-2-carboxylic acid (1.0 g, 4.5 mmol) and To a solution of SOCl2 (1.7 mL, 23 mmol) and MeOH (30 mL) at 0 °C, After the addition, the mixture was stirred at 0°C for 2 hours. After quenching with HCl, the mixture was extracted with DCM (40 mL x 2). The combined organic layer was washed with brine. The residue was washed, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by chromatography (PE:EA=5:1) and methyl 3-bromo-5-fluoro Lopicolinate was obtained as a pale yellow solid (1.0 g, yield: 94%). LC / MS ES I (m / z): 234 [M+H] + .

[0367] Synthesis of 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine [ka] 2,3-Dibromo-5-fluoropyridine (1.0 g, 3.9 mmol), hexamethoxazole Ludistannane (1.35 g, 4.12 mmol) and Pd(PPh3)4 (0.23 g, A mixture of 0.20 mmol) in toluene (50 mL) was heated to 110 °C under N2 for 16 h. The mixture was concentrated, diluted with EtOAc (50 mL) and added to brine (30 mL). The residue was washed with HCl, dried over anhydrous Na2SO4, and concentrated. Purification by HPLC (100% petroleum ether) gave 3-bromo-5-fluoro-2- (Trimethylstannyl)pyridine (1.2 g, 90% yield) was obtained as a colorless oil. MS (ESI) m / z: 340 [M+H] + .

[0368] Synthesis of (3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol [ka] Methyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (3.10 g, 18.4 mmol) in THF (60 mL), 46.1 mmol, 1.0 M toluene solution) was added at -78°C over 30 minutes. The reaction was monitored to maintain an internal temperature below -60°C. The mixture was stirred in a acetone bath for 1 hour and then in an ice bath for 1 hour. The mixture was cooled to -78°C and The excess EtOAc was added slowly. A saturated aqueous solution of HCl (1M) was added to the glass flask. The mixture was stirred at room temperature for 1 hour. The combined organics were washed with brine and MgSO The resulting material was purified by column chromatography on silica gel. Purification by column chromatography (50% EtOAc in PE) H-pyrazol-5-yl)methanol (2.2 g, 85%) was obtained as a colorless oil. / MS ESI (m / z): 141 [M+H] + .

[0369] Synthesis of (1-(2-fluoroethyl)-1H-pyrazol-4-yl)methanol [ka] Methyl 1-(2-fluoroethyl)-1H-pyrazole-4-carboxylate (53 To a solution of 100 mg (3.08 mmol) of DIBAL-H (2.5 M A solution of MePh (5.13 mL, 12.8 mmol) was added at -78°C. The mixture was stirred at room temperature for 16 hours, then added water (0.3 mL), aqueous NaOH (1 M, 0.3 mL), and more water (0.8 mL) were added successively with stirring. Partitioned between EA and water, then the aqueous phase was further extracted with EA (3 x 10 mL). The organic solution was washed with saturated aqueous NH4Cl (10 mL) and brine (10 mL) and The mixture was dried over Na2SO4 and concentrated in vacuo to give a residue which was subjected to flash chromatography. Purification was carried out by chromatography (0→50% PE containing EA), followed by elution with [1-(2-fluoroethyl)- 1H-pyrazol-4-yl]methanol (380 mg, yield: 86%) was obtained as a colorless liquid. LC / MS ESI (m / z): 145 [M+H] + .

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

[0371] Synthesis of (5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methanol [ka] 5-Bromo-1-cyclobutyl-1H-pyrazole-4-carbaldehyde (6.00g , 26.2 mmol) in THF (50 mL) 1.0 M toluene solution, 39.28 mL, 39.28 mmol) at -78°C for 30 min. (This protocol allows for the complete reduction of the ester to the alcohol.) (This can be modified by increasing the number of equivalents of reducing agent, as shown in the figure.) The internal temperature was monitored to maintain it below -60° C. The reaction was stirred at -78° C. for 1 hour. The mixture was then poured into aqueous HCl (1M) and extracted with ethyl acetate (100 mL× 2), then washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (30% ethyl acetate in petroleum ether). Purified by (5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methano The product (4.4 g, 73%) was obtained as a colorless oil. LC / MS ESI (m / z): 2 31 [M+H] + .

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

[0373] Synthesis of (3-bromo-5-fluoropyridin-2-yl)methanol [ka] Methyl 3-bromo-5-fluoropyridine-2-carboxylate (1.00 g, 4. To a solution of DIBAL-H (1.21 mL) in THF (15 mL) at -78 °C, (8.54 mmol) was added dropwise under a N2 atmosphere. The mixture was stirred at 0°C for 2 hours. Then, the mixture was quenched with ice water and extracted with DCM (40 mL x 2). The residue was washed with HCl, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography (DCM:MeOH=20:1) and (3-bromo-5 (-fluoropyridin-2-yl)methanol was obtained as a pale yellow solid (600 mg, yield :68%). LC / MS ESI (m / z): 206 [M+H] + .

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

[0375] Synthesis of 5-(4-fluoro-2-iodophenyl)-1H-tetrazole [ka] 4-Fluoro-2-iodobenzonitrile (2.5 g, 10 mmol), trimethylsilyl C13 azide (2.92 g, 25.3 mmol) and dibutylstannanone (0.50 g, 2 A mixture of 1.0 mmol) in toluene (20 mL) was stirred at 120°C for 18 hours. After cooling to warm, the mixture was filtered and the filtrate was concentrated under reduced pressure. (50 mL), then washed with water and brine, dried over anhydrous Na2SO4, and filtered. The residue was purified by flash chromatography (silica gel, 0→50% E Purified by PE containing A) and 5-(4-fluoro-2-iodophenyl)-1H-tetrahydrofuran. The benzol (2.4 g, 82% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 291 [M+H] + .

[0376] Synthesis of 4-(azidomethyl)-5-bromo-1-cyclobutyl-1H-pyrazole [ka] 5-Bromo-4-(chloromethyl)-1-cyclobutyl-1H-pyrazole (3.00 g, 12.0 mmol) in DMF (60 mL) After the addition, the resulting mixture was heated at 60° C. for 2.5 hours. After cooling to 0°C, the reaction mixture was diluted with water (200 mL) and extracted with EA. The combined extracts were washed with brine, concentrated in vacuo, and flash-dried. Purification by column chromatography (10% EtOAc in PE) gave 4-(azidomethyl) (1H-phenyl)-5-bromo-1-cyclobutyl-1H-pyrazole (2.91 g, yield: 95%) was obtained as a colorless oil. LC / MS ESI (m / z): 256 [M+H] + .

[0377] 5-((5-bromo-1H-1,2,4-triazol-1-yl)methyl)-3-ethoxy Synthesis of thylisoxazole [ka] 5-(chloromethyl)-3-ethyl-1,2-oxazole (2.00 g, 13.7 m mol), 3-bromo-1H-1,2,4-triazole (2.03 g, 13.7 mmol) l), ethylbis(propan-2-yl)amine (4.54 mL, 27.47 mmol) , potassium iodide (1.14 g, 6.87 mmol) in anhydrous MeCN (20 mL) was stirred at 80° C. for 2 hours. The reaction mixture was filtered to remove solids, and the filtrate The mixture was partitioned between EA and water and the layers were separated. The aqueous layer was further extracted with EA and the combined organic layer was The layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography ( 0→3% MeOH in DCM) to obtain a 5:1 mixture of regioisomers (3.0 g, The isomers were obtained as a colorless oil (yield: 85.7%). These isomers were separated by preparative SFC (ChiralP ak IG, 250×21.2mm ID, 5μm, 40%MeOH+0.1%NH 3 in water and CO2 at 50 mL / min) and 5-((5-bromo-1H-1,2,4 -triazol-1-yl)methyl)-3-ethylisoxazole (peak 1, small amount The isomers (650 mg, by NOESY analysis) were obtained as colorless oils. LC / MS ESI (m / z): 257 [M+H] + .

[0378] Ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate Synthesis of acetone [ka] Ethyl 5-bromo-1H-pyrazole-4-carboxylate (14.0 g, 63.9 To a solution of KF (7.96 g, 63.9 mmol) and KF (7.96 g, 63.9 mmol) in MeCN (60 mL), Diethyl (bromodifluoromethyl)phosphonate (27.43 g, 102.7 mmol) ) was added at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was slowly poured into ice water. The combined extracts were washed with brine and The residue was purified by flash chromatography (silica gel, 0→5% Purification by ethyl 5-bromo-1-(difluoromethyl)-2-(2-methyl-2-propanol) (Cycitriyl)-1H-pyrazole-4-carboxylate (4.0 g, 23% yield) was obtained as a white solid LC / MS ESI (m / z): 269 [M+H] + .

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

[0380] 1-[(5-bromo-1,3-thiazol-4-yl)methyl]pyrazole-4-carbohydrate Synthesis of bonitrile [ka] (5-bromo-1,3-thiazol-4-yl)methanol (400 mg, 2.06 m mol), 4-cyanopyrazole (288 mg, 3.09 mmol) and PPh3 (64 To a solution of DIAD (500 mg, 2.4 7 mmol) was added dropwise at 0°C. The mixture was then stirred at room temperature for 16 hours. was removed under vacuum, and the residue was purified by silica gel (PE / EA=1:1) to give 1-[( 5-Bromo-1,3-thiazol-4-yl)methyl]pyrazole-4-carbonitrile (460 mg, 83%) was obtained as a white solid. LC / MS ESI (m / z): 2 69 [M+H] + .

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

[0382] 5-((5-iodo-1H-pyrazol-1-yl)methyl)isoxazole-3- Carbonitrile synthesis [ka] 5-(bromomethyl)isoxazole-3-carbonitrile (2.20 g, 11.7 A solution of 2.50 g of 5-iodo-1H-pyrazole (2.50 mmol) in 100 mL of DMF , 12.9 mmol) and K2CO3 (4.90 g, 35.3 mmol) were added at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was diluted with EtOAc and then with H2O The organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate The mixture was concentrated in vacuo. The residue was purified by SFC (ChiralPak AD, 40% MeOH + 0 0.1% NH3·H2O) to separate the regioisomers and obtain the 5-((5-iodo) (1H-pyrazol-1-yl)methyl)isoxazole-3-carbonitrile Obtained as a pale yellow oil (350 mg, yield: 10%, minor regioisomer). LC / MS E SI (m / z): 301 [M+H] + .

[0383] The following intermediates were synthesized using similar experimental protocols: [Table 27] TIFF0007815341000180.tif48165

[0384] 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isothiazolinone Synthesis of isoxazole [ka] 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.00g , 36.7 mmol) and 1-nitropropane (7.00 g, 78.6 mmol) In a toluene (40 mL) solution, phenyl isocyanate (17.0 mL, 119 mmol) ) was added followed by the addition of triethylamine (2.94 mL, 21.2 mmol). The reaction mixture was heated to 120° C. and stirred for 24 hours. After cooling to room temperature, the reaction The mixture was quenched with 1 mL of water and stirred at room temperature for 1 h. The precipitate was removed by filtration. The residue was purified by silica gel column chromatography (0 → 20% EtOAc in PE) to give 3-ethyl-5-(((tetrahydro (2H-pyran-2-yl)oxy)methyl)isoxazole (10.0 g, yield 61 %) was obtained as a yellow syrup. LC / MS ESI (m / z): 212 [M+H ] + .

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

[0386] (2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)methano Synthesis of acetone [ka] (5-Fluoro-2-iodophenyl)methanol (25.0 g, 99.2 mmol) In a toluene (250 mL) solution of 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. The reaction was stirred under N2 at 120 °C for 12 h. The reaction was filtered and concentrated. The residue was purified by flash chromatography (5→25% Et PE containing OAc) and purified by (2-(3-chloro-1H-pyrazol-1-yl) )-5-fluorophenyl)methanol (21.1 g, 85% yield) was obtained as a white solid. Ta. LC / MS (ESI) (m / z): 227 [M+H] + .

[0387] 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo Synthesis of acetone [ka] 3-Methoxy-1H-pyrazole (1.00 g, 10.2 mmol) in THF (1 5 mL) solution, NaH (0.46 g, 12 mmol, 60% mineral oil solution) was added under N2 and After stirring at 0°C for 1 hour, [2-(chloromethoxy)ethyl]trimethyl A solution of silane (2.5 mL, 14 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 0°C for 1 h, quenched with saturated NH4Cl (10 mL), and added to EtOAc (100 mL). The organic phase was separated, dried over anhydrous Na2SO4, and concentrated to dryness to give 3- Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole( 2.20 g, 91% yield, was obtained as a yellow oil. LC / MS (ESI) (m / z): 229.1 [M+H] + .

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

[0389] (E)-1-(3-bromo-5-fluoropyridin-2-yl)-3-(dimethylamino) Synthesis of prop-2-en-1-one [ka] 1-(3-bromo-5-fluoropyridin-2-yl)ethan-1-one (2.60 g , 11.9 mmol) in (dimethoxymethyl)dimethylamine (10 mL) The mixture was stirred at 0° C. for 12 hours. After cooling to room temperature, the mixture was concentrated by oil pump. The residue was purified by flash chromatography on silica gel (0→40% EtOAc PE) and purified to give (E)-1-(3-bromo-5-fluoropyridin-2-yl)- 3-(Dimethylamino)prop-2-en-1-one (3.0 g, 92% yield) was obtained as a yellow solid. LC / MS ESI (m / z): 273 [M+H] + .

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

[0391] (5-Bromo-1,3-thiazol-4-yl)(1-ethyl-1H-1,2,3-thiazol-4-yl) Synthesis of riazol-4-ylmethanol [ka] In a sealed tube, bromoethane (1.68 g, 15.1 mmol), sodium azide (0. A solution of 98 g (15.1 mmol) of HCl in 5 mL of THF and 5 mL of HCl was heated at 80 °C. The mixture was stirred for 4 hours. After cooling to room temperature, 1-(5-bromo-1,3-thiazolinone) Azol-4-yl)prop-2-yn-1-ol (1.10 g, 5.04 mmol) , sodium ascorbate (0.20 g, 1.01 mmol), CuSO4 (0.16 g, 1 0.01 mmol) and t-BuOH (10 mL) were added successively. The mixture was heated to 50°C. After stirring for 18 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was washed with silica gel. Purification was performed by flash column chromatography (0 → 10% MeOH in DCM). , (5-bromothiazol-4-yl)(1-ethyl-1H-1,2,3-triazole (4-yl)methanol (0.7 g, 48%) was obtained as a colorless oil. MS (ESI): m / z = 289 [M+H] + .

[0392] 1-[(3-iodopyridin-2-yl)methyl]-1H-imidazole-4-carbohydrate Nitrile synthesis [ka] A solution of triphenylphosphane (712 mg, 2.72 mmol) in THF (7 mL) The mixture was cooled to 0°C under N2. THF (7 mL) was added, and the mixture was then stirred at 0° C. until a white solid precipitated. Next, 1H-imidazole-4-carbonitrile (152 mg, 1 0.63 mmol) in THF (4 mL) was added at 0° C. Then, to this mixture, T containing 3-iodopyridin-2-yl)methanol (319 mg, 1.36 mmol) HF (6 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated The solution was washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. The residue was purified by flash chromatography (silica gel, 0 → Purified with PE containing 100% EA and 1-[(3-iodopyridin-2-yl)methyl]methyl [Imidazole]-1H-imidazole-4-carbonitrile (309 mg, yield: 73%) was obtained as a yellow oil LC / MS (ESI) m / z: 311 [M+H] + .

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

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

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

[0396] 3-chloro-1-((1-(ethyl-d5)-1H-pyrazol-4-yl)methyl) Synthesis of 5-iodo-1H-pyrazole [ka] (1-(ethyl-d5)-1H-pyrazol-4-yl)methanol (1.07 g, 8 To a stirred solution of 1.16 mmol) in DCM (20 mL) was added SOCl2 (1.80 mL, 24. 5 mmol) was added at 0° C. The reaction was stirred at 25° C. for 16 hours. The mixture was concentrated to give crude 4-(chloromethyl)-1-(ethyl-d5)-1H-pyrazole (1 Obtained 0.22g, 99% yield as a yellow oil.

[0397] 3-chloro-5-iodo-1H-pyrazole (1.83 g, 8.02 mmol) and C A mixture of s2CO3 (7.84 g, 24.06 mmol) in DMF (30 mL) 4-(chloromethyl)-1-(ethyl-d5)-1H-pyrazole (1.20 g, 8.0 A solution of 2 mmol) in DMF (3 mL) was added under N2 at 0 °C. The reaction was heated to 80 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3 The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (PE:EA= 3:1) and then recrystallized from DCM and PE to give 3-chloro-1-((1 -(ethyl-d5)-1H-pyrazol-4-yl)methyl)-5-iodo-1H-pyrazol-4-yl The sol (700 mg, 26% yield) was obtained as a white solid. LC / MS (ESI) ( m / z): 342 [M+H] + .

[0398] 4-Bromo-3-ethyl-5-((5-iodo-1H-1,2,4-triazole-1 Synthesis of (-yl)methyl)isothiazole [ka] 5-((1H-1,2,4-triazol-1-yl)methyl)-4-bromo-3-en A solution of ethylisothiazole (1.90 g, 6.99 mmol) in stirred AcOH (60 To the resulting mixture was added NIS (3.60 g, 21.0 mmol). The mixture was stirred at 80° C. for 16 hours. The filtrate was extracted with EtOAc. The combined organic layer was The residue was washed with ethanol, dried over Na2SO4, and concentrated in vacuo. Purification by double-phase chromatography (0→30% EtOAc in petroleum ether) gave 4 -Bromo-3-ethyl-5-((5-iodo-1H-1,2,4-triazole-1-yl) (2.0 g) of (methyl)isothiazole was obtained as an off-white solid. LC-MS (ESI) m / z: 399 [M+H] + .

[0399] Synthesis of (3-ethylisoxazol-5-yl)methanol [ka] 3-ethyl-5-[(oxan-2-yloxy)methyl]-1,2-oxazole ( To a solution of Amberlyst (17.4 g, 82.4 mmol) in MeOH (10 mL), 15 (26 mg, 83 mmol) was added, and the mixture was stirred vigorously at 45 °C for 6 h. Filtration and removal of the solvent in vacuo gave a red residue, which was purified by column chromatography on silica gel. Purification by HPLC (15-30% EtOAc in PE) gave (3-ethyl-1 ,2-oxazol-5-yl)methanol (8.05 g, yield: 77%) was obtained as a pale yellow oil. LC / MS ESI (m / z): 128 [M+H] + .

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

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

[0402] 5-Bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole (1.80 g, 5.86 mmol) and TFA (3.00 mL, 40. A solution of 4 mmol) in DCM (15 mL) was stirred at 25° C. for 4 h. The reaction mixture The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and aqueous NH4OH (3.0 mL). The mixture was stirred at 25°C for 3 hours. Concentration under reduced pressure gave 5-bromo-3-methoxy-1H-pyrazole (1.5 g, yield 87%). was obtained as a yellow oil. LC / MS ESI (m / z): 177.0 [M+H] + .

[0403] 5-Bromo-1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl) Synthesis of (methyl)-1H-1,2,4-triazole [ka] 4-(chloromethyl)-1-(cyclopropylmethyl)-1H-pyrazole (950m g, 5.56 mmol) and K2CO3 (1.50 g, 11.1 mmol). In DMF (15 mL), 3-bromo-4H-1,2,4-triazole (906 mg, 6.10 mmol) was added, and the mixture was then stirred at 50°C for 2 hours. The reaction mixture was concentrated by oil pump and diluted with EtOAc. The solution was washed with brine. The residue was purified by preparative HPLC (column : YMC TA C18 250*20mm 5um, H2O+0.1% containing MeCN FA) and purified to give 5-bromo-1-((1-(cyclopropylmethyl)-1H-pyrazol-2-yl)- (4-(4-phenyl-4-ylmethyl)-1H-1,2,4-triazole (100 mg, in two steps) The compound was obtained as a white solid (6% yield). LC / MS ESI (m / z): 282 [M+ H] + .

[0404] The following intermediates were synthesized using similar experimental protocols: [Table 34] TIFF0007815341000200.tif115165

[0405] 4-[(5-bromo-1,3-thiazol-4-yl)methyl]-1-ethyl-1H- Synthesis of 1,2,3-triazole [ka] (5-Bromo-1,3-thiazol-4-yl)(1-ethyl-1H-1,2,3-thiazol-4-yl) Triazol-4-yl)methanol (700 mg, 2.42 mmol) in TFA (20 m To the solution was added triethylsilane (7.8 mL, 48 mmol). The mixture was then closed and stirred for 16 hours at 50° C. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography to obtain PE( Purification was performed by eluting with 0 → 100% 4-[(5-bromo-1,3-thiazol-4-yl )methyl]-1-ethyl-1H-1,2,3-triazole (0.6g, 91%) pale yellow Obtained as a colored solid. LC / MS (ESI): m / z = 273 [M+H] + .

[0406] The following intermediates were synthesized using similar experimental protocols: [Table 35] TIFF0007815341000203.tif245165TIFF0007815341000204.tif209165TIFF0007815341000205.tif228165

[0407] 5-((5-bromothiazol-4-yl)(hydroxy)methyl)-1-methyl-1 Synthesis of H-pyrazole-3-carbonitrile [ka] 5-Iodo-1-methyl-1H-pyrazole-3-carbonitrile (650 mg, 2. To a stirred solution of 79 mmol) of 1,2-dichloroisopropylmagnesium bromide (3. 1 mL of 1 M THF solution (3.1 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. After that, 5-bromo-1,3-thiazole-4-carbaldehyde (643 mg, 3.35 m A solution of 100 mol of HCl in 2 mL of THF was added dropwise. The reaction was stirred at 0° C. for an additional 30 min. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (50% EtOAc in PE). Purify and obtain 5-((5-bromothiazol-4-yl)(hydroxy)methyl)-1-methyl 1H-pyrazole-3-carbonitrile (450 mg, 54% yield) as a yellow oil Got it. LC / MS (ESI) (m / z): 299 [M+H] + .

[0408] The following intermediates were synthesized using similar experimental protocols: [Table 36] TIFF0007815341000208.tif232165TIFF0007815341000209.tif197165

[0409] [2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethylster Synthesis of Nan [ka] 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.0 g, 4. To a mixture of n-BuLi (1.78 mL, 4.45 mmol) in THF (20 mL), mol, 2.5 M) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour. trimethyltin chloride (4.45 mL, 4.45 mmol, 1.0 M in THF) was added dropwise to the mixture. The resulting mixture was stirred at -78°C for 15 minutes. The mixture was quenched with saturated NH4Cl (50 mL) at 0°C and extracted with EtOAc (50 mL The combined extracts were washed with brine (20 mL x 2) and dried over anhydrous Na2SO4. The residue was purified by flash chromatography on silica gel (10 % EtOAc in PE) to obtain [2-(1,3-dioxolan-2-yl)-4 -fluorophenyl]trimethylstannane (600 mg, yield: 44%) as a colorless oil Got it. LC / MS ESI (m / z): 333 [M+H] + .

[0410] 4-(5-ethyl-1,2-oxazole-3-carbonyl)-5-iodo-2-methyl Synthesis of benzoyl-2H-1,2,3-triazole [ka] 5-Ethyl-1,2-oxazole-3-carboxylic acid (1.6 g, 11.3 mmol) , EDCI (3.36g, 17.5mmol), HOBt (2.37g, 17.5mmol) l), N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.9 mmol) and A mixture of 2.29 g of TEA (22.7 mmol) in 10 mL of DMF was heated at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and diluted with EA. The organic layer was separated and extracted with saturated NaHCO3 aqueous solution (40 mL × 3) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1, V / V) and purified by 5-ethyl-N-methoxy-N-methyl-1,2-oxazole- The 3-carboxamide (1.5 g, 70%) was obtained as a pale yellow solid. LC / MS ESI (m / z): 185 [M+H] + .

[0411] 4,5-diiodo-2-methyl-2H-1,2,3-triazole (1.65 g, 4. A mixture of 100 ml of 10 ... Pill magnesium (3.79 mL, 4.93 mmol, 1.3 M 2-methyltetrahydrofuran The mixture was stirred at 0°C for 2 hours. 2-Oxazole-3-carboxamide (0.91 g, 4.93 mmol) was added to this mixture The mixture was added to a saturated aqueous solution of NH4Cl (100 mL) and stirred at 0°C for 2 hours. The mixture was quenched and extracted with EA (80 mL x 3). The organic layer was separated and washed with anhydrous Na2SO4 The mixture was dried at 77°C, filtered, and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel. The product was purified by a filtration method (PE:EA = 2:1, V / V) and purified as 4-(5-ethyl-1,2-oxo- (Sazol-3-carbonyl)-5-iodo-2-methyl-2H-1,2,3-triazolium The product (310 mg, 19%) was obtained as a pale yellow oil. LC / MS ESI (m / z): 333 [M+H] + .

[0412] 5-Bromo-1-((3-(cyclopropylmethyl)-1-methyl-1H-pyrazole Synthesis of (5-yl)methyl-1H-1,2,4-triazole [ka] (3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methano To a stirred solution of ethanol (1.05 g, 6.32 mmol) in DCM (20 mL) was added SOCl2 ( (1.40 mL, 19 mmol) was added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was The mixture was concentrated to give crude 5-(chloromethyl)-3-(cyclopropylmethyl)-1-methyl To give 1H-pyrazole (1.16 g, 99% yield) as a yellow oil.

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

[0414] 5-Bromo-1-((1-isobutyl-3-methyl-1H-pyrazol-4-yl)methyl)methyl Synthesis of (ethyl)-1H-1,2,4-triazole [ka] (1-isobutyl-3-methyl-1H-pyrazol-4-yl)methanol (800m g, 4.76 mmol) in anhydrous dichloromethane (30 mL) was treated with thionyl chloride (3. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to give crude 4-(chloromethyl)-1-isobutyl-3-methyl- 1H-pyrazole (950 mg) was obtained as a white solid.

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

[0416] 5-((5-bromo-2-methylthiazol-4-yl)(hydroxy)methyl)-1 Synthesis of 1H-methyl-1H-pyrazole-3-carbonitrile [ka] 5-Iodo-1-methyl-1H-pyrazole-3-carbonitrile (900 mg, 3. A solution of 86 mmol of isopropylmagnesium chloride-lithium chloride in 9 mL of THF was The hydroxybenzoate complex (3.27 mL, 4.25 mmol, 1.3 M THF solution) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. Carbaldehyde (796 mg, 3.86 mmol) was added, and the resulting mixture was cooled to room temperature. The reaction mixture was stirred overnight, and then saturated aqueous NH4Cl (10 mL) was added to the mixture. The mixture was quenched with EA (3 x 10 mL), extracted with EA (3 x 10 mL), and all organic phases were combined and washed with saturated NH Wash with water (10 mL) and brine (10 mL), dry over anhydrous Na2SO4, It was filtered and concentrated in vacuo. The residue was purified by flash chromatography (0→5% MeO Purification by 5-((5-bromo-2-methylthiazol-4-yl) ... HCl (DCM containing 5-bromo-2-methylthiazol-4-yl)methylthiazol-4-yl )(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile (55 3 mg, 46%) was obtained as a yellow viscous substance. LC / MS ESI (m / z): 31 3 [M+H] + .

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

[0418] (5-bromo-1-ethyl-1H-pyrazol-4-yl)(3-chloropyrazine-2 Synthesis of (-yl)methanol [ka] Dissolve 2-chloropyrazine (1.00 g, 8.73 mmol) in THF (35 mL) at -78 °C. ) solution, LiTMP (1.0 M in THF, 11.4 mL, 11.4 mmol) was added to After the addition, the mixture was stirred at -70°C for 0.5 hours, and then 5- Bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (2.13 g, 10.5 m A solution of 1.5 mol of HCl in 5 mL of THF was added. The resulting mixture was further stirred at -70°C for 1.5 min. The mixture was quenched with saturated NH4Cl solution and then extracted twice with DCM. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (30% EtO Purified by PE containing Ac) and (5-bromo-1-ethyl-1H-pyrazole-4-isothiazolinone (3-chloropyrazin-2-yl)methanol was obtained as a yellow oil (1.29 g, yield rate 47%). LC / MS ESI (m / z): 317 [M+H] + .

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

[0420] 4-[(4-cyclobutyl-1H-1,2,3-triazol-1-yl)methyl]- Synthesis of 5-iodo-2-methyl-2H-1,2,3-triazole [ka] (5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanol (900 mg, 4.00 mmol) in SOCl2 (5.8 mL, 80 mmol) The mixture was stirred at room temperature for 1 hour, and then cooled to 0°C with saturated aqueous NaHCO3 (20 mL). The organic layers were combined and extracted with anhydrous Na2SO4. Drying, filtration and concentration in vacuo gave a residue which was purified by flash chromatography (5 0% EtOAc in PE) to give 4-(chloromethyl)-5-iodo-2- Methyl-2H-1,2,3-triazole (900 mg, 87%) was obtained as a pale yellow oil. LC / MS (ESI) m / z: 258 [M+H] + .

[0421] 4-(chloromethyl)-5-iodo-2-methyl-2H-1,2,3-triazole ( Mixture of NaN3 (900 mg, 3.40 mmol) and NaN3 (454 mg, 6.90 mmol) The product in DMF (10 mL) was stirred at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (50 mL × 3). The organic layers were combined and washed with anhydrous Na2SO4. Drying, filtration and concentration in vacuo gave a residue which was purified by flash chromatography (5 Purification by PE (containing 0% EtOAc) and 4-(azidomethyl)-5-iodo-2-methyl Thiol-2H-1,2,3-triazole (880 mg, 95%) was obtained as a pale yellow oil.

[0422] 4-(azidomethyl)-5-iodo-2-methyl-2H-1,2,3-triazole ( 200mg, 0.75mmol), ethynylcyclobutane (182mg, 2.27mmol) l), CuSO4 (20 mg, 0.12 mmol), and sodium ascorbate (2 A mixture of 100 mg (0.10 mmol) of t-BuOH (10 mL) and HO (10 The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (40 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and purified. Concentration in air gave a residue which was purified by flash chromatography (D CM) and purified by 4-cyclobutyl-1-[(5-iodo-2-methyl-2H-1, 2,3-triazol-4-yl)methyl]-1H-1,2,3-triazole (100 mg, 38%) as a pale yellow oil. LC / MS ESI (m / z): 345 [ M+H] + .

[0423] (5-bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo-1-methyl Synthesis of (1H-imidazol-4-yl)methanol [ka] 4,5-diiodo-1H-imidazole (8.0 g, 25.01 mmol) and LiC To a suspension of 1000 ml (0.13 g, 3.13 mmol) in 50 mL of THF at -10 °C, Chilled magnesium (3M, 6.59 mL, 6.59 mmol) was added dropwise under a N2 atmosphere. The mixture was stirred at -10°C for 30 minutes. Then, isopropyl bromide was added to the mixture. Magnesium (1.3 M, 2.65 mL, 3.44 mmol) was added dropwise, and the resulting mixture was The mixture was stirred at room temperature for 1.5 hours, and then 5-bromo-1-ethyl-1H-pyridinium chloride was added to the mixture. 4-carbaldehyde (6.09 g, 30.0 mmol) was added at −10° C. The resulting mixture was stirred at room temperature for an additional 2 hours. (50 mL), extracted with EtOAc (3 x 50 mL), brine (30 mL ), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography. The product was purified by chromatography (silica gel, 0→30% MeOH in DCM) and (5- Bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo-1H-imidazole (4-yl)methanol was obtained as a white solid (3.5 g, yield: 35%). LC / MS (ESI) m / z: 397 [M+H] + .

[0424] (5-bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo-1H-imidazole) (4-( ... (60 mL) solution was added cesium carbonate (4.31 g, 13.2 mmol). The mixture was stirred at -10°C for 15 min. Then, the suspension was added with iodomethane (0.60 mL, 9.7 mmol) was added dropwise, and the resulting mixture was stirred at -10°C for 1.5 hours. The reaction mixture was then filtered, and the filtrate was diluted with water (50 mL) and extracted with EtOAc. The combined organic layers were concentrated and washed with saturated aqueous NH4Cl (3 x 30 mL). and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 → 10% MeOH in DCM ) and purified by (5-bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo) (1H-imidazol-4-yl)methanol was obtained as a white solid (9 03 mg, yield 25%). LC / MS (ESI) m / z: 411 [M+H] + .

[0425] (5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-iodo-1-methyl Synthesis of (1H-imidazol-5-yl)methanol [ka] 4,5-diiodo-1-methyl-1H-imidazole (2.00 g, 5.99 mmol) ) in DCM (100 mL) at -70 °C, mL, 6.59 mmol) was added dropwise under N2 atmosphere, and the mixture was heated at -70 °C for 30 min. The mixture was then added with 5-bromo-1-ethyl-1H-pyrazole-4-carboxylate. A solution of 1.34 g (6.59 mmol) of benzoyl aldehyde in 10 mL of DCM was added, and the resulting mixture was cooled to -7 The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL). Extracted with DCM (3 x 50 mL), washed with brine, dried over anhydrous Na2SO4, The residue was purified by silica gel column chromatography (30% EtOAc). c) and purified by PE (5-bromo-1-ethyl-1H-pyrazol-4-yl )(4-iodo-1-methyl-1H-imidazol-5-yl)methanol as a yellow oil (1.80 g, yield: 73%). LC / MS (ESI) m / z: 411 [ M+H] + .

[0426] (4-bromo-1-methyl-1H-pyrazol-3-yl)(1-(cyclopropylmethyl)methyl) Synthesis of (1H-pyrazol-4-yl)methanol [ka] 1-(cyclopropylmethyl)-4-iodo-1H-pyrazole (415 mg, 1.6 To a stirred solution of i-PrMgCl LiCl (1.3 mL) A 1.3 M THF solution (1.7 mmol) was added dropwise under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. After stirring, 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (316m g, 1.67 mmol) in THF (1 mL) was added at 0° C. The reaction was stirred at room temperature Stir for 2 h, quench with saturated NH4Cl (10 mL), and extract with EtOAc (10 mL). The residue was extracted with toluene, dried over Na2SO4, and concentrated to dryness. Purification by chromatography (PE: EtOAc = 1:1) and (4-bromo-1-methyl-1H -pyrazol-3-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl) Methanol (258 mg, 50% yield) was obtained as a yellow oil. LC / MS (ESI ) (m / z): 311 [M+H] + .

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

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

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

[0430] (5-ethyl-1,2-oxazol-3-yl)(5-iodo-2-methyl-2H- Synthesis of 1,2,3-triazol-4-yl)methanol [ka] 4-(5-ethyl-1,2-oxazole-3-carbonyl)-5-iodo-2-methyl Dibenzo-2H-1,2,3-triazole (310 mg, 0.93 mmol) in MeOH (2 To the mixture was added NaBH4 (35 mg, 0.93 mmol) and stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and extracted with EA. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1, V / V) and purified by (5-ethyl-1,2-oxazol-3-yl)(5-iodo -2-methyl-2H-1,2,3-triazol-4-yl)methanol (150 mg, 48.1%) as a pale yellow oil. LC / MS ESI (m / z): 335 [M +H] + .

[0431] The following intermediates were synthesized using similar experimental protocols: [Table 40] TIFF0007815341000227.tif244165TIFF0007815341000228.tif151165

[0432] 2-Ethyl-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-iodo Synthesis of 2H-1,2,3-triazole [ka] (1-ethyl-1H-pyrazol-4-yl)(2-ethyl-5-iodo-2H-1, 2,3-triazol-4-yl)methanol (190 mg, 0.547 mmol) D In a solution of CM (1 mL), EtSiH (191 mg, 1.64 mmol) and TFA (2 50 mg, 2.19 mmol) was added at 0°C, and then the mixture was stirred at 25°C for 2 hours. The mixture was concentrated and basified to pH 7 with saturated aqueous NaHCO3, then The combined organic layer was washed with brine (15 mL) and The residue was purified by flash chromatography (silica gel). Purification by column chromatography (10→50% EtOAc in PE) yielded 2-ethyl-4-[(1- Ethyl-1H-pyrazol-4-yl)methyl]-5-iodo-2H-1,2,3-trimethyl The azole (184 mg, 98% yield) was obtained as a pale yellow oil. LC / MS (ESI) m / z: 332.0 [M+H] + .

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

[0434] (3-cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H- Synthesis of 1,2,3-triazol-4-yl)methanol [ka] 4,5-diiodo-2-methyl-2H-1,2,3-triazole (1.1 g, 3.1 To a solution of 8 mmol) in THF (20 mL), isopropylmagnesium bromide (3.2 mL) ) was added at −15° C. The mixture was stirred for 1 hour, and then 3-cyclobutyl-1,2- Oxazole-5-carbaldehyde (400 mg, 2.65 mmol) in THF (10 m The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then rinsed with water. The mixture was quenched and extracted with EtOAc (100 mL). The combined EtOAc layers were purified with brine. The mixture was purified, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel. The product was purified by column chromatography eluting with MeOH in DCM (0% to 5%). 3-cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H-1, 2,3-Triazol-4-yl)methanol (420 mg, 44%) was obtained as a pale yellow oil. Ta. LC / MS (ESI): m / z = 361 [M+H] + .

[0435] The following intermediates were synthesized using similar experimental protocols: [Table 42] TIFF0007815341000233.tif53165

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

[0437] 4-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-5-iodo Synthesis of 2-methyl-2H-1,2,3-triazole [ka] (5-bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo-2-methyl -2H-1,2,3-triazol-4-yl)methanol (800 mg, 1.94 mm A mixture of TFA (5 mL) and TES (2.8 mL, 16 mmol) was added to 30 The mixture was stirred at 0° C. for 0.5 hours. The mixture was adjusted to pH 8 with NaHCO3 at 0° C., and then The combined organic phase was dried over anhydrous Na2SO4 and filtered. The residue was purified by flash chromatography on silica gel (30% EtOAc PE containing 4-[(5-bromo-1-ethyl-1H-pyrazole-4- yl)methyl]-5-iodo-2-methyl-2H-1,2,3-triazole (750m g, yield: 97%) as a pale yellow solid. LC / MS ESI (m / z): 39 6 [M+H] + .

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

[0439] 5-Bromo-1-(cyclopropylmethyl)-4-((5-iodo-1H-pyrazole Synthesis of (1-yl)methyl-3-methyl-1H-pyrazole [ka] 5-Bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4-carboxylate To a solution of methyl methyl ketone (1.00 g, 4.11 mmol) in THF (20 mL), DIBA LH (5.50 mL, 8.23 ​​mmol) was added dropwise to the reaction mixture at −78°C under N2. The mixture was stirred under N2 at -78°C for 2 hours. The reaction mixture was allowed to warm to room temperature. To the mixture was added saturated sodium potassium tartrate tetrahydrate solution, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine and anhydrous Na2 The residue was purified by flash column chromatography. This was purified and the resulting product was (5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazoline). (4-amino-4-yl)methanol (800 mg, 79%) was obtained as a white solid. LC / MS (ESI) m / z: 245 [M+H] + .

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

[0441] 5-Iodo-1H-pyrazole (662 mg, 3.42 mmol) and K2CO3 (1 A mixture of 5-bromo-4- (Chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole (9 A solution of 1000 mg (3.45 mmol) in DMF (1 mL) was added dropwise at 0° C. The mixture The mixture was stirred under N2 at 80 °C for 8 h. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated. Purification was carried out by flash column chromatography and further by SFC to obtain 5-bromo- Bromo-1-(cyclopropylmethyl)-4-((5-iodo-1H-pyrazol-1-yl) (1H-methyl)-3-methyl-1H-pyrazole (170 mg, 12%) was obtained as a colorless oil. Ta. LC / MS (ESI) m / z: 421 [M+H] + .

[0442] tert-Butyl 2-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)methyl Synthesis of ethyl)hydrazine-1-carboxylate [ka] tert-Butyl (E)-2-((5-bromo-1-ethyl-1H-pyrazole-4- (yl)methylene)hydrazine-1-carboxylate (4.71 g, 14.8 mmol) To a solution of AcOH (15 mL) and MeOH (10 mL), NaBH3CN (1.20 g) , 18.9 mmol) was added at room temperature, and the resulting mixture was stirred at 25° C. for 12 hours. After concentration under reduced pressure, the residue was dissolved in EtOAc and washed with aqueous Na2CO3 and brine. The residue was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (0→30% EtOAc in PE) was performed using tert-butyl ether. 2-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)hydrazine- The 1-carboxylate (3.5 g, 69% yield) was obtained as a white solid. ESI): m / z = 319 [M+H] + .

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

[0444] Synthesis of (R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate [ka] (1S)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (1.00 g, 3.76 mmol), benzoic acid (0.550 g, 4.51 mmol) and triphenyl To a mixture of 2,4-diaminobenzylphosphine (1.18 g, 4.51 mmol) in THF (30 mL), DIAD (0.89 mL, 4.5 mmol) was added dropwise under N2 at 0 °C. The resulting mixture The mixture was stirred at room temperature overnight, poured into water, and then extracted with EtOAc (50 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. Purify by chromatography (silica gel, 1-5% ethyl acetate in petroleum ether) , (1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (1.2 g , 86%) as a yellow solid. LC / MS (ESI): m / z = 371 [ M+H] + .

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

[0446] 1-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-5-iodo Synthesis of 4-(trimethylsilyl)-1H-1,2,3-triazole [ka] 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyrazole (1.20 g, 5 To a solution of CuI (1.12 g, 5.89 mmol) in MeCN (15 mL), l), DIPEA (760mg, 5.89mmol), NBS (1.05g, 5.89m mol) and ethynyltrimethylsilane (0.83 mL, 5.9 mmol) were added. The mixture was then degassed three times with N2 and stirred at 25 °C for 16 h. The residue was treated with ice water and EtOAc, the organic layer was separated and washed with brine. The residue was purified by flash chromatography. Purification by chromatography (silica gel, 0→20% MeOH in DCM) gave 1-[(5 -Bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-5-iodo-4-(trimethyl- (trimethylsilyl)-1H-1,2,3-triazole (320 mg, yield: 14%) Obtained as a colored oil. LC / MS (ESI) m / z: 454[M+H] + .

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

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

[0449] Under a N2 atmosphere, methyltriphenylphosphonium bromide (14.7 g, 41.1 mmol) A solution of 1,2-dichloro-2,4 ... After 15 minutes, 5-fluoro-2-iodoside (4.60 g, 41.1 mmol) was added. Dobenzaldehyde (8.60 g, 34.2 mmol) was added and the reaction mixture was heated at ambient temperature. The mixture was stirred at room temperature for 2 hours. Ice water (150 mL) was added and the mixture was extracted with EA (3 The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo at 25 °C. The residue was subjected to flash chromatography (0→20% EA in PE). The resulting product was purified by 2-ethenyl-4-fluoro-1-iodobenzene (10 g, yield: 118 %) was obtained as a colorless oil containing the solvent. LC / MS (ESI) m / z: 249 [M +H] + . 2-ethenyl-4-fluoro-1-iodobenzene (8.50 g, 34.3 mmol) In a solution of t-BuOH (75 mL) and HO (25 mL), N-methylmorpholine N- oxide (12.0 g, 51.4 mmol, 50% aqueous solution) and K2OsO4 2H2O (0.10 g, cat.) was added. The reaction was stirred at room temperature for 48 hours. The mixture was quenched by adding saturated aqueous Na2S2O3 solution. The mixture was stirred for another 4 hours. The mixture was extracted with EA (50 mL × 3) and anhydrous Na2SO4 The residue was purified by flash chromatography (0→100%). Purified by PE containing EA and purified by 1-(5-fluoro-2-iodophenyl)ethane-1 The 2-diol (6.1 g, yield: 63%) was obtained as a white solid. LC-MS ESI (m / z): 283 [M+H] +

[0450] 1-(5-fluoro-2-iodophenyl)ethane-1,2-diol (5.30 g, To a solution of imidazole (2.60 g, 37.6 mmol) in DMF (50 mL), mmol) and tert-butyldimethylsilyl chloride (3.00 g, 19.7 mmol) l) was added. The mixture was stirred at room temperature overnight, diluted with water and then extracted with EA ( The combined organic layers were washed with brine (50 mL) and extracted with anhydrous Na2SO4. It was dried, filtered and concentrated. The residue was purified by flash chromatography (0→50% EA PE containing 2-[(tert-butyldimethylsilyl)oxy]-1- (5-Fluoro-2-iodophenyl)ethan-1-ol was obtained (6.4 g, yield: 8 6%). LC-MS ESI (m / z): 397 [M+H] +

[0451] 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoro-2-iodo (3.0 g, 7.6 mmol) in THF (40.0 mL) ) solution, i-PrMgCl (14.6 mL, 18.9 mmol, 1.3 M) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 hour. Trimethyl borate (2.00 g, 18.9 (mmol) was added dropwise to this mixture at 0°C and stirring was continued at room temperature for 2 hours. It was quenched with aqueous NH4Cl and extracted with EA (3 x 30 mL). The residue was evaporated, washed with water, dried over anhydrous NaSO, filtered, and concentrated. The product was purified by column chromatography (0→100% PE containing EA) and 3-{[( tert-Butyldimethylsilyl)oxy]methyl}-5-fluoro-1,3-dihydro 1.3 g (yield: 58%) of 2,1-benzoxaborol-1-ol was obtained as a colorless oil. LC-MS ESI (m / z): 297 [M+H] + .

[0452] 5-Bromo-1-ethyl-4-(hydrazinylmethyl)-1H-pyrazole hydrochloride Growth [ka] tert-Butyl 2-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)methyl (ethyl)hydrazine-1-carboxylate (3.5 g, 11 mmol) in MeOH (15 To the solution of HCl in dioxane (10 mL, 4N) was added the reaction mixture. The mixture was stirred for 12 hours at 25° C. The mixture was concentrated under reduced pressure and the residue was triturated with PE. The resulting solid was collected by filtration, washed with PE and dried in vacuo to give 5-bromo-1- Ethyl-4-(hydrazinylmethyl)-1H-pyrazole hydrochloride (2.5 g, 89% yield) ) was obtained as a white solid. LC / MS (ESI): m / z = 219 [M+H] + .

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

[0454] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Synthesis of pyrazol-4-yl)prop-2-yn-1-ol [ka] 1-(2-bromo-4-fluorophenyl)prop-2-yn-1-ol (4.00 g, 17.5 mmol) and 3-chloro-1-ethyl-4-iodo-1H-pyrazole ( A mixture of Pd (4.90 g, 19.2 mmol) in triethylamine (40 mL) was (PPh3)2Cl2 (1.2 g, 1.7 mmol) and CuI (0.67 g, 3.5 mmol) mol) was added. The reaction was stirred under N2 at room temperature for 18 hours. Concentration in air was performed and the residue was purified by flash chromatography (0→50% EtOAc PE) and purified by 1-(2-bromo-4-fluorophenyl)-3-(3-chloro- 1-ethyl-1H-pyrazol-4-yl)prop-2-yn-1-ol (3.3 g, The product was obtained as a yellow oil in a 53% yield. LC / MS ESI (m / z): 357 [M+ H] + .

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

[0456] (R)-5-Fluoro-3-methylbenzo[c][1,2]oxaborole-1(3H Synthesis of )-ol [ka] (1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (300m g, 0.81 mmol) in methanol (8 mL) A solution of 10 mmol) in water (8 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was poured into water and then extracted with EtOAc (50 mL × 2). The residue was washed with water, dried over anhydrous Na2SO4, and concentrated. The (1R)- 1-(5-Fluoro-2-iodophenyl)ethan-1-ol (150 mg, 70%) was obtained as a white solid. LC / MS (ESI): m / z = 267 [M+H] + .

[0457] 1.3M THF solution of isopropylmagnesium chloride-lithium chloride complex (72.3 mL, 94.0 mmol) was added to (1R)-1-(5-fluoro-2-iodophenyl) ethoxylate Tan-1-ol (10.00 g, 37.59 mmol) in THF (120 mL) The mixture was stirred under N2 at -40 °C for 1 h, then After warming to -10 °C for an additional 0.5 h, trimethyl borate (10.67 mL, 93. 97 mmol) was added dropwise over 10 minutes at -10°C. After stirring overnight at room temperature under N2, The reaction mixture was poured into saturated NH4Cl solution (100 mL) and then extracted with EtOAc. (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, containing 1→10% EtOAc). The product was purified by PE (including PE) to give (R)-5-fluoro-3-methylbenzo[c][1,2]o Xaborol-1(3H)-ol (4.0 g, 64%) was obtained as a colorless oil. S (ESI): m / z = 167 [M+H] + .

[0458] 3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine synthesis [ka] 1-(5-fluoro-2-iodophenyl)ethan-1-ol (9.20 g, 34. To a solution of NaH (1.38 g, 34.6 mmol) in THF (180 mL) at 0 °C, ol, 60% mineral oil solution) was added in portions over 10 minutes. After the addition, the mixture was cooled to 0°C. Stir for 15 minutes, then add 3-fluoro-2-nitropyridine (4.91 g, 34.6 mm A solution of 100 ml of ethanol in 20 mL of THF was added dropwise. The ice bath was removed and the mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was partitioned between DCM (200 mL) and water (200 mL). The organic layer was separated, washed with brine and concentrated in vacuo. The residue was flash-coated. Purification by chromatography (0→30% EtOAc in PE) gave 3-(1-(5 -fluoro-2-iodophenyl)ethoxy)-2-nitropyridine (5.3 g, yield: 39%) as a white solid. LC / MS ESI (m / z): 389 [M+H ] +

[0459] The following intermediates were synthesized using similar experimental protocols: [Table 49] TIFF0007815341000252.tif239165TIFF0007815341000253.tif239165TIFF0007815341000254.t if239165TIFF0007815341000255.tif218165TIFF0007815341000256.tif239165TIFF0007815341 000257.tif239165TIFF0007815341000258.tif239165TIFF0007815341000259.tif228165TIFF00 07815341000260.tif239165TIFF0007815341000261.tif229165TIFF0007815341000262.tif69165

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

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

[0462] Ethyl 3-ethyl-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate Synthesis of silates [ka] Stir ethyl 2,4-dioxohexanoate (4.10 g, 23.8 mmol) in Ac In a solution of 33 mL of KOAc (5.83 g, 59.5 mmol) and [(4-methyl- (4.49 g, 23.8 mmol) of hydroxyphenylmethylhydrazine hydrochloride was added at 0°C. The reaction was stirred at 0° C. for 1 hour, and then the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (50 mL) and saturated N The residue was washed with HCl (50 mL), dried over anhydrous NaSO, and evaporated to dryness. was purified by silica gel column chromatography (10→25% EtOAc in PE) Purify and prepare ethyl 3-ethyl-1-[(4-methoxyphenyl)methyl]-1H-pyrazoline. The resulting product was methyl-5-carboxylate (3.8 g, 55%) as a yellow oil. LC / MS (E SI) (m / z): 289 [M+H] + .

[0463] tert-Butyl 2-((5-bromo-1-cyclobutyl-1H-pyrazole-4-yl) Synthesis of (methyl)hydrazinecarboxylate [ka] (E)-tert-butyl 2-((5-bromo-1-cyclobutyl-1H-pyrazole) (4-yl)methylene)hydrazinecarboxylate (3.14 g, 9.15 mmol) To a solution of this in MeOH (20 mL) was added acetic acid (20.0 mL, 349 mmol), followed by Then NaBH3CN (1.15 g, 18.3 mmol) was added at room temperature. After concentration, the residue was diluted with DCM and washed with saturated NaHCO3 and brine. The residue was washed with HCl, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by HPLC (silica gel, 0→100% PE containing EA) was performed. 2-((5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methyl) methyl Drazine carboxylate (2.65 g, 84%) was obtained as a colorless oil. LC / MS E SI (m / z): 345 [M+H] + .

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

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

[0466] 5-((5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methyl Synthesis of isoxazole-3-carboxamide [ka] Ethyl 5-[(5-iodo-2-methyl-2H-1,2,3-triazol-4-yl] )methyl]-1,2-oxazole-3-carboxylate (380 mg, 1.05 mm A solution of NH3 (5 mL, 25 mmol, 5N methanol) in MeOH (0.5 mL) was The resulting mixture was stirred at 60°C for 3 hours. The mixture was quenched with ice water and then diluted with EtOAc. The organic layer was separated and washed with saturated NH 4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0→40% EtOAc PE) and purified by 5-((5-iodo-2-methyl-2H-1,2,3-triazoline). (4-(4-yl)methyl)isoxazole-3-carboxamide (330 mg, 94%) was obtained as a yellow solid. LC / MS ESI (m / z): 334 [M+H] + .

[0467] 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2 -Amine synthesis [ka] (R)-3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine Lysine (15.5 g, 40.0 mmol), iron powder (22.4 g, 400 mmol) and N A mixture of HCl (21.6 g, 400 mmol) in EtOH (550 mL) and H The mixture was stirred at 80° C. for 1 h. After cooling to room temperature, the mixture was The residue was diluted with DCM (500 mL) and the It was then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification was performed by column chromatography on silica gel (50% EtOAc in PE). , 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2 The amine was obtained as a white solid (10.5 g, yield: 73%). LC / MS ESI ( m / z): 359 [M+H] + .

[0468] The following intermediates were synthesized using similar experimental protocols: [Table 52]

[0469] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Synthesis of pyrazol-4-yl)propan-1-one [ka] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Stirring DC (pyrazol-4-yl)propan-1-ol (3.3 g, 9.0 mmol) To a solution of M (50 mL) was added DMP (4.60 g, 10.8 mmol) at 0°C. The reaction was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was diluted with saturated NaHCO3 ( The mixture was washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (0→50% EtOAc in PE). 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1 H-pyrazol-4-yl)propan-1-one (2.06 g, 64% yield) as a yellow oil LC / MS ESI (m / z): 359 [M+H] + .

[0470] The following intermediates were synthesized using similar experimental protocols: [Table 53]

[0471] 5-(2-bromo-4-fluorophenyl)-4-((1-ethyl-1H-pyrazole Synthesis of (4-yl)methyl-2-methyloxazole [ka] Iodosobenzene (0.680 g, 3.07 mmol) and acetonitrile (15 mL To the solution of 1.15 g (7.68 mmol) of triflic acid was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then 1-(2-bromo-4-fluorophenyl)-3 -(1-ethyl-1H-pyrazol-4-yl)propan-1-one (1.00 g, 3. 07 mmol) was added. The mixture was stirred at 80°C for 16 hours. The reaction was saturated The reaction mixture was quenched with aqueous ammonium chloride and ice, concentrated, and diluted with DCM. This solution was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0→50% EA PE) and purified to give 5-(2-bromo-4-fluorophenyl)-4-[(1-ethyl -1H-pyrazol-4-yl)methyl]-2-methyl-1,3-oxazole (450 mg, 40% yield) as a white solid. LC / MS (ESI) m / z: 364 [M+H] + .

[0472] The following intermediates were synthesized using similar experimental protocols: [Table 54]

[0473] 3-Bromo-2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl) Synthesis of (methyl)-1H-pyrazol-5-yl)-5-fluoropyridine [ka] (E)-1-(3-bromo-5-fluoropyridin-2-yl)-3-(dimethylamino) (3.00 g, 11.0 mmol) in AcOH (20 m L) Solution of 5-bromo-1-ethyl-4-(hydrazinylmethyl)-1H-pyrazole Hydrochloride (2.81 g, 11.0 mmol) and sodium acetate (4.51 g, 54.9 mmol) mol) was added. The resulting mixture was stirred at 80°C for 16 hours. After concentration in vacuo, The residue was dissolved in DCM, then washed with water and brine, and dried over anhydrous Na2SO4 The residue was purified by flash chromatography on silica gel (0→4 0% EtOAc in PE) and purified to give 3-bromo-2-(1-((5-bromo-1 -ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-5-yl)-5 1.2 g, 25% yield. LC / MS E SI (m / z): 428 [M+H] + .

[0474] The following intermediates were synthesized using similar experimental protocols: [Table 55]

[0475] 5-Bromo-3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy] Synthesis of pyridin-2-amine [ka] 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2 A solution of the amine (21.0 g, 58.6 mmol) in HOAc (2000 mL) at 0 °C, N-Bromosuccinimide (12.52 g, 70.36 mmol) of HOAc (360 m L) solution was added dropwise over 30 minutes. After the addition, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated directly in vacuo and the residue purified by flash chromatography (0→20 5-Bromo-3-[(1R)-1-(5-fluorouracil]-2-yl]propanol] was purified by PE containing 100% EtOAc to give 5-bromo-3-[(1R)-1-(5-fluorouracil]-2-yl]propanol]. [fluoro-2-iodophenyl]ethoxypyridin-2-amine (10.5 g, yield 41 %) as a white solid. LC / MS ESI (m / z): 437 [M+H] + .

[0476] The following intermediates were synthesized using similar experimental protocols: [Table 56]

[0477] 5-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1-(4 Synthesis of (2-fluoro-iodophenyl)-1H-1,2,4-triazole [ka] 2-(5-Bromo-1-ethyl-1H-pyrazol-4-yl)acetamide (500 mg, 2.15 mmol) in DMF-DMA (3.46 mL, 25.9 mmol) The resulting mixture was stirred at 25° C. for 14 hours. The residue was concentrated by oil pump. ) Hydrazine HCl salt (712 mg, 3.02 mmol) in AcOH (10 mL) The mixture was stirred at 70° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was treated with saturated NaHCO3 (100 mL). The extract was then extracted twice with EA (70 mL). The combined extracts were concentrated and purified by flash chromatography. The product was purified by chromatography (0→80% PE containing EA) to give 5-[(5-bromo-1- Ethyl-1H-pyrazol-4-yl)methyl]-1-(4-fluoro-2-iodophenyl) (480 mg, 47%) of 1H-1,2,4-triazole was obtained as a white solid. . LC / MS (ESI): m / z = 476 [M+H] +

[0478] 1-(2-(1-((3-ethylisoxazol-5-yl)methyl)-1H-1, Synthesis of 2,4-triazol-5-yl-5-fluorophenylethan-1-ol [ka] 5-Bromo-1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-1H 1,2,4-triazole (260 mg, 1.01 mmol) in toluene (10 mL) Into the solution, 5-fluoro-3-methyl-1,3-dihydro-2,1-benzoxaborole -1-ol (250 mg, 1.52 mmol), Pd(PPh3)4 (0.12 g, 0 0.10 mmol), EtOH (5 mL) and aqueous Na2CO3 (2.0 mL, 4.0 m mol, 2.0 M) was added. The resulting mixture was charged twice with N2 and then The mixture was stirred at 0°C for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and then washed with water and brine. The residue was purified by silica gel column chromatography. Purification by chromatography (0→3% MeOH in DCM) gave 1-(2-{1-[( 3-Ethyl-1,2-oxazol-5-yl)methyl]-1H-1,2,4-triazo {5-yl}-5-fluorophenyl)ethan-1-ol (200 mg, yield: 6 3%) as a white solid. LC / MS ESI (m / z): 317 [M+H] + .

[0479] The following intermediates were synthesized using similar experimental protocols: [Table 57] TIFF0007815341000283.tif223165TIFF0007815341000284.tif244165TIFF00078153410 00285.tif234165TIFF0007815341000286.tif244165TIFF0007815341000287.tif244165 TIFF0007815341000288.tif203165TIFF0007815341000289.tif203165TIFF00078153410 00290.tif244165TIFF0007815341000291.tif213165TIFF0007815341000292.tif146165

[0480] 1-(2-(1-((3-ethylisoxazol-5-yl)methyl)-1H-tetrahydrofuran Synthesis of (5-hydroxyl-5-yl)-5-fluorophenyl)ethan-1-one [ka] 3-Ethyl-5-((5-(4-fluoro-2-iodophenyl)-1H-tetrazole (1.6 g, 4.0 mmol), tributyl ( 1-ethoxyethenyl)stannane (2.17 g, 6.01 mmol), CuI (80 mg , 0.40 mmol) and Pd(PPh3)4 (460 mg, 0.40 mmol) The product in toluene (20 mL) was stirred at 120 °C under N for 12 h. Diluted with CM (30 mL), then washed with water and brine, dried over Na2SO4, and filtered. The residue was purified by silica gel column chromatography (0→50% EA The residue was purified by PE (containing PE) to give a residue, which was dissolved in THF (30 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was stirred for 2 hours, adjusted to pH 8 with saturated aqueous NaHCO3, and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0→50% EA in PE). Purify and prepare 1-(2-(1-((3-ethylisoxazol-5-yl)methyl)-1H (1.0 g, yield)-tetrazol-5-yl)-5-fluorophenyl)ethan-1-one The product was obtained as a yellow oil in a 79% yield. LC / MS (ESI) m / z: 316 [M+H ] + .

[0481] The following intermediates were synthesized using similar experimental protocols: [Table 58]

[0482] (R)-5-Bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl) Synthesis of (ethoxy)pyridin-2-amine [ka] 5-Bromo-3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy] Pyridin-2-amine (4.60 g, 10.5 mmol) in toluene (200 mL) tetrakis(triphenylphosphine)palladium (1.36 g, 1.18 mmol) ) and hexamethyldistannane (2.40 mL, 11.6 mmol) were added to the mixture. The mixture was stirred at 110°C for 12 hours under N2 atmosphere. After cooling to room temperature, the mixture was The mixture was treated with aqueous KF and EtOAc, separated, and the organic layer was washed with brine and anhydrous N The residue was dried over Na2SO4, filtered, and concentrated. The product was purified by a cyclohexanediaminetetraacetic acid (PE:EA=10:1, V / V) to give the desired product (1.95 g, yield 39%) as a white solid. LC / MS ESI (m / z): 475 [M+ H] + .

[0483] The following intermediates were synthesized using similar experimental protocols: [Table 59]

[0484] 1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-5-(4 (2-fluoro-iodophenyl)-3-methyl-1H-1,2,4-triazole Growth [ka] 4-Fluoro-2-iodobenzoic acid (500 mg, 1.88 mmol), ethanimid Amide hydrochloride (0.25 mL, 2.8 mmol) and HATU (786 mg, 2.07 m mol) in DMF (10 mL), DIPEA (729 mg, 5.64 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then 5-bromo-1-ethyl-4-(hydroxybenzoate) was added. Razinylmethyl)-1H-pyrazole hydrochloride (722 mg, 2.82 mmol) and HO Ac (1.13 g, 18.8 mmol) was added, and stirring was continued at 80° C. for 3 hours. The mixture was diluted with DCM (60 mL) and then washed with saturated aqueous NaHCO3 and brine. The residue was washed, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by chromatography (PE:EA=1:1, V / V) to give 1-((5-bromo- 1-Ethyl-1H-pyrazol-4-yl)methyl)-5-(4-fluoro-2-iodo (phenyl)-3-methyl-1H-1,2,4-triazole (360 mg, yield: 39%) ) was obtained as a yellow solid. LC-MS (ESI): m / z 490 [M+H] + .

[0485] The following intermediates were synthesized using similar experimental protocols: [Table 60]

[0486] 5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4 (2-fluoro-iodophenyl)-3-methyl-1H-1,2,4-triazole Growth [ka] 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-N-(1-(dimethylamino)methyl) (amino)ethylidene)acetamide (760 mg, 2.02 mmol) in acetic acid ( 5 mL) solution, (4-fluoro-2-iodophenyl)hydrazine hydrochloride (801 mg (2.78 mmol) was added. The mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated in vacuo to remove AcOH, and the residue was washed with saturated aqueous NaHCO3. Basify to pH 8, extract with EtOAc (3 x 10 mL), and add brine (10 mL). The residue was washed, dried over anhydrous Na2SO4, filtered, and concentrated. The 5-((5 -bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro- 2-iodophenyl)-3-methyl-1H-1,2,4-triazole was obtained as an orange-red solid. (580 mg, yield: 59%). LC / MS ESI (m / z): 490 [ M+H] + .

[0487] 1-[(5-bromo-3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl ]-5-(4-fluoro-2-iodophenyl)-1H-1,2,4-triazole Growth [ka] 5-Bromo-3-chloro-1-ethyl-4-(hydrazinylmethyl)-1H-pyrazoline (2.70 g, 10.7 mmol), N-[(1E)-(dimethylamino)methylidene ]-4-fluoro-2-iodobenzamide (3.40 g, 10.7 mmol) and Na A mixture of OAc (3.50 g, 42.6 mmol) in AcOH (50 mL) was added to 90 The mixture was stirred at 5°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL). The organic layer was washed with an aqueous solution of NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (0→50% EtOAc in PE). and purified from 1-[(5-bromo-3-chloro-1-ethyl-1H-pyrazole-4-yl] [4-fluoro-2-iodophenyl]-1H-1,2,4-trimethyl-5-(4-fluoro-2-iodophenyl)-1H-trimethyl- The sol (1.5 g, 28%) was obtained as a pale yellow solid. LC / MS (ESI): m / z = 510 [M+H] + .

[0488] (R)-(1-ethyl-1H-pyrazol-4-yl)(4-(4-fluoro-2-( 1-Hydroxyethyl)phenyl)-1,2,5-thiadiazol-3-yl)methanone Synthesis of [ka] Methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (900mg , 4.04 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]ox Saborol-1(3H)-ol (700 mg, 4.04 mmol), Pd(dppf) A solution of Cl2 (16 mg, 0.022 mmol) in 1,4-dioxane (20 mL) and water (4 To the solution of 1 mL of potassium carbonate (1.12 g, 8.07 mmol) was added. The mixture was degassed with N2 three times and then stirred at 80 °C overnight. The solution was cooled and filtered, and the filtrate was diluted with water (20 mL) and adjusted to pH 3 with 1N aqueous HCl. The mixture was acidified with EA and extracted with EA (2 x 20 mL). The combined organic phase was washed with brine (20 mL). The residue was washed with HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The (R)-8- Fluoro-6-methyl-4H,6H-benzo[5,6]oxepino[3,4-c][1, 2,5]Thiadiazol-4-one (550 mg, 49%) was obtained as a white solid. / MS ESI (m / z): 251 [M+H] + .

[0489] 1-Ethyl-4-iodo-1H-pyrazole (352 mg, 1.58 mmol) TH To a solution of F (7 mL), isopropylmagnesium chloride-lithium chloride complex (1.27 mL , 1.65 mmol, 1.3 M THF solution) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. After 2 hours, (R)-8-fluoro-6-methyl-4H,6H-benzo[5,6]oxepide No[3,4-c][1,2,5]thiadiazol-4-one (285 mg, 1.14 mm ol) was added and the resulting mixture was stirred at room temperature for an additional hour. The mixture was quenched by adding saturated aqueous NH4Cl (5 mL) and EA (3 x 5 The combined organic phases were extracted with saturated aqueous NH4Cl (5 mL) and brine (5 mL). mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. was purified by flash chromatography (0→50% EtOAc in PE) R)-(1-ethyl-1H-pyrazol-4-yl)(4-(4-fluoro-2-(1- Hydroxyethyl)phenyl)-1,2,5-thiadiazol-3-yl)methanone(2 20 mg, 50%) was obtained as a yellow solid. LC / MS ESI (m / z): 347 [M+H] + .

[0490] 1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl )-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)ethan-1-ol Synthesis of phenanthrene [ka] 3-Bromo-2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl) Methyl)-1H-pyrazol-5-yl)-5-fluoropyridine (800 mg, 1.8 6 mmol) and tributyl(1-ethoxyvinyl)stannane (1.1 g, 2.8 mmol) To a solution of Pd(PPh3)4 (430 mg, 0.370 mmHg) in toluene (50 mL), ol) was added under N2. The resulting mixture was stirred at 100 °C under N2 for 8 hours. The mixture was cooled to room temperature and 1N aqueous HCl (20 mL) was added. The mixture was stirred at room temperature for 1 hour and then neutralized to pH 8 with saturated Na2CO3. The mixture was extracted with EA, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash chromatography on silica gel. The product was purified by chromatography (0→40% EtOAc in PE) to give 1-(2-(1- ((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazo (5-fluoropyridin-3-yl)ethan-1-one (200 mg, yield The compound was obtained as a yellow solid (yield 27%). LC / MS ESI (m / z): 392 [M+ H] + .

[0491] The following intermediates were synthesized using similar experimental protocols: [Table 61]

[0492] 3-chloro-1-((3-ethyl-1-(4-methoxybenzyl)-1H-pyrazole Synthesis of (5-yl)methyl-5-iodo-1H-pyrazole [ka] {3-ethyl-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-5-yl To a solution of {methyl}methanol (2.57 g, 10.4 mmol) in DCM (30 mL), l2 (1.89 mL, 26.044 mmol) was added dropwise at 0 °C. Then, the reaction mixture The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and The mixture was neutrali...

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, Q is CH or N; Z is CR ５ or N, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, imidazolylene, isothiazolylene, triazolylene, and pyrrolylene, and the 5-membered heteroarylene is selected from the group consisting of 0, 1, or 2 R ２ is replaced by Y is a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroarylene is selected from the group consisting of 0, 1, or 2 R ３ is replaced by in Y, the points of attachment to the methylene groups bonded to X and Y and to the aromatic ring containing Z are on adjacent atoms, and the ring atom of the 5- to 6-membered heteroarylene that is alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring containing Z is nitrogen; R １ is selected from the group consisting of H, methyl, and hydroxymethyl; R ２ Each instance of 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 selected from the group consisting of cycloalkyl, and 3- to 6-membered heterocycloalkyl; R ３ Each instance of is independently H, halo, CN, C １－４ Alkoxy, halo-C １－４ Alkyl, and C １－４ is selected from the group consisting of alkyl, R ４ and R ５ each is independently H or F; X is 【Chemistry 2】 where R 2 is not H, but ＊ indicates the point of attachment of X to the methylene group attached to X and Y, and The compound is 【Transformation 3】 or a pharmaceutically acceptable salt thereof, or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. Compounds of formula (I) 【Chemistry 4】 (In the formula, Q is CH or N; Z is CR ５ or N, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, imidazolylene, isothiazolylene, triazolylene, and pyrrolylene, and the 5-membered heteroarylene is selected from the group consisting of 0, 1, or 2 R ２ is replaced by Y is 1, 2 ＊ -substituted imidazolylene, 4 ＊ ,5-substituted imidazolylene, 4,5 ＊ -substituted imidazolylene, 4 ＊ ,5-substituted 1,2,3-oxadiazolylene, 3 ＊ ,4-substituted 1,2,5-oxadiazolylene, 3 ＊ , 4-substituted 1,2-oxazolylene, 4 ＊ , 5-substituted 1,3-oxazolylene, 2 ＊ , 3-substituted pyrazinylene, 1 ＊ , 5-substituted pyrazolylene, 3 ＊ , 4-substituted pyrazolylene, 3 ＊ , 4-substituted pyridazinylene, 2 ＊ , 3-substituted pyridinylene, 4 ＊ , 5-substituted pyrimidinylene, 2 ＊ , 3-substituted pyrrolylene, 5 ＊ ,6-substituted 1,2,3,4-tetrazinylene, 1 ＊ ,5-substituted 1,2,3,4-tetrazolylene, 1,5 ＊ -substituted 1,2,3,4-tetrazolylene, 4 ＊ ,5-substituted 1,2,3-thiadiazolylene, 3 ＊ ,4-substituted 1,2,5-thiadiazolylene, 3 ＊ , 4-substituted 1,2-thiazolylene, 4 ＊ ,5-substituted 1,3-thiazolylene, 4 ＊ ,5-substituted 1,2,3-triazinylene, 5 ＊ ,6-substituted 1,2,4-triazinylene, 5,6 ＊ -substituted 1,2,4-triazinylene, 1 ＊ ,5-substituted 1,2,3-triazolylene, 4 ＊ ,5-substituted 1,2,3-triazolylene, 1 ＊ ,5-substituted 1,2,4-triazolylene, 1,5 ＊ -substituted 1,2,4-triazolylenes, and 3 ＊ , 4-substituted 1,2,4-triazolylene, wherein the heteroarylene is selected from the group consisting of 0, 1, or 2 R ３ is replaced by ＊ indicates the point of attachment of Y to the methylene groups attached to X and Y, in Y, the heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring containing Z is nitrogen; R １ is selected from the group consisting of H, methyl, and hydroxymethyl; R ２ Each instance of 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 selected from the group consisting of cycloalkyl, and 3- to 6-membered heterocycloalkyl; R ３ Each instance of is independently H, halo, CN, C １－４ Alkoxy, halo-C １－４ Alkyl, and C １－４ is selected from the group consisting of alkyl, R ４ and R ５ each is independently H or F; X is 【Transformation 5】 where R 2 is not H, * indicates the point of attachment of X to the methylene group bonded to X and Y, and The compound is 【Transformation 6】 or a pharmaceutically acceptable salt thereof, or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. X is a 5-membered heteroarylene selected from the group consisting of: 【Transformation 7】 (In the formula, ＊ indicates the point of attachment of X to the methylene group attached to X and Y, and R ２ Each instance of 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 3. The compound of claim 1 or 2, wherein the aryl group is selected from the group consisting of cycloalkyl, and 3- to 6-membered heterocycloalkyl.

4. Y is a heteroarylene selected from the group consisting of 【Transformation 8】 (In the formula, ＊ indicates the point of attachment of Y to the methylene groups attached to X and Y, and R ３ H, halo, CN, C １－４ Alkoxy, halo-C １－４ Alkyl, and C １－４ The compound of any one of claims 1 to 3, wherein the aryl group is selected from the group consisting of alkyl.

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 of any one of claims 1 to 5, wherein is H.

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

8. The compound is a compound of formula (IB) 【Chemistry 9】 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. (i) R ２ each instance of is independently selected from the group consisting of H, chloro, CN, methyl, ethyl, isobutyl, methoxy, trifluoromethyl, cyclopropylmethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, and oxetanyl; and / or (ii) R ３ is independently selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl. The compound according to any one of claims 1 to 8.

10. A compound of any of the following formulas: Table 1 3. A compound according to claim 1 or 2, or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. A compound of the following: Table 2 or a pharmaceutically acceptable salt thereof.

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

13. A compound according to any one of claims 1 to 11 or 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

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

15. The solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus tumor, cholangiocarcinoma, and neuroblastoma, or 15. The pharmaceutical composition of claim 14, wherein the hematological malignancy is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

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

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

18. The pharmaceutical composition of claim 13, wherein the cancer is Spitz nevoid melanoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, papillary thyroid carcinoma, or serous ovarian carcinoma.

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

20. The pharmaceutical composition according to any one of claims 13 to 18, wherein the cancer is ALK (anaplastic lymphoma kinase)-positive cancer.

21. The pharmaceutical composition of any one of claims 13 to 19, wherein the cancer comprises expression of an oncogenic ROS1 gene or an oncogenic ROS1 gene fusion.

22. 22. The pharmaceutical composition of claim 21, wherein the oncogenic ROS1 gene or oncogenic ROS1 gene fusion comprises one or more mutations of the human ROS1 gene.

23. the one or more mutations in the oncogenic ROS1 gene or oncogenic ROS1 gene fusion, (i) a ROS1 protein having a mutation at L1951, L1982, S1986, F2004, L2026, G2032, D2033, F2075, or G2101, or a combination thereof, is expressed; (ii) expressing a ROS1 protein having an L1951R, L1982F, S1986F, F2004C, F2004V, L2026M, G2032R, D2033N, F2075V, or G2101A mutation, or a combination thereof; (iii) a ROS1 protein having a G2032R mutation is expressed; or 23. The pharmaceutical composition of claim 22, wherein the composition expresses (a) a ROS1 fusion protein selected from the group consisting of CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1, and CEP85L-ROS1, and / or (b) a ROS1 protein having an L1982F, S1986F, F2004C, F2004V, L2026M, G2032R, D2033N, or G2101A mutation, or a combination thereof.

24. The pharmaceutical composition according to any one of claims 13 to 18 and 20, wherein the cancer comprises expression of an oncogenic ALK gene or an oncogenic ALK gene fusion.

25. 25. The pharmaceutical composition of claim 24, wherein the oncogenic ALK gene or the oncogenic ALK gene fusion comprises one or more mutations in the human ALK gene.

26. the one or more mutations in the oncogenic ALK gene or oncogenic ALK gene fusion, (i) (a) an ALK fusion protein selected from the group consisting of EML4-ALK and NPM1-ALK, and / or (b) an ALK protein having a G1202R, L1196M, L1198F, G1269A, D1203N, or I1171N mutation, or a combination thereof, is expressed; (ii) expresses an ALK protein with one or more mutations at I1171, L1196, L1198, G1202, D1203, or G1269, or a combination thereof; or 26. The pharmaceutical composition of claim 25, wherein (iii) an ALK protein having one or more mutations selected from the group consisting of G1202R, L1196M, L1198F, G1269A, D1203N, and I1171N is expressed.

27. A pharmaceutical composition for selectively inhibiting ROS1 or ALK over TRK, wherein the inhibition is carried out in a subject suffering from cancer, and the pharmaceutical composition comprises a compound or 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition for use in a method for reducing the level of ROS1 or ALK in a cell, comprising a compound according to any one of claims 1 to 11 or 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition of any one of claims 13 to 28, for use in combination with one or more further therapeutic agents.

30. (i) the additional therapeutic agent is a TKI, and optionally the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, or ensartinib; or 30. The pharmaceutical composition of claim 29, wherein (ii) the additional therapeutic agent is a chemotherapeutic agent, a cancer immunotherapeutic agent, an SH2 inhibitor, a MEK inhibitor, a MET inhibitor, an SHP2 inhibitor, an anti-PD-1 agent, or a RAS inhibitor.

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

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