Heteroaromatic macrocyclic ether chemotherapeutic agents

Abstract

The present application relates to heterocyclic heteroaromatic macrocyclic ether compounds of general formula (I), pharmaceutically acceptable salts of said compounds, and pharmaceutical compositions thereof. The compounds are selective inhibitors of ROS1 and / or ALK and are useful in the treatment or prevention of cancer. # imgabs0 #

Description

[0001] 1. Cross-reference to related applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 417,368, filed on October 19, 2022, the entire contents of which are incorporated herein by reference. 2. Background technology

[0003] Receptor tyrosine kinase (RTK) is a cell surface enzyme that receives external signals (such as whether to grow and divide) and transmits these signals inside the cell through kinase activity. Many RTKs are proto-oncogenes; abnormal RTK activity can drive cell survival, growth and proliferation, leading to cancer and related conditions. This abnormal kinase activity may be caused by mutations (such as activating mutations in the kinase domain), gene rearrangements (leading to fusion proteins containing complete kinase domains), amplification and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB), NTRK3 (encoding TRKC).

[0004] ROS1 is a RTK proto-oncogene, wherein ROS1 rearrangement is detected in non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma and spitzoid melanoma. Oncogenic ROS1 gene fusion contains the kinase domain of ROS1 (3' region) fused with the 5' region of multiple partner genes. Examples of ROS1 fusion partner genes observed in NSCLC include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (presumed), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8 and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (putative), EEF1G, KIF21A (putative), KLC1, SART3, ST13 (putative), TRIM24 (putative), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0005] ALK is an RTK proto-oncogene, and ALK rearrangements have been detected in many cancers, including NSCLC, anaplastic large cell lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, papillary thyroid cancer, and Spitz nevus tumors, as well as ALK activating mutations detected in neuroblastoma. Oncogenic ALK gene fusions contain the kinase domain (3' region) of ALK fused to the 5' region of more than 20 different partner genes, the most common being EML4 in NSCLC and NPM in ALCL. Other partner genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B.

[0006] NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes encoding TRK family kinases, and chromosomal rearrangements of NTRK1, NTRK2 and NTRK3 are detected at low frequencies in many cancers. However, for the treatment of ROS1-positive or ALK-positive patients, TRK inhibition (especially in the central nervous system (CNS)) is associated with adverse reactions, including dizziness / ataxia / gait disorders, paresthesia, weight gain and cognitive changes.

[0007] Existing drugs for the treatment of oncogenic ROS1 and ALK have significant deficiencies. These deficiencies may represent one or more of the following: associated TRK inhibition, limited CNS activity, and insufficient activity against antagonistic mutations. Treatment of ROS1-positive or ALK-positive patients with concomitant TRK inhibition has been associated with adverse effects, particularly in the CNS, including dizziness / ataxia / gait disturbance, paresthesias, weight gain, and cognitive changes. Additionally, there is a need for CNS penetrants and TRK sparing inhibitors of wild-type ROS1 kinase domains and ROS1 with acquired resistance mutations, which occur alone or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. Likewise, there is a need for CNS penetrants and TRK sparing inhibitors of ALK with acquired resistance mutations. A variety of ALK resistance mutations have been reported, either alone or in combination, including G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. 3. Summary of the invention

[0008] In one embodiment, provided herein is a compound of formula (I):

[0009]

[0010] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q, Z, L, X, Y, R 1 and R 4 As defined herein or elsewhere.

[0011] In one embodiment, provided herein is a pharmaceutical composition suitable for treating or preventing cancer in a subject, comprising an effective amount of any compound described herein (e.g., a compound provided herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation can be used to treat or prevent an illness or disease as described herein.

[0012] In one embodiment, provided herein is a method for treating a cancer characterized by one or more mutations in the ROS1 or ALK gene, comprising administering to a subject in need thereof an effective amount of a compound provided herein (e.g., a compound of formula (I) or any embodiment thereof provided 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 an inhibitor of ROS1 and ALK. In some aspects, human subjects need such treatment. In one embodiment, without being bound by a particular theory, one or more compounds provided herein selectively inhibit ALK mutations rather than TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the ALK mutation is I1171X 1 (X 1 is N, S or T) and / or D1203N.

[0013] These cancers include, but are not limited to, non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, Spitz nevus melanoma, glioblastoma, bile duct cancer, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, papillary thyroid cancer, and neuroblastoma.

[0014] In some embodiments, methods of treating or preventing cancer may comprise administering a compound of Formula (I) in combination with one or more other chemotherapeutic agents. 4. Specific implementation methods

[0015] 4.1 Definition

[0016] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art in the field of the present disclosure. The following references provide general definitions of many terms used in the present disclosure to technicians: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise indicated, the following terms have the following meanings assigned to them.

[0017] In some embodiments, chemical structures and corresponding chemical names are disclosed. In the event of a conflict, the chemical structure, rather than the name, controls the meaning.

[0018] As used herein and unless otherwise specified, "comprises," "comprises," "containing," and "having," etc. may have the meanings ascribed to them in U.S. Patent Law, and may mean "includes," "including," etc.; "consisting essentially of" or "consisting essentially of" also have the meanings ascribed to them in U.S. Patent Law, and the terms are open-ended, allowing for more than what is listed, as long as the basic or novel features of the listed contents are not substantially altered by the presence of more than what is listed, but do not include implementations of the prior art.

[0019] Unless specifically stated or obvious from the context, as used herein, the term "or" should be understood as inclusive. Unless specifically stated or obvious from the context, as used herein, the terms "a / an" and "the" should be understood as singular or plural.

[0020] As used herein, stereoisomers refer to various stereoisomeric forms of compounds containing one or more asymmetric centers or sterically hindered structures. In some embodiments, stereoisomers are enantiomers, mixtures of enantiomers, atropisomers, mixtures of atropisomers, tautomers thereof, or mixtures of tautomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer (e.g., atropisomers), or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. In some embodiments, compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers produced due to hindered rotation around a single bond, wherein energy differences due to steric strain or other factors produce sufficiently high rotational barriers to allow separation of a single conformer. Stereoenantiomers may be separated from a mixture by methods known to those skilled in the art (including the formation and crystallization of chiral high pressure liquid chromatography (HPLC) and chiral salts); or in one embodiment, preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Additionally provided herein are compounds in the form of individual isomers that are substantially free of other isomers and alternatively in the form of mixtures of various isomers.

[0021] The term "acyl" is art recognized and refers to a group represented by the general formula hydrocarbylC(O)-, and in one embodiment, alkylC(O)-.

[0022] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0023] The term "acyloxy" is art recognized and refers to a group represented by the general formula hydrocarbyl C(O)O-, and in one embodiment, alkyl C(O)O-.

[0024] The term "alkoxy" refers to an alkyl group, in one embodiment a lower alkyl group, attached to an oxygen. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0025] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, and may be represented by the general formula alkyl-O-alkyl.

[0026] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond, and is intended to include "unsubstituted alkenyl" and "substituted alkenyl", the latter referring to an alkenyl moiety having a substituent replacing a hydrogen on one or more carbons of the alkenyl. Such substituents may appear on one or more carbons that may or may not be contained in one or more double bonds. In addition, unless stability is limited, as described below, these substituents include all substituents considered for alkyl. For example, it is contemplated that alkenyl is substituted by one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl.

[0027] "Alkyl" or "alkane" is a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, unless otherwise defined, a straight or branched chain alkyl group has 1 to about 20 carbon atoms, and in one embodiment 1 to about 10 carbon atoms. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl. 1 -C 6 A straight chain or branched chain alkyl group is also referred to as a "lower alkyl group".

[0028] In addition, as used throughout the specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone. If not otherwise indicated, such substituents may include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that, where appropriate, the moieties substituted on the hydrocarbon chain may themselves also be substituted. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonate), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF 3, -CN, etc. Exemplary substituted alkyl groups are described below. The cycloalkyl group may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl, -CF 3 , -CN, etc.

[0029] The term "C x-y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing from x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups containing x to y carbons in the chain, including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. 0 Alkyl represents hydrogen where the group is in terminal position, or internally, a bond. 2-y "Alkenyl" and "C 2-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively.

[0030] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0031] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and can be represented by the general formula alkylS-.

[0032] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing hydrogen on one or more carbons of the alkynyl. Such substituents may appear on one or more carbons that are included or not included in one or more triple bonds. In addition, unless stability is limited, such substituents include all substituents contemplated for alkyl groups as discussed above. For example, it is contemplated that alkynyl groups are substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

[0033] As used herein, the term "amide" refers to a group

[0034]

[0035] Each R 30 independently represent hydrogen or a hydrocarbon group, or two R 30 Together with the N atom to which they are attached they form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0036] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, such as the moiety represented by the formula

[0037]

[0038] Each R 31 independently represent hydrogen or a hydrocarbon group, or two R 31 Together with the N atom to which they are attached they form a heterocycle having 4 to 8 atoms in the ring structure. As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0039] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0040] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each ring atom is carbon. In one embodiment, the ring is a 5-7 ring, in one embodiment a 6-ring. The term "aryl" also includes a polycyclic system with two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0041] The term "carbamate" is art-recognized and refers to a group,

[0042]

[0043] Where R 32 and R 33 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R 32 and R 33 Together with the intervening atoms, a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0044] As used herein, the terms "carbocycle" and "carbocyclic" refer to a saturated or unsaturated ring in which each ring atom is carbon. The term carbocycle includes aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, in which at least one double bond is contained.

[0045] The term "carbocycle" includes 5-7 membered monocycles and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with another ring. Each ring of the fused carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). As long as valence permits, any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. "Carbocycle" may be substituted at any position or positions capable of carrying a hydrogen atom.

[0046] "Cycloalkyl" is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, unless otherwise defined, monocyclic cycloalkyl has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms. The second ring of a bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with another ring. The second ring of a fused bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds.

[0047] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0048] As used herein, the term “C 3-4 "Cycloalkylmethyl" refers to a methyl group substituted by a carbocyclic group containing 3 to 4 carbon atoms.

[0049] The term "carbonate" is art-recognized and refers to the group -OCO 2 -R 34 , where R 34 It represents a hydrocarbon group.

[0050] As used herein, the term "carboxyl" refers to a group of the formula -CO 2 The group represented by H.

[0051] As used herein, the term "ester" refers to the group -C(O)OR 35 , where R35 It represents a hydrocarbon group.

[0052] As used herein, the term "ether" refers to a hydrocarbyl group connected to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. An ether may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0053] As used herein, the terms "halo," and "halogen" refer to halogen, and include chloro, fluoro, bromo, and iodo.

[0054] As used herein, the terms "heteroaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

[0055] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein the two heteroatoms are non-adjacent.

[0056] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, in one embodiment 5 to 7 rings, in one embodiment 5 to 6 rings, whose ring structure includes at least one heteroatom, in one embodiment one to four heteroatoms, in one embodiment one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems with two or more rings, wherein two or more carbons are common to two adjacent rings, wherein at least one ring is heteroaromatic, for example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine etc.

[0057] The asterisk (*) symbol on the heteroarylene ring portion corresponding to X or Y in the compounds of formula (I) represents the portion of the ring atom that is bonded to the L group between X and Y, as exemplified below:

[0058]

[0059] For example, "1*,5-substituted imidazolyl" for Y means substituted:

[0060]

[0061] As shown above, throughout the specification, the IUPAC numbering rules for heteroarylene rings are used to specify the positions of ring atoms. In this example, the 1-position of the imidazolyl group is bonded to the L group and is thus denoted by an asterisk. The asterisk symbol is used in the names and structures of the heteroaryl groups for X and Y. Here, for Y, the ring atom at the 5-position is not marked because it is bonded to the ring carrying the variable R 4 and is thus denoted by an asterisk. The asterisk symbol is used in the names and structures of the heteroaryl groups for X and Y. Here, for Y, the ring atom at the 5-position is not marked because it is bonded to the ring carrying the variable R

[0062] For X, an exemplary ring would be a "1,5*-substituted imidazolyl" as shown below.

[0063]

[0064] In the names and structures of the ring X heteroarylene, the ring atoms (in this example, the 5-position) bonded to the L group are all denoted by an asterisk. The ring atoms bonded to the aromatic ring carrying Q are not marked.

[0065] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. In one embodiment, the heteroatom is nitrogen, oxygen, and sulfur.

[0066] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, which in one embodiment are 3- to 10-membered rings, in one embodiment 3- to 7-membered rings, whose ring structures contain at least one heteroatom, which in one embodiment contains one to four heteroatoms, and in one embodiment contains one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic systems having two or more rings, where two or more carbons are common to two adjacent rings, where at least one ring is heterocyclic, e.g., the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0067] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group.

[0068] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom, which group does not have =O or =S substituents and generally has at least one carbon-hydrogen bond and a predominantly carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups for the purposes of this application, but substituents such as acetyl (which has an =O substituent on the linking carbon) and ethoxy (which is linked through oxygen rather than carbon) are not hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0069] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0070] When used in connection with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, the term "lower" is meant to include groups in which there are ten or fewer, in one embodiment six or fewer non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms, in one embodiment six or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitation of hydroxyalkyl and aralkyl (in which case, for example, when counting the carbon atoms in the alkyl substituent, the atoms in the aryl are not counted).

[0071] The terms "polycyclic group", "polycycle" and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic), where two or more atoms are common to two adjacent rings, e.g., the rings are "fused". Each ring of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains 3 to 10 atoms in the ring, in one embodiment 5 to 7.

[0072] The term "silyl" refers to a silicon moiety bonded to three hydrocarbon moieties.

[0073] The term "substituted" refers to a substituent having a hydrogen substitution on one or more carbons of the skeleton. It should be understood that "substituted" or "substituted" includes implicit restrictive conditions, i.e., such substitutions meet the allowed valences of the atoms and substituents substituted, and the substitutions produce stable compounds, for example, they do not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all allowed substituents of organic compounds. In a broad sense, allowable substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, allowable substituents can be one or more and the same or different. As used herein and unless otherwise indicated, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any allowable substituents of organic compounds described herein that meet heteroatomic valences. Substituents may include any substituent described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that, where appropriate, the substituent itself may be substituted. Unless specifically stated as "unsubstituted", chemical moieties referred to herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variants.

[0074] The term "sulfate" is art-recognized and refers to the group -OSO 3 H, or a pharmaceutically acceptable salt thereof.

[0075] The term "sulfonamide" is art-recognized and refers to a group represented by the general formula

[0076]

[0077] Where R 36 and R 37 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R 36 and R 37 Together with the intervening atoms, a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0078] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 38 , where R 38 It represents a hydrocarbon group.

[0079] The term "sulfonate" is art-recognized and refers to the group SO3 H, or a pharmaceutically acceptable salt thereof.

[0080] The term "sulfone" is art-recognized and refers to the group -S(O) 2 -R 39 , where R 39 It represents a hydrocarbon group.

[0081] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0082] As used herein, the term "thioester" refers to the group -C(O)SR 40 or -SC(O)R 40 , where R 10 It represents a hydrocarbon group.

[0083] As used herein, the term "thioether" is equivalent to an ether in which the oxygen is replaced by sulfur.

[0084] The term "urea" is art-recognized and can be represented by the general formula

[0085]

[0086] Where R 41 and R 42 independently represent hydrogen or a hydrocarbon group, such as an alkyl group, or R 41 The emergence of R 42 Together with the intervening atoms, a heterocyclic ring is formed having 4 to 8 atoms in the ring structure.

[0087] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of the functional group. Typically, during the synthesis, the protecting group can be selectively removed as needed. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd edition, 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vol. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), etc. Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxy group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

[0088] In certain embodiments, provided herein are compounds that can be racemic. In certain embodiments, provided herein are compounds that may be enriched in one enantiomer. For example, provided herein are compounds that may have greater than about 30%ee, about 40%ee, about 50%ee, about 60%ee, about 70%ee, about 80%ee, about 90%ee or even about 95% or greater ee. In certain embodiments, provided herein are compounds that may have more than one stereocenter. In certain such embodiments, provided herein are compounds that may be enriched in one or more diastereomers. For example, provided herein are compounds that may have greater than about 30%de, about 40%de, about 50%de, about 60%de, about 70%de, about 80%de, about 90%de or even about 95% or greater de.

[0089] In certain embodiments, therapeutic preparations can be enriched to mainly provide one enantiomer of a compound (e.g., a compound of formula (I)). A mixture rich in enantiomers may include, for example, at least about 60 mol % of one enantiomer, or in one embodiment at least about 75, about 90, about 95 or even about 99 mol %. In certain embodiments, a compound rich in one enantiomer is substantially free of another enantiomer, wherein "substantially free" means that the substance in question accounts for less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, as compared to the amount of another enantiomer in, for example, a composition or a mixture of compounds. For example, if a composition or a mixture of compounds contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, it can be said that it contains about 98 mol % of the first enantiomer and only about 2% of the second enantiomer.

[0090] In certain embodiments, the therapeutic preparation can be enriched to provide primarily one diastereomer of a compound (e.g., a compound of formula (I)). A diastereomerically enriched mixture can contain, for example, at least about 60 mol % of one diastereomer, or in one embodiment at least about 75, about 90, about 95, or even about 99 mol %.

[0091] In some embodiments, a portion of a compound exists as a mixture of tautomers. A "tautomer" is a structural isomer of a portion or compound that is easily interconverted with another structural isomer. For example, a pyrazole ring has two tautomers:

[0092]

[0093] They differ in the position of pi bonds and hydrogen atoms. Unless specifically stated otherwise, a drawing of one tautomer of a moiety or compound includes all possible tautomers.

[0094] The term "subject" intended for administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds, including commercially relevant birds, such as chickens, ducks, geese, quail and / or turkeys. In one embodiment, the subject is a human.

[0095] As used herein, the therapeutic agent of "preventing" a disease or illness refers to a compound that, in a statistical sample, reduces the incidence of a disease or illness in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a disease or illness relative to an untreated control sample or reduces its severity. These effects are also referred to as "preventive" effects. Therefore, as used herein and unless otherwise indicated, the term "prevention (prevention / preventing)" refers to a method for obtaining a beneficial or desired result, including but not limited to a preventive benefit. For preventive benefit, a therapeutic agent can be administered to a patient at risk of suffering from a specific disease or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease may not yet be made. In one embodiment, a therapeutic agent is administered before the clinical manifestation of an unwanted disease (e.g., a disease or other unwanted state of a subject) to obtain a preventive benefit (e.g., it protects the subject from suffering from an unwanted disease).

[0096] As used herein and unless otherwise indicated, the term "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, overall or partial alleviation of symptoms associated with a disease or disorder or patient, reduction in disease extent, a stable (i.e., non-worsening) disease state, a delay or slowing of disease progression, an improvement or alleviation of the disease state, and relief (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonged survival, such as compared to expected survival when not receiving treatment. In one embodiment, "treatment" includes administering a therapeutic agent after the occurrence of an unwanted disorder (i.e., intended to alleviate, improve, or stabilize an existing unwanted disorder or its side effects).

[0097] As used herein and unless otherwise indicated, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth, including solid tumors (named after the cell type that forms them), blood cancers, bone marrow cancers, or cancers of the lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemias, lymphomas, and myelomas. Cancers include, but are not limited to, primary cancers that originate from a specific site in the body, metastatic cancers that spread from the primary site to other parts of the body, recurrences after the initial primary cancer has remitted, and second primary cancers (i.e., new primary cancers of a different type from the previous cancer in people with a history of previous cancer).

[0098] As used herein and unless otherwise indicated, "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous). In some embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0099] In some embodiments, the abnormal cell growth is a cancer mediated by anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK is a genetically altered ALK. In other embodiments, the abnormal cell growth is a cancer mediated by ROS1 kinase. In some such embodiments, the ROS1 kinase is a genetically altered ROS1 kinase. In some embodiments, the abnormal cell growth is a cancer, specifically NSCLC. In some such embodiments, NSCLC is mediated by ALK or ROS1. In specific embodiments, the cancer is NSCLC mediated by genetically altered ALK or genetically altered ROS1.

[0100] As used herein and unless otherwise indicated, the term "managing" encompasses preventing recurrence of a particular disease or condition in a patient already suffering from that disease or condition, prolonging the time a patient already suffering from that disease or condition maintains remission, reducing mortality in a patient, and / or maintaining a reduction in the severity of symptoms or avoiding symptoms associated with the disease or condition being managed.

[0101] The term "prodrug" is intended to include compounds (e.g., compounds of formula (I)) that can be converted to therapeutic agents provided herein under physiological conditions. Common methods for preparing prodrugs will include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohol or formic acid) are prodrugs provided herein. In certain embodiments, some or all of the compounds of formula (I) in the formulations shown above can be replaced with corresponding suitable prodrugs, for example, wherein the hydroxyl group in the parent compound is present in the form of an ester or carbonate or formic acid.

[0102] 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 therapeutic effect. For example, a therapeutically effective amount may refer to an amount sufficient to ameliorate at least one sign or symptom of cancer.

[0103] A "response" to a treatment method can include a decrease or improvement in negative symptoms, a slowing of progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, partial or complete cure of the disease, etc.

[0104] As used herein and unless otherwise indicated, the term "relapse" refers to a condition, disease or disorder that responded to (eg, achieved a complete response) a previous treatment and then progressed. The previous treatment may include one or more therapies.

[0105] As used herein, and unless otherwise indicated, the term "refractory" refers to a condition, disease, or disorder that has not responded to previous treatment including one or more therapies.

[0106] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in connection with a dose, amount or weight percentage of a composition or dosage form ingredient means a dose, amount or weight percentage that one of ordinary skill in the art considers to provide a pharmacological effect equivalent to that obtained by a specified dose, amount or weight percentage. In certain embodiments, the terms "about" and "approximately" when used in this context encompass doses, amounts or weight percentages within 30%, within 20%, within 15%, within 10% or within 5% of a specified dose, amount or weight percentage.

[0107] The term "between" includes the endpoint numbers on both ends of the range. For example, the range described by "between 3 and 5" includes the numbers "3" and "5".

[0108] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable" refers to salts that are suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1–19. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benthamine, benzathine, betaine, calcium hydroxide, choline, danol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, salts of Na, Ca, K, Mg, Zn, or other metals.

[0109] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be derived from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental to such solvent.

[0110] Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camphorsulfonate, carbonate, chloride, citrate, caprate, edetate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, caproate, hydroxy naphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, caprylate, oleate, palmitate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, theophyllinate, and toluenesulfonate.

[0111] 4.2 Compounds

[0112] In one embodiment, the present disclosure provides a compound of formula (I):

[0113]

[0114] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

[0115] Q is CH or N;

[0116] Z is CR 5 or N;

[0117] L is -CH 2 -, C═O or -O-;

[0118] X is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein said 5-membered heteroaryl group is substituted with 1, 2, or 3 R 2 substituents;

[0119] Y is a 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein said 5-membered or 6-membered heteroaryl group is substituted with 0, 1, or 2 R 3 substituents;

[0120] R 1 is selected from the group consisting of H, methyl, and hydroxymethyl;

[0121] Each R 2 is independently selected from the group consisting of: H, CN, halo, -CO-C 1-4 alkyl, 5-membered heteroaryl, C 1-4 alkyl-SO-, C 1-4 alkyl-SO 2 -, C 1-4Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 Heterocyclyl; provided that, when L is -CH 2 -, at least one R 2 for -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -; and wherein the heteroaryl, cycloalkyl, heterocyclyl or alkyl group is further allowed to be substituted by 0, 1, 2 or 3 C 1-4 Alkyl or halogen substituted;

[0122] Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted;

[0123] Each R° is independently H or C 1-4 alkyl;

[0124] Each R 3 are independently selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl; and

[0125] R 4 and R 5 are each independently H or F.

[0126] In one embodiment, provided herein is a compound of formula (I):

[0127]

[0128] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein:

[0129] Q is CH or N;

[0130] Z is CR 5 or N;

[0131] L is -CH 2 -, C=O or -O-;

[0132] X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein said 5-membered heteroarylene is substituted with 1, 2 or 3 R 2 substituents;

[0133] Y is a heteroarylene selected from the group consisting of: 2*,3-substituted furanylene, 2,3*-substituted furanylene, 3*,4-substituted furanylene, 1*,2-substituted imidazolyl, 1*,5-substituted imidazolyl, 1,5*-substituted imidazolyl, 4,5*-substituted 1,2,3-oxadiazolyl, 3,4*-substituted 1,2-oxazolyl, 4*,5-substituted 1,2-oxazolyl, 4,5*-substituted 1,2-oxazolyl, 4,5*-substituted 1,3-oxazolyl, 1*,2-substituted phenylene, 1,5*-substituted pyrazolyl, 4*,5-substituted pyrazolyl, 3,4*-substituted pyridazinyl, 4*,5-substituted pyridazinyl, 2,3*-substituted pyridinyl, 3*,4-substituted pyridinyl, 3,4*-substituted pyridinyl, 4,5*-substituted pyrimidinyl, 1*,2-substituted pyrrolyl, 1,2*-substituted pyrrolyl, 2,3*-substituted pyrrolyl, 3*,4-substituted pyrrolyl, 4,5*-substituted 1,2,3-thiadiazolyl, 3,4*-substituted 1,2-thiazolyl, 4*,5-substituted 1,2-thiazolyl, 4,5*-substituted 1,2-thiazolyl, 4*,5-substituted 1,3-thiazolyl, 4,5*-substituted 1,3-thiazolyl, 2*,3-substituted thiophenylene, 2,3*-substituted thiophenylene, 3*,4-substituted thiophenylene, 4,5*-substituted 1,2,3-triazinyl, 4*,5-substituted triazolyl, 1,5*-substituted 1,2,3-triazolyl, 4*,5-substituted 1,2,3-triazolyl, 1*,5-substituted 1,2,4-triazolyl, 1,5*-substituted 1,2,4-triazolyl and 3,4*-substituted 1,2,4-triazolyl;

[0134] wherein the heteroarylene is substituted with 0, 1 or 2 R 3 substituents;

[0135] * represents the point of attachment of X or Y to the L group bonded to X and Y;

[0136] R 1 is selected from the group consisting of H, methyl and hydroxymethyl;

[0137] Each R 2are independently selected from the group consisting of: H, CN, halogen, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO 2 -、C 1-4 Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 Heterocyclic group; provided that, when L is -CH 2 -, at least one R 2 for -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -; and wherein the heteroaryl, cycloalkyl, heterocyclyl or alkyl group is further allowed to be substituted by 0, 1, 2 or 3 C 1-4 Alkyl or halogen substitution;

[0138] Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substitution;

[0139] Each R ° are independently H or C 1-4 alkyl;

[0140] Each R 3 are independently selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl; and

[0141] R 4 and R 5 are each independently H or F.

[0142] In one embodiment, provided herein is a compound of formula (I):

[0143]

[0144] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein:

[0145] Q is CH or N;

[0146] Z is CR 5 or N;

[0147] L is -CH 2 -, C=O, -CH(OH)-, or -O-;

[0148] X is a 5-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene group is surrounded by 1, 2 or 3 R 2 replace;

[0149] Y is a 5-membered or 6-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered or 6-membered heteroarylene group is surrounded by 0, 1 or 2 R 3 replace;

[0150] R 1 Selected from the group consisting of H, methyl and hydroxymethyl;

[0151] Each R 2 are independently selected from the group consisting of: H, CN, halogen, -SC 1-4 Alkyl, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO 2 -、C 1-4 Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 Heterocyclyl; provided that, when L is -CH 2 -, at least one R 2 for -CO-C 1-4 Alkyl, 5-membered heteroaryl, -SC 1-4 Alkyl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -; and wherein the heteroaryl, cycloalkyl, heterocyclyl, alkoxy or alkyl group is further allowed to be substituted by 0, 1, 2 or 3 C 1-4Alkyl, Si(C 1-4 alkyl) 3 or halogen substitution;

[0152] Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted;

[0153] Each R ° are independently H or C 1-4 alkyl;

[0154] Each R 3 are independently selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl; and

[0155] R 4 and R 5 are each independently H or F.

[0156] In one embodiment, Si(C 1-4 alkyl) 3 Si(Me) 3 .

[0157] In some embodiments, L is -CH 2 -. In some embodiments, L is C=O. In some embodiments, L is -O-. In some embodiments, L is -CH(OH)-. In some embodiments, L is -CH(OH)-, and the carbon has S chirality. In some embodiments, L is -CH(OH)-, and the carbon has R chirality.

[0158] In one embodiment, the compound is of formula (IA):

[0159]

[0160] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula (IA-1):

[0161]

[0162] or a pharmaceutically acceptable salt thereof.

[0163] In one embodiment, the compound is of formula (IA-2):

[0164]

[0165] or a pharmaceutically acceptable salt thereof.

[0166] In one embodiment, the compound is of formula (IB):

[0167]

[0168] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula (IB-1):

[0169]

[0170] or a pharmaceutically acceptable salt thereof.

[0171] In one embodiment, the compound is of formula (IB-2):

[0172]

[0173] or a pharmaceutically acceptable salt thereof.

[0174] In one embodiment, the compound is of formula (IC):

[0175]

[0176] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula (IC-1):

[0177]

[0178] or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the compound is of formula (IC-2):

[0180]

[0181] or a pharmaceutically acceptable salt thereof.

[0182] In one embodiment, the compound is of formula (ID):

[0183]

[0184] or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula (ID-1):

[0185]

[0186] or a pharmaceutically acceptable salt thereof.

[0187] In one embodiment, the compound is of formula (ID-1-1):

[0188]

[0189] or a pharmaceutically acceptable salt thereof.

[0190] In one embodiment, the compound is of formula (ID-1-2):

[0191]

[0192] or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment, in Y, the points of attachment to the L group bonded to X and Y and to the aromatic ring containing Z are on adjacent atoms, and the 5- to 6-membered heteroarylene ring atom that is alpha to the point of attachment to the L group and beta to the point of attachment to the aromatic ring containing Z is nitrogen.

[0194] In one embodiment, in Y, the points of attachment to the L group bonded to X and Y and to the aromatic ring containing Z are on adjacent atoms, and the 5- to 6-membered heteroarylene ring atom that is alpha to the point of attachment to the L group and beta to the point of attachment to the aromatic ring containing Z is carbon, oxygen or sulfur.

[0195] In some embodiments, X is a 5-membered heteroaryl selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is selected from the group consisting of 4*,5-substituted pyrazolylene, 4,5*-substituted pyrazolylene, 1*,5-substituted pyrazolylene, 4*,5-substituted isoxazolylene, 3*,4-substituted isoxazolylene, 3*,4-substituted isothiazolylene, 4*,5-substituted isothiazolylene, 4*,5-substituted imidazolylene, 1*,5-substituted imidazolylene, 1*,5-substituted triazolylene, and 4*,5-substituted triazolylene.

[0196] In some embodiments, X is a 5-membered heteroaryl selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is selected from the group consisting of 4*,5-substituted pyrazolylene, 4,5*-substituted pyrazolylene, 1*,5-substituted pyrazolylene, 4*,5-substituted isoxazolylene, 4,5*-substituted isoxazolylene, 3*,4-substituted isoxazolylene, 3*,4-substituted isothiazolylene, 4*,5-substituted isothiazolylene, 4,5*-substituted isothiazolylene, 4*,5-substituted imidazolylene, 1*,5-substituted imidazolylene, 1*,5-substituted triazolylene, and 4*,5-substituted triazolylene.

[0197] In one embodiment, X is a 5-membered heteroaryl selected from the group consisting of 3*,4-substituted pyrazolylene, 4*,5-substituted pyrazolylene, 4,5*-substituted pyrazolylene, 1*,5-substituted pyrazolylene, 4*,5-substituted imidazolylene, 1*,5-substituted imidazolylene or 4*,5-substituted triazolylene, wherein * represents the point of attachment of X or Y to the L group bonded to X and Y.

[0198] In certain embodiments, X is selected from the group consisting of:

[0199]

[0200] * represents the point of attachment of X to the L group bonded to X and Y.

[0201] In certain embodiments, X is selected from the group consisting of:

[0202]

[0203] * represents the point of attachment of X to the L group bonded to X and Y.

[0204] In one embodiment, X is pyrazolylene. In one embodiment, X is not 3*,4-substituted pyrazolylene. In one embodiment, X is not In one embodiment, X is not In one embodiment, X is In one embodiment, X is In another embodiment, X is 3*,4-substituted pyrazolylene. In another embodiment, X is 4*,5-substituted pyrazolylene. In another embodiment, X is 4,5*-substituted pyrazolylene. In another embodiment, X is 1*,5-substituted pyrazolylene. In one embodiment, X is In one embodiment, X is In one embodiment, X is In one embodiment, X is

[0205] In one embodiment, X is And the R at the ** position 2 for -SC 1-4 Alkyl, CN, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -.

[0206] In one embodiment, X is isoxazolylene. In one embodiment, X is 4*,5-substituted-isoxazolylene. In one embodiment, X is 4,5*-substituted-isoxazolylene. In one embodiment, X is 3*,4-substituted-isoxazolylene. In one embodiment, X is In one embodiment, X is

[0207] In one embodiment, X is isothiazolylene. In one embodiment, X is 3*,4-substituted isothiazolylene. In one embodiment, X is 4*,5-substituted isothiazolylene. In one embodiment, X is 4,5*-substituted isothiazolylene. In one embodiment, X is In one embodiment, X is

[0208] In one embodiment, X is imidazolylidene. In one embodiment, X is 4*,5-substituted imidazolylidene. In one embodiment, X is 1*,5-substituted imidazolylidene. In one embodiment, X is

[0209] In one embodiment, X is triazolylene. In one embodiment, X is 1*,5-substituted triazolylene. In one embodiment, X is 4*,5-substituted triazolylene. In one embodiment, X is In one embodiment, X is

[0210] In some embodiments, X is replaced by 0 R 2 In one embodiment, X is replaced by 1 R other than H. 2 In one embodiment, X is replaced by 2 R 2 replace.

[0211] In some embodiments, at least one R 2 (For example, one and only one R 2 ) are independently selected from the group consisting of: H, CN, halogen, C 1-4 Alkoxy, C 1-4 Alkyl, -SC 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 In some embodiments, at least one R 2 (For example, one and only one R 2 ) are independently selected from the group consisting of H, fluorine, chlorine, CN, methyl and ethyl. In some embodiments, at least one R 2 (For example, one and only one R 2 ) are independently selected from the group consisting of CN and methyl. In some embodiments, there are two R 2 , one of which R 2 is CN and the other R 2 It is methyl.

[0212] In some embodiments, at least one R 2 (For example, one and only one R 2 )for In some embodiments, at least one R 2 (For example, one and only one R 2 )for In some embodiments, at least one R 2 (For example, one and only one R 2 )for In some embodiments, at least one R 2 (For example, one and only one R 2 ) is -CO-C 1-4 Alkyl (e.g. -C(=O)-CH 3 ). In some embodiments, at least one R 2 (For example, one and only one R 2 ) is a 5-membered heteroaryl. In some embodiments, at least one R 2(For example, one and only one R 2 ) is C 1-4 Alkyl-SO- (e.g., -SO-CH 3 ). In some embodiments, at least one R 2 (For example, one and only one R 2 ) is C 1-4 Alkyl-SO 2 -(For example, -SO 2 -CH 3 ).

[0213] In some embodiments, an R 2 Is it 1, 2 or 3 Cs? 1-4 In some embodiments, one R 2 It was a C 1-4 A 5-membered heteroaryl group substituted with an alkyl group (eg, a methyl group).

[0214] In some embodiments, R n is H. In some embodiments, R n In some embodiments, R n In some embodiments, R n In some embodiments, R n In some embodiments, R n -CH 2 CF 3 In some embodiments, two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted.

[0215] In some embodiments, R ° is H. In some embodiments, R ° It is methyl.

[0216] In some embodiments, each R 2 Independently selected from CN, -CH 2 -cyclopropyl, -CH 2 CH 2 OCH 3 , -CO 2 Et, methyl, ethyl, -C(=O)-N(CH 3 ) 2 、-C(=O)-N(CH 3 ) i Pr, -C(=O)-N(CH 3)Et, -C(=O)-NH 2 、-C(=O)-N(CH 3 )(CH 2 CF 3 )、-C(=O)-N(CH 3 )(cyclopropyl), -C(=O)-CH 3 、-C(=O)-N(CH 3 )-OCH 3 , CH 2 -O(CH 2 ) 2 -Si(CH 3 ) 3 、-CH 2 -cyclobutyl, CH 2 -cyclopropyl, -(CH 2 ) 2 -OCH 3 , -SO-CH 3 and-SO 2 -CH 3 .

[0217] In some embodiments, Y is a 5-membered heteroarylene group comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered heteroarylene group is surrounded by 0, 1, or 2 R 3 In some embodiments, Y is a 6-membered heteroarylene group comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 6-membered heteroarylene group is replaced by 0, 1, or 2 R 3In some embodiments, Y is a heteroarylene group selected from the group consisting of 2*,3-substituted furanylene, 2,3*-substituted furanylene, 3*,4-substituted furanylene, 1*,2-substituted imidazolylene, 1*,5-substituted imidazolylene, 1,5*-substituted imidazolylene, 4,5*-substituted 1,2,3-oxadiazolylene, 3,4*-substituted 1,2-oxazolylene, 4* ,5-substituted 1,2-oxazolylene, 4,5*-substituted 1,2-oxazolylene, 4,5*-substituted 1,3-oxazolylene, 1*,2-substituted phenylene, 1,5*-substituted pyrazolylene, 4*,5-substituted pyrazolylene, 3,4*-substituted pyridazinylene, 4*,5-substituted pyridazinylene, 2,3*-substituted pyridinylene, 3*,4-substituted pyridinylene, 3,4* -substituted pyridinylene, 4,5*-substituted pyrimidinylene, 1*,2-substituted pyrrolylene, 1,2*-substituted pyrrolylene, 2,3*-substituted pyrrolylene, 3*,4-substituted pyrrolylene, 4,5*-substituted 1,2,3-thiadiazolylene, 4*,5-substituted 1,2-thiazolylene, 4,5*-substituted 1,2-thiazolylene, 4*,5-substituted 1,3-thiazolylene substituted 1,2,3-triazinylene, 1,5*-substituted 1,2,3-triazolylene, 4,5*-substituted triazolylene and 3,4*-substituted 1,2,4-triazolylene; wherein the heteroarylene is replaced by 0, 1 or 2 R 3 In some embodiments, Y is selected from the group consisting of 1*,5-substituted pyrazolylene, 3*,4-substituted pyrazolylene, 2,3*-substituted pyridinylene, 3*,4-substituted pyridinylene, 3,4*-substituted pyridinylene, 4,5*-substituted 1,3-thiazolylene, 4*,5-substituted 1,2,3-triazolylene, 1*,5-substituted 1,2,4-triazolylene, 1,5*-substituted 1,2,4-triazolylene, and 4*,5-substituted 1,3-thiazolylene, wherein * represents the point of attachment to L bonded to X.

[0218] In certain embodiments, Y is selected from the group consisting of:

[0219]

[0220] * represents the point of attachment of Y to the L group bonded to X and Y.

[0221] In certain embodiments, Y is * represents the point of attachment of Y to the L group bonded to X and Y.

[0222] In certain embodiments, Y is a 5-membered heteroarylene. In certain embodiments, Y is a pyrazolylene. In certain embodiments, Y is a 1,5*-substituted pyrazolylene. In certain embodiments, Y is a 4*,5-substituted pyrazolylene. In certain embodiments, Y is a 3,4*-substituted pyrazolylene. In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is

[0223] In certain embodiments, Y is imidazolylidene. In certain embodiments, Y is 1*,2-substituted imidazolylidene. In certain embodiments, Y is 5*,1-substituted imidazolylidene. In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is

[0224] In certain embodiments, Y is 1,2-thiazolylene. In certain embodiments, Y is 3,4*-substituted 1,2-thiazolylene. In certain embodiments, Y is 4*,5-substituted 1,2-thiazolylene. In certain embodiments, Y is In certain embodiments, Y is

[0225] In certain embodiments, Y is 1,3-thiazolylene. In certain embodiments, Y is 4,5*-substituted 1,3-thiazolylene. In certain embodiments, Y is In certain embodiments, Y is 4*,5-substituted 1,3-thiazolylene. In certain embodiments, Y is

[0226] In certain embodiments, Y is 1,2-oxazolylene. In certain embodiments, Y is 3,4*-substituted 1,2-oxazolylene. In certain embodiments, Y is 4*,5-substituted 1,2-oxazolylene. In certain embodiments, Y is In certain embodiments, Y is

[0227] In certain embodiments, Y is triazolylene. In certain embodiments, Y is 1,5*-substituted 1,2,3-triazolylene. In certain embodiments, Y is 3,4*-substituted 1,2,4-triazolylene. In certain embodiments, Y is In certain embodiments, Y is

[0228] In certain embodiments, Y is a 6-membered heteroarylene. In certain embodiments, Y is a pyridylene. In certain embodiments, Y is a 2,3*-substituted pyridylene. In certain embodiments, Y is a 3*,4-substituted pyridylene. In certain embodiments, Y is a 4*,3-substituted pyridylene. In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is In certain embodiments, Y is

[0229] In certain embodiments, Y is pyrimidinylene. In certain embodiments, Y is 4,5*-substituted pyrimidinylene. In certain embodiments, Y is

[0230] In certain embodiments, Y is replaced by 0 R 3 In certain embodiments, Y is replaced by 1 R other than H. 3 In certain embodiments, Y is replaced by 2 R 3 replace.

[0231] In certain embodiments, R 3 Selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 In certain embodiments, R 3 is not H. In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 For CN.

[0232] In some embodiments, Q is CH. In other embodiments, Q is N.

[0233] In some embodiments, Z is CR 5 In a specific embodiment, R 5 is H. In a specific embodiment, R 5 In other embodiments, Z is N.

[0234] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is hydroxymethyl.

[0235] In some embodiments, R 4 is H. In other embodiments, R 4 For F.

[0236] In one embodiment of Formula (IB), (IB-1) or (IB-2), X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In another embodiment, X is And Y is In one embodiment, R 2 Selected from the group consisting of: H, methyl, ethyl, CN, -C(=O)-N(CH 3 ) 2 , methoxyethyl, isopropyl and cyclopropylmethyl. In one embodiment, R 3 is selected from the group consisting of H and methyl. 1 Selected from the group consisting of H and methyl.

[0237] In one embodiment, the compound is a compound of any of the following formulae:

[0238]

[0239]

[0240] or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, the compounds in Table 1 are provided herein:

[0241] Table 1.

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] or a pharmaceutically acceptable salt thereof.

[0249] In certain embodiments, the compounds in Table 1A are provided herein:

[0250] Table 1A.

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, the compounds in Table 1B are provided herein:

[0259] Table 1B.

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] or a pharmaceutically acceptable salt thereof.

[0267] For any compound in Table 1, Table 1A or Table 1B that has a chiral center due to the presence of a non-hydrogen R 1 , the R-enantiomer, S-enantiomer and racemic compound of this compound are specifically provided herein, even if not specifically shown in Table 1, Table 1A or Table 1B.

[0268] In certain embodiments, pharmaceutically acceptable salts of the compounds of formula (I) are provided herein. In certain embodiments, pharmaceutically acceptable salts of any compound in Table 1, Table 1A or Table 1B are provided herein.

[0269] In certain embodiments, the pharmaceutically acceptable salts of the compound are selected from the group consisting of alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, dimethylethanolamine salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts and Zn salts.

[0270] In a specific embodiment, the pharmaceutically acceptable salt is a solvate selected from the group consisting of water, methanol, ethanol and dimethylformamide.

[0271] In certain embodiments, the compound is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0272] In a specific embodiment, the form of the composition is selected from the group consisting of tablets, capsules, granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, transdermal delivery systems and solutions suitable for topical administration.

[0273] 4.3 Method of Use

[0274] Methods for treating cancer are provided herein, which comprise administering a compound provided herein, such as a compound of formula (I) or a stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof.

[0275] Cancer is a disease of uncontrolled cell proliferation caused by changes in certain genes. Some of these changes occur in genes encoding receptor tyrosine kinases (RTKs), which are membrane-bound protein families that can transmit signals from outside the cell to promote cell survival, growth and proliferation. Abnormal RTK activation can cause excessive cell growth, thereby causing cancer. Typically, RTK contains an N-terminal domain, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction in conjunction with an extracellular ligand.

[0276] In some embodiments, the compound of formula (I) is an inhibitor of human ROS1. ROS1 is an RTK encoded by the ROS1 gene. The ligands and biological functions of human ROS1 are unclear, but its homologs in some other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is necessary for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are a well-documented cause of cancer, accounting for 1-2% of non-small cell lung cancer (NSCLC) and a subset of many other cancers. These rearrangements result in the fusion of the C-terminus of ROS1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity, which drives tumor growth through MAPK, PI3K and JAK / STAT signaling pathways. Small molecule tyrosine kinase inhibitors (TKIs) have been used to target ROS1 fusions in cancer, including crizotinib and entrectinib. Crizotinib is the first FDA-approved TKI for the treatment of ROS1-positive NSCLC, with an overall response rate of 60-80% and a median progression-free survival of 9-19 months. Despite initial responses, most patients develop resistance to crizotinib and relapse. The main resistance mechanism is the G2032R mutation on the solvent front, which significantly reduces the affinity of crizotinib. The FDA has not yet approved an inhibitor that is active against the ROS1-G2032R fusion, indicating that there is a need in this area.

[0277] In some embodiments, the compound of formula (I) is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is an RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily and their kinase domains share approximately 80% sequence similarity. Although the role of ALK in humans is still inconclusive, a large amount of evidence from mouse studies indicates that it is essential for the development of the nervous system. Like ROS1, ALK chromosomal rearrangements can also lead to constitutively active fusion proteins that promote oncogenic transformation through MAPK, JAK / STAT or other signaling pathways. ALK rearrangements account for 3-5% of NSCLC, roughly half of anaplastic large cell lymphoma (ALCL), and a subset of many other cancers, with the most predominant fusions being EML4-ALK in NSCLC and NPM1-ALK in ALCL. Oncogenic point mutations and ALK amplifications have also been observed, although their frequency is much lower than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for the treatment of ALK-positive NSCLC and other cancers and can be used as first-line therapy or after previous therapy. For example, crizotinib shows an overall response rate of 60-80% and a median progression-free survival of 8-11 months, which is comparable to its activity in ROS1-positive NSCLC. For the above FDA-approved TKIs, despite initial responses, many resistance mutations have emerged. Some of these mutations, such as a combination of the L1196M gatekeeper mutation and the G1202R solvent front mutation, are resistant to all approved drugs. There is a need in the art for new treatments for ALK-positive cancers with resistance mutations.

[0278] In other embodiments, the compound of formula (I) is an inhibitor of human tropomyosin receptor kinase (TRK). The TRK family includes receptor tyrosine kinases TRKA, TRKB and TRKC, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Each TRK is activated by a set of different but overlapping neurotrophic factor ligands such as NGF, BDNF and NT-3. All TRKs regulate similar downstream signaling pathways, consistent with sequence divergence in the ligand binding domain but convergence in the kinase domain (90% similarity). TRK plays an important role in the nervous system of developing and adult mammals by regulating processes such as memory, movement, pain and proprioception. Like ROS1 and ALK, NTRK rearrangement produces constitutively active TRK fusions that drive carcinogenic transformation through MAPK, PI3K and other pathways. TRK fusions have been found in many cancers and account for more than 80% of cases in secretory breast cancer, breast-like secretory carcinoma, infantile fibrosarcoma and congenital mesodermal nephroma. Therefore, inhibition of TRK is beneficial for treating cancers expressing TRK fusions.

[0279] Many existing ROS1 and ALK inhibitors also show effective inhibition of native non-oncogenic TRKs. This is a substantial disadvantage because native TRKs play important functions in the nervous system and unintentional inhibition of native TRKs is associated with adverse reactions including dizziness, ataxia, gait disorders, paresthesias, weight gain, and cognitive changes. There is a need in the art for new therapies that selectively target non-mutated and / or mutated forms of ROS1 and / or ALK without damaging TRKs.

[0280] In certain embodiments, provided herein is a method for reducing ROS1 or ALK levels in a cell, comprising contacting the cell with a compound or pharmaceutical composition or drug combination provided herein. In one embodiment, such contact occurs in a mammal (such as a human) cell. In one embodiment, such contact occurs in a human patient suffering from a cancer provided herein.

[0281] In certain embodiments, the compound selectively inhibits ROS1 but not TRK (e.g., TRKA, TRKB and / or TRBC). As non-limiting examples, the selectivity ratio can be greater than about 5 times, greater than about 10 times, greater than about 50 times, greater than about 100 times, greater than about 200 times, greater than about 400 times, greater than about 600 times, greater than about 800 times, greater than about 1000 times, greater than about 1500 times, greater than about 2000 times, greater than about 5000 times, greater than about 10,000 times, or greater than about 20,000 times, wherein the selectivity can be measured by IC 50 In some embodiments, the selectivity of ROS1 relative to TRK is measured by the IC 50 Values ​​and IC for ROS1 50 Measured as a ratio of values.

[0282] In certain embodiments, the compounds provided herein selectively inhibit ALK. In certain embodiments, the compounds selectively inhibit ALK but not ROS1. As non-limiting examples, the ratio of selectivity can be greater than a factor of about 1.5, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, or greater than a factor of about 10, wherein the selectivity can be measured by IC 50 In some embodiments, the selectivity of ALK for ROS1 is measured by the IC 50 Values ​​and IC against ALK 50 It is measured by the ratio of values.

[0283] In certain embodiments, the compound selectively inhibits ALK but not TRK (e.g., TRKA, TRKB and / or TRBC). As non-limiting examples, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, or greater than a factor of about 10,000, where selectivity can be measured by a ratio of IC50 values, etc. In certain embodiments, the selectivity of ALK over TRK is measured by the ratio of IC50 values ​​for TRK. 50 Values ​​and IC against ALK 50 It is measured by the ratio of values.

[0284] In one embodiment, without being bound by a particular theory, one or more compounds provided herein selectively inhibit ALK mutations but not TRK (e.g., TRKA, TRKB and / or TRBC), wherein the ALK mutation is I1171X 1 (X 1 is N, S or T) and / or D1203N. In one embodiment, the compound selectively inhibits I1171X 1 (X 1 is N, S or T) but not TRKA. In one embodiment, the compound selectively inhibits I1171X 1 (X 1 is N, S or T) but not TRKB. In one embodiment, the compound selectively inhibits I1171N but not TRKB. In one embodiment, the compound selectively inhibits D1203N but not TRKB. In one embodiment, the compound selectively inhibits I1171X 1 (X 1 In one embodiment, the compound selectively inhibits I1171N and D1203N but not TRKB. In one embodiment, the ratio of selectivity is at least about 5 times. In one embodiment, the ratio of selectivity is at least about 10 times. In one embodiment, the ratio of selectivity is at least about 30 times. In one embodiment, the ratio of selectivity is at least about 50 times. In one embodiment, the ratio of selectivity is at least about 100 times. In one embodiment, the selectivity of ALK mutations relative to TRK is determined by IC against TRK. 50 Values ​​and IC against ALK 50 It is measured by the ratio of values.

[0285] In certain embodiments, the compound selectively inhibits ROS1 and ALK but not TRK (e.g., TRKA, TRKB and / or TRBC). As non-limiting examples, the selectivity ratio can be greater than about 5 times, greater than about 10 times, greater than about 50 times, greater than about 100 times, greater than about 200 times, greater than about 400 times, greater than about 600 times, greater than about 800 times, greater than about 1000 times, greater than about 1500 times, greater than about 2000 times, greater than about 5000 times, greater than about 10,000 times, or greater than about 20,000 times, wherein the selectivity can be measured by IC 50 In some embodiments, the selectivity of ROS1 and ALK relative to TRK is measured by the IC 50 Values ​​and IC values ​​for ROS1 and ALK 50 It is measured as a ratio of values.

[0286] As used herein, in some embodiments, selectivity or selectivity ratio is measured in a biochemical assay or a cell proliferation assay. In some embodiments, the cell proliferation assay is a Ba / F3 proliferation assay.

[0287] In certain embodiments, a method of selectively inhibiting ROS1 but not TRK (e.g., TRKA, TRKB and / or TRBC) is provided herein, wherein the inhibition occurs in a cell. In certain embodiments, the method includes contacting ROS1 with an effective amount of a compound provided herein. In one embodiment, such contact occurs in a cell. In one embodiment, such contact occurs in a mammal (such as a human) cell. In one embodiment, such contact occurs in a human patient suffering from a cancer provided herein.

[0288] In certain embodiments, provided herein is a method of selectively inhibiting ROS1 but not TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein is a method of treating a subject with a cancer associated with ROS1, the method comprising selectively inhibiting ROS1 relative to TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ROS1 but not TRK (e.g., TRKA, TRKB, and / or TRBC).

[0289] In certain embodiments, provided herein is a method for selectively inhibiting ALK but not ROS1, wherein the inhibition occurs in a cell. In certain embodiments, provided herein is a method for selectively inhibiting ALK but not TRK (e.g., TRKA, TRKB and / or TRBC), wherein the inhibition occurs in a cell. In certain embodiments, the method includes contacting ALK with an effective amount of a compound provided herein. In one embodiment, such contact occurs in a cell. In one embodiment, such contact occurs in a mammal (such as a human) cell. In one embodiment, such contact occurs in a human patient suffering from a cancer provided herein.

[0290] In certain embodiments, provided herein are methods of selectively inhibiting ALK but not ROS1, wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods of treating a subject with a cancer associated with ALK, the method comprising selectively inhibiting ALK but not ROS1 by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK but not ROS1.

[0291] In certain embodiments, provided herein are methods of selectively inhibiting ALK but not TRK, wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods of treating a subject with a cancer associated with ALK, the method comprising selectively inhibiting ALK but not TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK but not TRK (e.g., TRKA, TRKB, and / or TRBC).

[0292] As used herein, unless otherwise indicated, inhibition of ROS1 includes inhibition of wild-type ROS1 or a mutation thereof; inhibition of ALK includes inhibition of wild-type ALK or a mutation thereof; inhibition of TRK includes inhibition of wild-type TRK or a mutation thereof.

[0293] Cancers treated by the methods provided herein include, but are not limited to, lung cancer (e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor), ovarian cancer (e.g., serous ovarian cancer), melanoma (e.g., Spitzoid melanoma), glioblastoma, bile duct cancer (e.g., cholangiocarcinoma), gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer (e.g., esophageal squamous cell carcinoma), kidney cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), thyroid cancer (e.g., papillary thyroid carcinoma), neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and Spitzoid tumor.

[0294] Cancers treated by the methods provided herein include cancers derived from one or more oncoproteins selected from ROS1, ALK, TRKA, TRKB and TRKC. In certain embodiments, cancers treated by the methods provided herein include cancers that are resistant to treatments directed against one or more oncoproteins selected from ROS1, ALK, TRKA, TRKB and TRKC.

[0295] In one embodiment, the cancer in the method provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein, unless otherwise specified, "ALK positive" (ALK+) cancer, disease or condition refers to a cancer, disease or condition characterized by inappropriate high expression of the ALK gene and / or the presence of a mutation in the ALK gene and / or the presence of a partially deleted ALK protein. In one embodiment, "ALK positive" (ALK+) cancer, disease or condition refers to a cancer, disease or condition characterized by inappropriate high expression of the ALK gene and / or the presence of a mutation in the ALK gene. In one embodiment, "ALK positive" (ALK+) cancer, disease or condition refers to a cancer, disease or condition characterized by the presence of a partially deleted ALK protein (e.g., NB1, AskaSS). In one embodiment, the mutation changes the biological activity of an ALK nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a "mutation" or "mutant" of ALK comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations or amplifications in the amino acid or nucleotide sequence of ALK or a fragment thereof. As used herein, unless otherwise specified, ALK "rearrangement" refers to a genetic translocation involving the ALK gene, which can produce an ALK fusion gene and / or an ALK fusion protein. The ALK fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, amplifications, or fragments thereof, as long as the mutant retains kinase phosphorylation activity.

[0296] In certain embodiments, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the methods provided herein includes one or more mutations in the ALK kinase. In certain embodiments, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In certain embodiments, the one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, G1269S, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, F1174L, G1202del, D1203N, S1206R, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, F1245V, and T1151_L1152insT. In certain embodiments, the ALK mutation is selected from the group consisting of: G1202R, L1196M, G1269A, D1203N, I1171N, I1171S, I1171T, C1156Y, F1174L, S1206R, G1269S and T1151_L1152insT. In certain embodiments, the ALK mutation is G1202R. In certain embodiments, the ALK mutation is L1196M. In certain embodiments, the ALK mutation is G1269A. In certain embodiments, the ALK mutation is L1198F. In certain embodiments, the ALK mutation is a co-mutation of G1202R and one or more mutations selected from L1196M, G1269A and L1198F. In certain embodiments, the ALK mutation is a G1202R / L1196M double mutation. In certain embodiments, the ALK mutation is a G1202R / G1269A double mutation. In certain embodiments, the ALK mutation is a G1202R / L1198F double mutation. In certain embodiments, the ALK mutation is I1171N. In certain embodiments, the ALK mutation is I1171S. In certain embodiments, the ALK mutation is I1171T. In certain embodiments, the ALK mutation is D1203N. In certain embodiments, the ALK mutation is F1174L. In certain embodiments, the ALK mutation is an I1171N / D1203N double mutation. In certain embodiments, the ALK mutation is an I1171N / L1198F double mutation.In certain embodiments, the ALK mutation is a I1171N / L1198Y double mutation. In certain embodiments, the ALK mutation is a I1171N / L1198I double mutation. In certain embodiments, the ALK mutation is a I1171T / D1203N double mutation. In certain embodiments, the ALK mutation is a I1171S / D1203N double mutation. In certain embodiments, the ALK mutation is a I1171T / L1198Y double mutation. In certain embodiments, the ALK mutation is a I1171T / L1198F double mutation. In certain embodiments, the ALK mutation is a I1171T / L1198I double mutation. In certain embodiments, the ALK mutation is a I1171S / L1198Y double mutation. In certain embodiments, the ALK mutation is a I1171S / L1198F double mutation. In certain embodiments, the ALK mutation is an I1171S / L1198I double mutation.

[0297] In one embodiment, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the methods of the present disclosure includes one or more mutations in the ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1129, E1210, F1245, G1269 and R1275. In one embodiment, the one or more ALK point mutations are selected from R1060H, F1174C / I / L / S / V, F1245C / I / L / V, R1275L / Q, T1151M, M1166R, I1171N, I1171S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, G1286R and T1343I. In some embodiments, the one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151-L1152 insT, F1174C, G1202del, D1203N, S1206Y, S1206C, S1206F, L1152R, L1196Q, L1198P, L1198F, L1198H, R1275Q, L1152P, C1156T, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, and F1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is G1269V. In one embodiment, the ALK mutation is L1198F. In one embodiment, the ALK mutation is L1198H. In one embodiment, the ALK mutation is T1151M. In one embodiment, the ALK mutation is F1174L. In one embodiment, the ALK mutation is F1174I. In one embodiment, the ALK mutation is F1174S. In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is I1171S. In one embodiment, the ALK mutation is I1171T.In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is E1129K. In one embodiment, the ALK mutation is S1206F. In one embodiment, the ALK mutation is E1210K. In one embodiment, the ALK mutation is D1203N. In one embodiment, the ALK mutation is R1275G. In one embodiment, the ALK mutation is F1245C. In one embodiment, the ALK mutation is T1151K. In one embodiment, the ALK mutation is I1268V. In one embodiment, the ALK mutation is F1174V. In one embodiment, the ALK mutation is L1198Q. In one embodiment, the ALK mutation is S1206A.

[0298] As used herein and unless otherwise indicated, "co-mutation" refers to mutations that occur simultaneously, i.e., when two or more mutations are present at the same time, e.g., in the same cell and on the same allele, in the same cell but on different alleles, or in different cells.

[0299] As used herein and unless otherwise indicated, "compound mutation" refers to two or more mutations located on the same allele. Compound mutations are a subset of co-mutations. If there are two mutations located on the same allele, compound mutations are sometimes also referred to as double mutations.

[0300] In certain embodiments, the ALK mutation is I1171X 1 (X 1 (N, S or T) and a compound mutation in combination with one or more of the following mutations: D1203N, L1198X 2 (X 2 Y, F, I), L1196X 3 (X 3 M or Q), C1156X 4 (X 4 Y or F), G1269A, F1174X 5 (X 5 L, C, V, I, S) and G1202X 6 (X 6 In certain embodiments, the ALK mutation is I1171X 1 (X 1 (N, S or T) and one of the following mutations: D1203N, L1198X 2 (X 2 Y, F, I), L1196X 3 (X 3M or Q), C1156X 4 (X 4 Y or F), G1269A, F1174X 5 (X 5 L, C, V, I, S) and G1202X 6 (X 6 In certain embodiments, the ALK mutation is I1171X 1 (X 1 (N, S or T) and one of the following mutations: D1203N, L1198X 2 (X 2 for Y, F, I).

[0301] In some embodiments, the ALK mutation is a co-mutation of G1202R and one or more mutations selected from L1196M, G1269A, T1151M, F1174S, and L1198F. In one embodiment, the ALK mutation is a G1202R / L1196M compound mutation. In one embodiment, the ALK mutation is a G1202R / G1269A compound mutation. In one embodiment, the ALK mutation is a G1202R / L1198F compound mutation. In one embodiment, the ALK mutation is a G1202R / T1151M compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174S compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174L compound mutation. In one embodiment, the ALK mutation is a co-mutation of C1156Y and one or more mutations selected from L1256F, S1206F, F1174V and F1174I. In one embodiment, the ALK mutation is a C1156Y / L1256F compound mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I compound mutation. In one embodiment, the ALK mutation is a co-mutation of L1196M and one or more mutations selected from L1198H, I1179V and L1256F. In one embodiment, the ALK mutation is a L1196M / L1198H compound mutation. In one embodiment, the ALK mutation is a L1196M / I1179V compound mutation. In one embodiment, the ALK mutation is a L1196M / L1256F compound mutation.

[0302] In one embodiment, the ALK mutation is a G1202R / L1196M double mutation. In one embodiment, the ALK mutation is a G1202R / G1269A double mutation. In one embodiment, the ALK mutation is a G1202R / L1198F double mutation. In one embodiment, the ALK mutation is a G1202R / T1151M double mutation. In one embodiment, the ALK mutation is a G1202R / F1174S double mutation. In one embodiment, the ALK mutation is a G1202R / F1174L double mutation. In one embodiment, the ALK mutation is a C1156Y / L1256F double mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I double mutation. In one embodiment, the ALK mutation is a L1196M / L1198H double mutation. In one embodiment, the ALK mutation is a L1196M / I1179V double mutation. In one embodiment, the ALK mutation is a L1196M / L1256F double mutation.

[0303] In certain embodiments, the ALK mutation comprises one or more ALK rearrangements (in certain embodiments, a rearrangement). In certain embodiments, the ALK mutation comprises one or more ALK fusions (in certain embodiments, a fusion). In some embodiments, the cancer treated by the method provided herein comprises ALK fusion. In certain embodiments, ALK fusion is a fusion with one of the following fusion partners: EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC and KIF5B. In some embodiments, ALK fusion is a fusion with NPM1, STRN or EML4. In certain embodiments, the ALK mutation is EML4-ALK, i.e., a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. There are many variants of EML4-ALK, which differ in the breakpoint connection, of which variant 1 (v1) and variant 3 (v3) are the most common in clinical practice. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0304] In one embodiment, the ALK mutation comprises one or more ALK rearrangements (in one embodiment, one rearrangement). In one embodiment, the ALK mutation comprises one or more ALK fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods of the present disclosure comprises an ALK fusion. In one embodiment, the ALK fusion is with one of the fusion partners described in Ou et al., JTO Clinical and Research Reports, 1(1): 1-10, the entire contents of which are incorporated herein by reference. In one embodiment, the ALK fusion is with one of the fusion partners selected from the group consisting of: EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, SOCS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ, PICALM, CLIP1, BCL11A, GCC2, LMO7, PHACTR1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VKORC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CAMKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, LPIN1, WDPCP, CEP55, ERC1, SLC16A7, TNIP2, ATAD2B, SLMAP, FBN1, SWAP70, TCF12, TRIM66, WNK3, AKAP8L, SPECC1L, PRKCB, CDK15, LCLAT1, YAP1, PLEKHM2, DCHS1, PPFIBP1, ATP13A4, C12orf7 5. EPAS1, FAM179A, FUT8, LIMD1, LINC00327, LOC349160, LYPD1, RBM20, TACR1, TANC1, TTC27, T UBBB, SMPD4, SORCS1, LINC00211, SOS1, C9orf3, CYBRD1, MTA3, THADA, TSPYL6, WDR37 and PLEKHH2.In one embodiment, the ALK fusion is performed with one of the fusion partners selected from the group consisting of EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, MSN, ALO17, MYH9, LRRFIP1-ALK, TDRD15-ALK and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. EML4-ALK has many variants, which differ in that the breakpoints are connected, of which variant 1 (v1) and variant 3 (v3) are the most common clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0305] In one embodiment, the ALK mutation includes an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wild type ("wt") (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variant 4, 5, 6 or 7). In one embodiment, the ALK mutation is EML4-ALK wt (variant 8, 9, 10, 11, 12, 13, 14 or 15). As used herein, each variant also includes a subvariant within a variant. In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK I1171N. In one embodiment, the ALK mutation is EML4-ALK I1171S. In one embodiment, the ALK mutation is EML4-ALK I1171T. In one embodiment, the ALK mutation is EML4-ALKL1196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R. In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALKG1202R / T1151M. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L. In one embodiment, the ALK mutation is EML4-ALK I1171N / D1203N. In one embodiment, the ALK mutation is EML4-ALK I1171S / D1203N. In one embodiment, the ALK mutation is EML4-ALK I1171T / D1203N.

[0306] In some embodiments, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the methods provided herein includes one or more mutations in the ALK kinase. In certain embodiments, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In one embodiment, the one or more ALK point mutations are selected from T1151_L1152insT, L1152R, T1151M, L1152P, C1156Y, C1156T, I1171T, I1171N, I1171S, F1174C, F1174S, F1174L, V1180L, L1196M, L1196Q, L1198P, L1198F, G1202R, G1202K, G1202del, D1203N, S1206Y, S1206C, E1210K, F1245V, G1269A and R1275Q. In certain embodiments, the ALK mutation is selected from the group consisting of: G1202R, L1196M, G1269A, D1203N, I1171N, I1171S, I1171T, C1156Y, F1174L, and T1151_L1152insT. In certain embodiments, the ALK mutation is G1202R. In certain embodiments, the ALK mutation is L1196M. In certain embodiments, the ALK mutation includes F1174S or F1174L. In certain embodiments, the ALK mutation includes R1275Q. In certain embodiments, the ALK mutation includes T1151M. In certain embodiments, the ALK mutation includes I1171T, I1171S, or I1171N. In one embodiment, the ALK mutation includes one or more compound mutations. In one embodiment, the compound mutation is selected from G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, G1202R / F1174S, I1171T / D1203N, I1171T / L1198Y, I1171T / 1198F, I1171T / 1198I, I1171S / D1203N, I1171S / L1198Y, I1171S / 1198F, I1171S / 1198I, I1171N / D1203N, I1171N / L1198Y, I1171N / 1198F and I1171N / 1198I.In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F. In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2-17del.

[0307] In one embodiment, the ALK-positive solid tumor is characterized by the presence of a mutation in the ALK gene. In one embodiment, the ALK mutation comprises one or more ALK rearrangements, one or more ALK point mutations, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, F1174S, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T or F1245V, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R. In one embodiment, the ALK mutation comprises F1174S or F1174L. In one embodiment, the ALK mutation comprises I1171S. In one embodiment, the ALK mutation comprises I1171T. In one embodiment, the ALK mutation comprises I1171N. In one embodiment, the ALK mutation comprises F1171M. In one embodiment, the ALK mutation comprises D1203N and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises C1156Y and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises R1275Q. In one embodiment, the ALK mutation comprises T1151M. In one embodiment, the ALK mutation comprises one or more compound mutations. In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F. In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the compound mutation is I1171N / D1203N. In one embodiment, the compound mutation is I1171S / D1203N. In one embodiment, the compound mutation is I1171T / D1203N. In one embodiment, the compound mutation is I1171M / D1203N.In one embodiment, the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2-17del.

[0308] In one embodiment, the partially deleted ALK protein affects the proliferation and metastatic properties of cancer cells. The ALK protein can be partially deleted by a variety of mechanisms. The first mechanism is shedding, in which the 80kDa extracellular domain of the ALK protein is post-translationally cleaved near residue Asn654, leaving a 140kDa C-terminal transmembrane and intracellular domain on the cell. Shedding has been observed in many cell lines expressing ALK, most notably cell lines from neuroblastoma disease backgrounds. In preclinical models of cancer in vitro and in vivo, shedding increases the migration and proliferation of cancer cells (Moog-Lutz, JBC (2005), Huang, Cell Reports (2021)). The second mechanism is alternative transcription initiation (ATI), in which transcription of the ALK gene starts from an alternative start site downstream of the original site, resulting in the deletion of exons 1-18 and part of exon 19. ALK ATI has been identified in 11% of melanomas and a small number of lung cancers and anaplastic thyroid cancers. Expression of ALK ATI transforms Ba / F3 and NIH3T3 cells, giving them oncogenic potential. One ALK ATI patient showed clinical response to ALK inhibitor therapy, suggesting that ALK ATI may be a targetable driver mutation (Wiesner, Nature (2015)). The third mechanism is partial deletion of the ALK gene, such as through a chromosomal rearrangement event. A variety of deletion variants have been identified, including deletions of exons 2-3, exons 1-5, exons 4-11, and exons 2-17, some of which have been shown to activate ALK signaling and transform Ba / F3 or NIH3T3 cells. Partial deletions of ALK have been detected in neuroblastomas, sarcomas, and lymphomas. (Okubo, Oncogene (2012); Cazes, Can Res (2013); Fransson, Genes Chromosomes & Cancer (2014); Fleuren, Can Res (2017); Fukuhara, Hematol Oncol (2017)).

[0309] In certain embodiments, the ALK mutation includes an ALK rearrangement and one or more ALK point mutations. In certain embodiments, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variant 4, 5, 6 or 7). In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK I1171N. In one embodiment, the ALK mutation is EML4-ALK I1171S. In one embodiment, the ALK mutation is EML4-ALK I1171T. In one embodiment, the ALK mutation is EML4-ALK L1196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R. In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALK G1202R / T1151M. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L. In certain embodiments, the ALK mutation is EML4-ALK I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK I1171N / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) L1196M / G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) L1196M / G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) L1196M / G1202R.In certain embodiments, the ALK mutation is EML4-ALK (variant 1) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171S. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171T. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) L1196M. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171N. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171S. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171T. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) L1196M. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171N / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171N. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171S. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171T. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) L1196M. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) D1203N.In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171N / L1198F.

[0310] In certain embodiments, one or more mutations disclosed herein result in a partial loss of ALK protein. In certain embodiments, ALK+ cancers are characterized by a partially lost ALK protein (e.g., a partially lost ALK protein identified in NB-1 (e.g., ex2-3del) and Aska-SS (e.g., ex2-17del) cell lines). In some embodiments, ALK+ cancers are characterized by an ALK F1174L mutation (e.g., a mutation identified in Kelly and SH-SY5Y cell lines).

[0311] In certain embodiments, ALK+ cancer is determined by an FDA-approved test or other test known in the art. Tests that may be used include, for example, FoundationOne CDx TM(F1CDx) (a sequencing-based in vitro diagnostic device for the detection of substitutions, insertion and deletion changes (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements as well as genomic features including microsatellite instability (MSI) and tumor mutation burden (TMB) using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx assay (a qualitative detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained with the BenchMarkXT or BenchMark ULTRA automated stainers); and Vysis ALK Break ApartFISH Probe Kit test (a qualitative detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens by fluorescence in situ hybridization (FISH H) Qualitative test for detecting rearrangements involving the ALK gene). In certain embodiments, the test is a fluorescent in situ hybridization (FISH) test, e.g., the Vysis ALK Break Apart FISH Probe Kit test. For more information on FDA-approved tests, visit, e.g., http: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitro Diagnostics; and for more information on the Vysis ALK BreakApart FISH Probe Kit, visit, e.g., https: / / www.molecular.abbott / us / en / products / onc ology / vysis-alk-break-apart-fish-probe-kit; all of which are incorporated herein by reference.

[0312] Also provided is a method for treating a subject with cancer (e.g., ALK-positive cancer), comprising: determining whether cancer cells in a sample obtained from a subject with cancer and previously administered a first ALK inhibitor have one or more ALK inhibitor resistance mutations; and if the subject has cancer cells with one or more ALK inhibitor resistance mutations, administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in combination with another anticancer agent to the subject. In some embodiments, one or more ALK inhibitor resistance mutations confer increased resistance to cancer cells or tumors to treatment with a first ALK inhibitor. In some embodiments, one or more ALK inhibitor resistance mutations include one or more ALK inhibitor resistance mutations. For example, the one or more ALK inhibitor resistance mutations may include substitutions at one or more of amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, such as G1202R, L1196M, G1269 A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T and F1245V. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anticancer agent can be another ALK inhibitor (e.g., a second ALK inhibitor).

[0313] In certain embodiments, the cancer in the methods provided herein is ROS1-positive (ROS1+) cancer. As used herein, unless otherwise specified, a “ROS1-positive” (ROS1+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriate high expression of the ROS1 gene and / or the presence of a mutation in the ROS1 gene. In certain embodiments, the mutation alters the biological activity of the ROS1 nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a “mutation” or “mutant” of ROS1 includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequence of ROS1 or a fragment thereof. As used herein, unless otherwise specified, a ROS1 “rearrangement” refers to a genetic translocation involving the ROS1 gene, which can give rise to a ROS1 fusion gene and / or a ROS1 fusion protein. The ROS1 fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof, provided that the mutant retains kinase phosphorylation activity.

[0314] In certain embodiments, ROS1 mutations include one or more ROS1 point mutations. In some embodiments, the cancer treated by the methods provided herein includes one or more mutations in ROS1 kinases. In certain embodiments, one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, and L2155. In certain embodiments, one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S and L2086F. In certain embodiments, ROS1 mutates to G2032R. In certain embodiments, ROS1 mutates to S1986F. In certain embodiments, ROS1 mutates to S1986Y. In certain embodiments, ROS1 mutates to L2026M. In certain embodiments, ROS1 mutates to D2033N. In certain embodiments, ROS1 mutates to L2086F. In certain embodiments, ROS1 mutates to F2004C. In certain embodiments, ROS1 mutates to F2004V. In certain embodiments, ROS1 mutates to G2101A. In certain embodiments, ROS1 mutates to L1982F. In certain embodiments, ROS1 mutates to a co-mutation of one or more of G2032R and S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

[0315] In certain embodiments, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, one rearrangement). In certain embodiments, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods provided herein comprises a ROS1 fusion. In certain embodiments, the ROS1 fusion is a fusion with one of the following fusion partners: SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, CCDC6, CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In certain embodiments, the ROS1 fusion is a CD74-ROS1 fusion. In certain embodiments, the ROS1 fusion is a SDC4-ROS1 fusion. In certain embodiments, the ROS1 fusion is an EZR-ROS1 fusion. In certain embodiments, the ROS1 fusion is a SLC34A2-ROS1 fusion. In certain embodiments, the ROS1 fusion is a GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In certain embodiments, the ROS1 fusion is a CEP85L-ROS1 fusion.

[0316] In certain embodiments, ROS1 mutations include a ROS1 rearrangement and one or more ROS1 point mutations. In certain embodiments, ROS1 mutations include one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L) and CEP85L-ROS1 and one or more ROS1 point mutations selected from F2004C, F2004V and G2032R. In certain embodiments, ROS1 mutations include one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1 and SLC34A2-ROS1 and a ROS1 point mutation of G2101A.

[0317] In certain embodiments, ROS1 mutates to CD74-ROS1 F2004C. In certain embodiments, ROS1 mutates to CD74-ROS1 F2004V. In certain embodiments, ROS1 mutates to CD74-ROS1 G2101A. In certain embodiments, ROS1 mutates to CD74-ROS1 G2032R. In certain embodiments, ROS1 mutates to CD74-ROS1 S1986F. In certain embodiments, ROS1 mutates to CD74-ROS1 L2026M. In certain embodiments, ROS1 mutates to CD74-ROS1 D2033N. In certain embodiments, ROS1 mutates to EZR-ROS1 F2004C. In certain embodiments, ROS1 mutates to EZR-ROS1 F2004V. In certain embodiments, ROS1 mutates to EZR-ROS1 G2101A. In certain embodiments, ROS1 is mutated to EZR-ROS1 G2032R. In certain embodiments, ROS1 is mutated to SLC34A2-ROS1F2004C. In certain embodiments, ROS1 is mutated to SLC34A2-ROS1 F2004V. In certain embodiments, ROS1 is mutated to SLC34A2-ROS1 G2101A. In certain embodiments, ROS1 is mutated to SLC34A2-ROS1 G2032R. In certain embodiments, ROS1 is mutated to GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-LF2004C). In certain embodiments, ROS1 is mutated to GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In certain embodiments, ROS1 is mutated to GOPC-ROS1 G2032R (e.g., GOPC-ROS1-SG2032R, GOPC-ROS1-L G2032R). In certain embodiments, ROS1 is mutated to CEP85L-ROS1F2004C. In certain embodiments, ROS1 is mutated to CEP85L-ROS1 F2004V. In certain embodiments, ROS1 is mutated to CEP85L-ROS1G2032R. In certain embodiments, ROS1 is mutated to GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In certain embodiments, ROS1 is mutated to CD74-ROS1L1982F.

[0318] In certain embodiments, ROS1+ cancers are determined by an FDA-approved test or other tests known in the art. Tests that can be used include, for example, the OncomineTM Dx Target Test performed by Thermo Fisher Scientific. (A qualitative in vitro diagnostic test that uses targeted high-throughput parallel sequencing technology and the Ion PGM Dx System to detect sequence variations in 23 genes in DNA and RNA isolated from formalin-fixed paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC)); the Vysis ROS1 Break Apart FISH Probe Kit (a qualitative test for detecting rearrangements involving ROS1 gene rearrangements at 6q22 in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue samples by fluorescence in situ hybridization (FISH)) or RT real-time polymerase chain reaction (RT-PCR) or NGS Next Generation sequencing performed by local diagnostic tests.

[0319] Also provided is a method for treating a subject with cancer (e.g., a ROS1-positive cancer), comprising: determining whether the cancer cells in a sample obtained from a subject with cancer and previously administered a first ROS1 inhibitor have one or more ROS1 inhibitor resistance mutations; and if the subject has cancer cells with one or more ROS1 inhibitor resistance mutations, administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in combination with another anticancer agent to the subject. In some embodiments, the one or more ROS1 inhibitor resistance mutations confer increased resistance to treatment with a first ROS1 inhibitor on the cancer cells or tumors. In some embodiments, the one or more ROS1 inhibitor resistance mutations include one or more ROS1 inhibitor resistance mutations. For example, the one or more ROS1 inhibitor resistance mutations may include substitutions at one or more of amino acid positions 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, such as G2032R, D2032R, or D2032A. 3N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K and L2086F. In some embodiments, the another anticancer agent is any anticancer agent known in the art. For example, the another anticancer agent can be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[0320] In certain embodiments, provided herein is a compound that is a CNS permeable compound. In certain embodiments, after administering an effective amount of a compound provided herein (e.g., orally or intravenously), the compound can penetrate the CNS (e.g., blood-brain barrier) and reach a concentration in the CNS (e.g., brain) that is still sufficient to inhibit (e.g., selectively inhibit) ROS1 or ALK or both.

[0321] In certain embodiments, provided herein is a method for treating CNS metastasis of cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein, such as a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, the CNS metastasis is a brain metastasis. In certain embodiments, the cancer is a ROS1+ cancer. In certain embodiments, the cancer is an ALK+ cancer.

[0322] In one embodiment, the solid tumor (or cancer) is positive for leukocyte receptor tyrosine kinase (LTK). In one embodiment, the solid tumor is LTK positive NSCLC. In one embodiment, the solid tumor is LTK positive breast invasive ductal carcinoma, prostate adenocarcinoma, pancreatic adenocarcinoma, adenocarcinoma of unknown primary or bladder urothelial carcinoma. In one embodiment, the solid tumor is LTK positive lung cancer. In one embodiment, the solid tumor is LTK positive NSCLC. In one embodiment, the solid tumor (or cancer) has LTK mutation. In one embodiment, the LTK mutation is G269A, F218I, N257T, A13fs or A214fs. In one embodiment, the solid tumor (or cancer) has LTK fusion. In one embodiment, the LTK fusion is CLIP1-LTK. See Cooper AJ, Sequist LV, Johnson TW, Lin JJ. LTK fusions: A new target emerges in non-smallcell lung cancer. Cancer Cell. 2022 Jan 10;40(1):23-25; and Izumi, H., Matsumoto, S., Liu, J. et al. The CLIP1–LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature 600, 319–323 (2021), each reference is incorporated herein by reference in its entirety.

[0323] In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinase A, B or C. In certain embodiments, the IC50 of the compound for inhibiting mutant or non-mutated ROS1 or ALK is no more than one-fifth of the IC50 of the compound for inhibiting wild-type tropomyosin receptor kinase A, B or C. TRK inhibition, particularly in the central nervous system (CNS), has been associated with adverse reactions including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes.

[0324] In some embodiments, there is provided a method for minimizing adverse events in a subject in need of treating cancer (e.g., ROS1 positive cancer or ALK positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, for example, a compound of formula (I), a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt, and wherein the method minimizes adverse events associated with TRK inhibitors. In some embodiments, cancer is ROS1-related cancer or ALK-related (or ALK+) cancer. In some embodiments, adverse events are TRK-related CNS adverse events.

[0325] As used herein, "minimizing" adverse events refers to the incidence of adverse events in subjects or patient populations treated with TRK inhibitors (e.g., entrectinib, ripretinib or lorlatinib) compared to the typical incidence of adverse events in subjects or patient populations. In some embodiments, the incidence of adverse events refers to the frequency or percentage of specific adverse events occurring in subjects or patient populations. In some embodiments, the incidence of adverse events refers to the total number of adverse events experienced by individual subjects. In some embodiments, minimizing adverse events refers to minimizing TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 40% of patient populations have TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% of patient populations have TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 12% of patient populations have more than one TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% of the patient population has more than one TRK-related CNS adverse event.

[0326] In some embodiments, a TRK-related CNS adverse event refers to one or more of the following: dizziness, ataxia, gait disturbance, paresthesia, weight gain, excessive eating, paresthesia, abnormal movements, cognitive changes, speech effects (e.g., dysarthria, bradyspeech, or language disorders), mood disorders (e.g., irritability, anxiety, depression, affective lability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoria, or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, concentration disorder, delirium, psychological injury, attention-deficit / hyperactivity disorder, dementia, or dyslexia).

[0327] In certain embodiments, there is provided herein a method for preventing or limiting CNS side effects or adverse events associated with TRK in cancer treatment, comprising administering an effective amount of a compound provided herein to a subject in need, such as a compound of formula (I) or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, the method prevents the occurrence of CNS adverse events associated with TRK. In certain embodiments, the method limits the frequency of occurrence of CNS adverse events associated with TRK. In certain embodiments, the method limits the severity of TRK-related side effects. In certain embodiments, there is provided herein a method for treating CNS metastasis of cancer and reducing TRK-related side effects, comprising administering an effective amount of a compound provided herein to a subject in need, such as a compound of formula (I) or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, the reduction / limitation / prevention of CNS side effects or adverse events compared to standard care treatment is determined in a statistical sample, and the standard care treatment is, for example, an approved ROS1 and / or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib or lopatinib) for ROS1+ and / or ALK+ cancer. In certain embodiments, the TRK-related side effects are TRKB-related CNS side effects. In certain embodiments, the TRK-related CNS side effects or adverse events are dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorders, or sleep disorders.

[0328] In certain embodiments, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, such as a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, the cancer is a ROS1-related cancer. In certain embodiments, the cancer is a ROS1+ cancer. In certain embodiments, the cancer is an ALK-related cancer. In certain embodiments, the cancer is an ALK+ cancer. In certain embodiments, the cancer is identified as ROS1+. In certain embodiments, the cancer is identified as ALK+.

[0329] In certain embodiments, provided herein is a method for treating ROS1+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0330] In certain embodiments, provided herein is a method for treating ALK+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0331] In certain embodiments, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the subject's cancer as ROS1+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0332] In certain embodiments, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the subject's cancer as ALK+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0333] In certain embodiments, cancer (or ROS1+ cancer or ALK+ cancer) is a solid tumor. In certain embodiments, cancer (or ROS1+ cancer or ALK+ cancer) is lung cancer (e.g., non-small cell lung cancer (NSCLC)), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer (e.g., bile duct cancer (cholangiocarcinoma)), ovarian cancer (e.g., serous ovarian cancer), gastric cancer, colorectal cancer, angiosarcoma, melanoma (e.g., Spitz nevus melanoma), epithelioid hemangioendothelioma, esophageal cancer (e.g., esophageal squamous cell carcinoma (ESCC)), kidney cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), colon cancer, thyroid cancer (e.g., papillary thyroid cancer), Spitzoid tumor or neuroblastoma.

[0334] In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is ALK+ non-small cell lung cancer. In certain embodiments, the cancer is relapsed or refractory non-small cell lung cancer. In certain embodiments, the cancer is relapsed or refractory ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is relapsed or refractory ALK+ non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed ALK+ non-small cell lung cancer.

[0335] In certain embodiments, the cancer is a glioblastoma. In certain embodiments, the cancer is a ROS1+ glioblastoma. In certain embodiments, the cancer is an ALK+ glioblastoma. In certain embodiments, the cancer is a recurrent or refractory glioblastoma. In certain embodiments, the cancer is a recurrent or refractory ROS1+ glioblastoma. In certain embodiments, the cancer is a recurrent or refractory ALK+ glioblastoma. In certain embodiments, the cancer is a newly diagnosed glioblastoma. In certain embodiments, the cancer is a newly diagnosed ROS1+ glioblastoma. In certain embodiments, the cancer is a newly diagnosed ALK+ glioblastoma.

[0336] In certain embodiments, the cancer is IMT. In certain embodiments, the cancer is ROS1+IMT. In certain embodiments, the cancer is ALK+IMT. In certain embodiments, the cancer is relapsed or refractory IMT. In certain embodiments, the cancer is relapsed or refractory ROS1+IMT. In certain embodiments, the cancer is relapsed or refractory ALK+IMT. In certain embodiments, the cancer is newly diagnosed IMT. In certain embodiments, the cancer is newly diagnosed ROS1+IMT. In certain embodiments, the cancer is newly diagnosed ALK+IMT.

[0337] In certain embodiments, the cancer is cholangiocarcinoma. In certain embodiments, the cancer is cholangiocarcinoma. In certain embodiments, the cancer is ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is ALK+ cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory ALK+ cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed ALK+ cholangiocarcinoma.

[0338] In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is ROS1+ ovarian cancer. In certain embodiments, the cancer is ALK+ ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ ovarian cancer. In certain embodiments, the cancer is newly diagnosed ovarian cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ ovarian cancer. In certain embodiments, the cancer is newly diagnosed ALK+ ovarian cancer. In certain embodiments, the ovarian cancer is serous ovarian cancer. In certain embodiments, the ovarian cancer is high-grade serous ovarian cancer.

[0339] In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is ROS1+ gastric cancer. In certain embodiments, the cancer is ALK+ gastric cancer. In certain embodiments, the cancer is recurrent or refractory gastric cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ gastric cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ gastric cancer. In certain embodiments, the cancer is newly diagnosed gastric cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ gastric cancer. In certain embodiments, the cancer is newly diagnosed ALK+ gastric cancer.

[0340] In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is ROS1+ colorectal cancer. In certain embodiments, the cancer is ALK+ colorectal cancer. In certain embodiments, the cancer is relapsed or refractory colorectal cancer. In certain embodiments, the cancer is relapsed or refractory ROS1+ colorectal cancer. In certain embodiments, the cancer is relapsed or refractory ALK+ colorectal cancer. In certain embodiments, the cancer is newly diagnosed colorectal cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ colorectal cancer. In certain embodiments, the cancer is newly diagnosed ALK+ colorectal cancer.

[0341] In certain embodiments, the cancer is angiosarcoma. In certain embodiments, the cancer is ROS1+ angiosarcoma. In certain embodiments, the cancer is ALK+ angiosarcoma. In certain embodiments, the cancer is recurrent or refractory angiosarcoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ angiosarcoma. In certain embodiments, the cancer is recurrent or refractory ALK+ angiosarcoma. In certain embodiments, the cancer is a newly diagnosed angiosarcoma. In certain embodiments, the cancer is a newly diagnosed ROS1+ angiosarcoma. In certain embodiments, the cancer is a newly diagnosed ALK+ angiosarcoma.

[0342] In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a Spitz-like tumor. In certain embodiments, the cancer is a Spitz-like melanoma. In certain embodiments, the cancer is a ROS1+ Spitz-like melanoma. In certain embodiments, the cancer is an ALK+ Spitz-like melanoma. In certain embodiments, the cancer is a recurrent or refractory Spitz-like melanoma. In certain embodiments, the cancer is a recurrent or refractory ROS1+ Spitz-like melanoma. In certain embodiments, the cancer is a recurrent or refractory ALK+ Spitz-like melanoma. In certain embodiments, the cancer is a newly diagnosed Spitz-like melanoma. In certain embodiments, the cancer is a newly diagnosed ROS1+ Spitz-like melanoma. In certain embodiments, the cancer is a newly diagnosed ALK+ Spitz-like melanoma.

[0343] In certain embodiments, the cancer is epithelioid hemangioendothelioma. In certain embodiments, the cancer is ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is ALK+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory ALK+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.

[0344] In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is ESCC. In certain embodiments, the cancer is ROS1+ESCC. In certain embodiments, the cancer is ALK+ESCC. In certain embodiments, the cancer is recurrent or refractory ESCC. In certain embodiments, the cancer is recurrent or refractory ROS1+ESCC. In certain embodiments, the cancer is recurrent or refractory ALK+ESCC. In certain embodiments, the cancer is newly diagnosed ESCC. In certain embodiments, the cancer is newly diagnosed ROS1+ESCC. In certain embodiments, the cancer is newly diagnosed ALK+ESCC.

[0345] In certain embodiments, the cancer is renal cancer. In certain embodiments, the cancer is renal medullary carcinoma. In certain embodiments, the cancer is ROS1+ renal medullary carcinoma. In certain embodiments, the cancer is ALK+ renal medullary carcinoma. In certain embodiments, the cancer is recurrent or refractory renal medullary carcinoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ renal medullary carcinoma. In certain embodiments, the cancer is recurrent or refractory ALK+ renal medullary carcinoma. In certain embodiments, the cancer is newly diagnosed renal medullary carcinoma. In certain embodiments, the cancer is newly diagnosed ROS1+ renal medullary carcinoma. In certain embodiments, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In certain embodiments, the cancer is renal cell carcinoma. In certain embodiments, the cancer is ROS1+ renal cell carcinoma. In certain embodiments, the cancer is ALK+ renal cell carcinoma. In certain embodiments, the cancer is recurrent or refractory renal cell carcinoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ renal cell carcinoma. In certain embodiments, the cancer is recurrent or refractory ALK+ renal cell carcinoma. In certain embodiments, the cancer is newly diagnosed renal cell carcinoma. In certain embodiments, the cancer is newly diagnosed ROS1+ renal cell carcinoma. In certain embodiments, the cancer is newly diagnosed ALK+ renal cell carcinoma.

[0346] In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is ROS1+ breast cancer. In certain embodiments, the cancer is ALK+ breast cancer. In certain embodiments, the cancer is relapsed or refractory breast cancer. In certain embodiments, the cancer is relapsed or refractory ROS1+ breast cancer. In certain embodiments, the cancer is relapsed or refractory ALK+ breast cancer. In certain embodiments, the cancer is newly diagnosed breast cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ breast cancer. In certain embodiments, the cancer is newly diagnosed ALK+ breast cancer. In certain embodiments, the breast cancer is triple-negative breast cancer.

[0347] In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is ROS1+ colon cancer. In certain embodiments, the cancer is ALK+ colon cancer. In certain embodiments, the cancer is recurrent or refractory colon cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ colon cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ colon cancer. In certain embodiments, the cancer is newly diagnosed colon cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ colon cancer. In certain embodiments, the cancer is newly diagnosed ALK+ colon cancer.

[0348] In certain embodiments, the cancer is thyroid cancer. In certain embodiments, the cancer is papillary thyroid cancer. In certain embodiments, the cancer is ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is ALK+ papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed ALK+ papillary thyroid cancer.

[0349] In certain embodiments, the cancer is neuroblastoma. In certain embodiments, the cancer is ROS1+ neuroblastoma. In certain embodiments, the cancer is ALK+ neuroblastoma. In certain embodiments, the cancer is recurrent or refractory neuroblastoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ neuroblastoma. In certain embodiments, the cancer is recurrent or refractory ALK+ neuroblastoma. In certain embodiments, the cancer is newly diagnosed neuroblastoma. In certain embodiments, the cancer is newly diagnosed ROS1+ neuroblastoma. In certain embodiments, the cancer is newly diagnosed ALK+ neuroblastoma.

[0350] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is a blood cancer. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is lymphoma. In certain embodiments, the lymphoma is non-Hodgkin lymphoma. In certain embodiments, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to blood cancers, methods for treating other blood disorders or blood malignancies that are ROS1+ or ALK+ are also provided herein.

[0351] In certain embodiments, the cancer is ALCL. In certain embodiments, the cancer is ROS1+ ALCL. In certain embodiments, the cancer is ALK+ ALCL. In certain embodiments, the cancer is recurrent or refractory ALCL. In certain embodiments, the cancer is recurrent or refractory ROS1+ ALCL. In certain embodiments, the cancer is recurrent or refractory ALK+ ALCL. In certain embodiments, the cancer is newly diagnosed ALCL. In certain embodiments, the cancer is newly diagnosed ROS1+ ALCL. In certain embodiments, the cancer is newly diagnosed ALK+ ALCL.

[0352] In certain embodiments, the cancer is DLBCL. In certain embodiments, the cancer is ROS1+ DLBCL. In certain embodiments, the cancer is ALK+ DLBCL. In certain embodiments, the cancer is recurrent or refractory DLBCL. In certain embodiments, the cancer is recurrent or refractory ROS1+ DLBCL. In certain embodiments, the cancer is recurrent or refractory ALK+ DLBCL. In certain embodiments, the cancer is newly diagnosed DLBCL. In certain embodiments, the cancer is newly diagnosed ROS1+ DLBCL. In certain embodiments, the cancer is newly diagnosed ALK+ DLBCL.

[0353] In certain embodiments, the cancer is large B-cell lymphoma. In certain embodiments, the cancer is ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is ALK+ large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed ALK+ large B-cell lymphoma.

[0354] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is newly diagnosed. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) has not been previously treated.

[0355] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is relapsed or refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is refractory.

[0356] In certain embodiments, the subject is treatment-naive. In certain embodiments, the subject has not been treated with tyrosine kinase inhibitor (TKI) therapy. In certain embodiments, the subject has received prior first-line or multiple lines of therapy. In certain embodiments, the subject has received prior two or more lines of therapy. In certain embodiments, the subject has developed resistance to one or more prior lines of therapy. In certain embodiments, the prior therapy includes tyrosine kinase inhibitor (TKI). In certain embodiments, the prior therapy includes one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, loxitinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, and ensartinib. In certain embodiments, the prior therapy includes one or more chemotherapies. In certain embodiments, one or more chemotherapies are in addition to TKI therapy.

[0357] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is resistant to tyrosine kinase inhibitor (TKI).

[0358] In certain embodiments, the cancer is resistant lung cancer. In certain embodiments, the cancer is resistant non-small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer that is resistant to TKI. In certain embodiments, the cancer is ROS1+ non-small cell lung cancer that is resistant to TKI. In certain embodiments, the cancer is ALK+ non-small cell lung cancer that is resistant to TKI.

[0359] In certain embodiments, the cancer is lung cancer (eg, NSCLC), and the cancer has relapsed following treatment with a TKI or was refractory prior to said treatment.

[0360] In certain embodiments, provided herein are compounds administered as first-line treatments. In certain embodiments, provided herein are compounds administered as second-line treatments. In certain embodiments, provided herein are compounds administered as third-line or fourth-line treatments.

[0361] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is metastatic. In certain embodiments, the cancer has CNS metastases. In certain embodiments, the cancer has brain metastases. In certain embodiments, the cancer is metastatic non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is metastatic ROS1+NSCLC. In certain embodiments, the cancer is metastatic ALK+NSCLC.

[0362] In certain embodiments, provided herein is a method for treating a patient with metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0363] In certain embodiments, provided herein is a method for treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0364] In certain embodiments, the patient is an adult patient. In certain embodiments, the patient is a pediatric patient.

[0365] In certain embodiments, provided herein is a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0366] In certain embodiments, provided herein is a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant to at least one prior TKI therapy.

[0367] In certain embodiments, provided herein is a method for treating an adult patient with metastatic NSCLC that is ROS1+ and has a solvent front mutation G2032R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant to at least 1 prior TKI therapy.

[0368] In certain embodiments, provided herein is a method for treating a ROS1-related (or ROS1+) cancer in a subject in need thereof, wherein the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0369] In certain embodiments, provided herein is a method for treating a ROS1-related (or ROS1+) cancer in a subject in need thereof, wherein the cancer is resistant to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ROS1 inhibitor resistance mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, one or more ROS1 inhibitor resistance mutations include one or more amino acid substitutions at amino acid positions selected from 1986, 2004, 2026, 2032, and 2033. In certain embodiments, one or more ROS1 inhibitor resistance mutations include one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In certain embodiments, one or more ROS1 inhibitor resistance mutations are G2032R. In certain embodiments, the one or more ROS1 inhibitor resistance mutations comprise G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101 A. In certain embodiments, the ROS1 inhibitor resistance mutation is L2086F.

[0370] In certain embodiments, provided herein is a method for treating ALK-related (or ALK+) cancer in a subject in need thereof, wherein the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0371] In certain embodiments, provided herein is a method for treating ALK-related (or ALK+) cancer in a subject in need thereof, wherein the cancer is resistant to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. In certain embodiments, one or more ALK inhibitor resistance mutations include one or more amino acid substitutions at amino acid positions selected from 1196, 1198, 1202, and 1269. In certain embodiments, one or more ALK inhibitor resistance mutations include one or more amino acid substitutions selected from L1196M, L1198F, G1202R, and G1269A. In certain embodiments, one or more ALK inhibitor resistance mutations are G1202R. In certain embodiments, one or more ALK inhibitor resistance mutations include one or more of G1202R and L1196M, L1198F, and G1269A.

[0372] In certain embodiments, provided herein is a method for treating an adult patient with metastatic NSCLC that is ALK+ with the mutation G1202R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant to at least one prior TKI therapy.

[0373] In certain embodiments, provided herein is a method for treating ALK-related (or ALK+) cancer in a subject in need thereof, wherein the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0374] In certain embodiments, the TKI is a ROS1 inhibitor. In certain embodiments, the TKI is an ALK inhibitor. In certain embodiments, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ripretinib, cabozantinib, foretinib, mesartinib, taretinib, masitinib or ensartinib. In certain embodiments, the TKI is crizotinib. In certain embodiments, the TKI is entrectinib. In certain embodiments, the TKI is alectinib. In certain embodiments, the TKI is lorlatinib.

[0375] In certain embodiments, cancer or disease occurs in pediatric patients (including infant patients). In certain embodiments, cancer is ALK+ systemic anaplastic large cell lymphoma (ALCL) in pediatric patients and young people aged 1 year or more. In another embodiment, cancer is ALK+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) in pediatric patients and young people aged 1 year or more. In certain embodiments, cancer is ROS1+ systemic anaplastic large cell lymphoma (ALCL) in pediatric patients and young people aged 1 year or more. In another embodiment, cancer is ROS1+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) in pediatric patients and young people aged 1 year or more.

[0376] In certain embodiments, methods for treating or preventing cancer can be demonstrated by one or more responses such as increasing apoptosis, inhibiting tumor growth, reducing tumor metastasis, inhibiting tumor metastasis, reducing microvessel density, reducing neovascularization, inhibiting tumor migration, tumor regression, and increasing the survival of the subject.

[0377] 4.4 Combination therapy

[0378] In some embodiments, methods of treating or preventing cancer may comprise administering a compound of Formula (I) in combination with one or more other chemotherapeutic agents.

[0379] As used herein, unless otherwise indicated, "in conjunction with" or "combination" does not mean that the other agent and the compound of formula (I) must be administered at the same time and / or formulated for delivery together, although such delivery methods are also provided herein. Compounds provided herein can be administered simultaneously with one or more other agents (e.g., one or more other additional agents), before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks), or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks). In general, each therapeutic agent is administered according to the dosage and / or schedule determined for that particular agent. The other therapeutic agent can be administered with the compounds provided herein in a single composition or separately in different compositions.Triple combination therapy is also contemplated herein.

[0380] Chemotherapeutic agents that can be administered in combination with the compounds provided herein include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-hydroxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate. 4-[2-Anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib maleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, bacillus Calmette-Guérin (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, Dacarbazine, actinomycin D, daunorubicin, demethoxychlorobenzene, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, nitrogen mustard, medroxyprogesterone, megestrol acetate, melphalan , mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylaminomethsulfonyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, primycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolophylline, romidepsin, rucaparib, selumetinib, sirolimus, 2,4-dinitrobenzenesulfonate sodium, sorafenib, streptozotocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, dichlorocyclopentadiene titanium, tonafolium (tonapofylline), topotecan, trametinib, trastuzumab, retinoic acid, veliparib, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA). In other embodiments, the chemotherapeutic agents that can be administered in combination with the compounds provided herein include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be administered in combination with the compounds provided herein include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-hydroxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate. [4-Fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthrylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylaminomethylthioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolophylline sodium 2,4-dinitrobenzenesulfonate, sumarin and tonaphylline. ,

[0381] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, the compounds provided herein (e.g., compounds of formula (I)) can be administered in combination with one or more combination therapies. Table 2 lists examples of combination therapies that can be administered in combination with the compounds provided herein.

[0382] Table 2: Exemplary combination therapies for treating cancer

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] In certain embodiments, the combination therapy provided herein includes co-administration with other types of chemotherapeutic agents such as immuno-oncology agents. Cancer cells typically have specific cell surface antigens that can be recognized by the immune system. Therefore, immuno-oncology agents such as monoclonal antibodies can selectively bind to cancer cell antigens and cause cell death. Other immuno-oncology agents can inhibit tumor-mediated inhibition of natural immune responses, or activate immune responses, thereby promoting the immune system to recognize tumors. Exemplary antibody immuno-oncology agents include, but are not limited to, aba govomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox), apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumabozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatumumab Atumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samal izumab and tremelimumab. In some embodiments, the antibody immuno-oncology agent is selected from anti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD-1 mAb and anti-CTLA4 mAb. Therefore, in some embodiments, the methods provided herein include the combined administration of one or more immuno-oncology agents, such as the agents described above.

[0389] In some embodiments, combination therapy includes administering a compound provided herein (eg, a compound of Formula (I)) in combination with an SH2 inhibitor (eg, CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056).

[0390] In some embodiments, combination therapy includes administering a compound provided herein (e.g., a compound of Formula (I)) in combination with a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733).

[0391] In some embodiments, the combination therapy comprises administering a compound provided herein (e.g., a compound of Formula (I)) in combination with a MET inhibitor selected from JNJ-38877605, PF-04217903, foreitinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

[0392] In some embodiments, the combination therapy comprises administering a compound provided herein (eg, a compound of Formula (I)) in combination with a SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0393] In some embodiments, combination therapy includes administering a compound provided herein (e.g., a compound of Formula (I)) in combination with a RAS inhibitor selected from the group consisting of aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0394] In some embodiments, combination therapy includes administering a combination of a compound provided herein (e.g., a compound of formula (I)) and a TKI. In certain embodiments, the TKI is a ROS1 inhibitor. In certain embodiments, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ripretinib, cabozantinib, foretinib, tarentinib, mesartinib, masitinib or ensartinib. In certain embodiments, the TKI is crizotinib. In certain embodiments, the TKI is entrectinib. In certain embodiments, the TKI is alectinib. In certain embodiments, the TKI is brigatinib.

[0395] In some embodiments, the combination therapy includes the co-administration of a compound provided herein (e.g., a compound of formula (I)) and an anti-PD-1 therapy. In certain embodiments, the combination therapy includes the co-administration of a compound provided herein (e.g., a compound of formula (I)) and oxaliplatin. In other embodiments, the combination therapy includes the co-administration of a compound provided herein (e.g., a compound of formula (I)) and doxorubicin.

[0396] In certain embodiments, provided herein are compounds that can be administered in combination with non-chemical methods for cancer treatment. In certain embodiments, provided herein are compounds that can be administered in combination with radiotherapy. In certain embodiments, provided herein are compounds that can be administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination of these therapies.

[0397] In certain embodiments, the compounds provided herein can be administered in combination with an agent that inhibits the CD47 / SIRPα interaction. In certain embodiments, the agent that inhibits the CD47 / SIRPα interaction is a CD47 inhibitor. In certain embodiments, the CD47 inhibitor is an anti-CD47 antibody. In certain embodiments, the anti-CD47 antibody is AO-176, CC-90002, GenSci-059, IMC-002, lemzoparlimab, letaplimab, ligufalimab, magrolimab, MIL-95, SHR-1603, ZL-1201, STI-6643, SRF231, TQB2928, or SGN-CD47M. In certain embodiments, the anti-CD47 antibody is magrolimab. In certain embodiments, the CD47 inhibitor is a small molecule. In certain embodiments, the CD47 inhibitor is RRx-001. In certain embodiments, the agent that inhibits the CD47 / SIRPα interaction is an anti-CD47 bispecific antibody. In certain embodiments, the anti-CD47 bispecific antibody is BAT-7104, HX-009, IBI-322, IMM-0306, JMT-601, SG-12473, SIRPα-Fc-CD40L, TG-1801, HX009, PF-07257876, DVD-Ig SL / LL, SIRPa-γ-CD20 HC, CD20-2GL-SIRPa HC, CD20-4GL-SIRPa HC, bi-scFv RTX-CD47, LQ007, HMBD004A, HMBD004B, NI-1801, NI-2401, NI-2601, PT-886, PT-796, PT-217, IMM-26011, IMM-2902, SG3847, BH-29XX, PMC-122, ABP-160, IMM-2505, TJ-L1C4, IAB, SL-172154, DSP107, TJ C4GM, or IMM-0207. In certain embodiments, the agent that inhibits the CD47 / SIRPα interaction is a SIRPα inhibitor. In certain embodiments, the SIRPα inhibitor is an anti-SIRPα antibody. In certain embodiments, the anti-SIRPα antibody is BI-765063, CC-95251, GS-0189, HSIRPB, H21, ES004, AL008, ADU-1805, or Abx701. In certain embodiments, the SIRPα inhibitor is a small molecule. In certain embodiments, the agent that inhibits the CD47 / SIRPα interaction is a SIRPα / Fc fusion protein antibody.In certain embodiments, the SIRPα / Fc fusion protein antibody is DSP-107, evorpacept, IMM-01, TTI-621, or TTI-622.

[0398] In certain embodiments, the compounds provided herein can be co-administered with one or more other compounds provided herein. In addition, such combinations can be co-administered with other therapeutic agents, such as other agents suitable for treating cancer, immunology or neurological diseases, such as the agents described above. In certain embodiments, co-administering one or more additional chemotherapeutic agents with the compounds provided herein provides a synergistic effect. In certain embodiments, co-administering one or more additional chemotherapeutic agents provides an additive effect.

[0399] 4.5 Pharmaceutical Compositions

[0400] In certain embodiments, provided herein are pharmaceutical preparations suitable for human patients, comprising any of the compounds shown above (e.g., compounds disclosed herein, such as compounds of formula (I)) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations can be used to treat or prevent an illness or disease as described herein. Any compound provided herein can be used to manufacture a drug for treating any disease or illness provided herein.

[0401] The compositions and methods provided herein can be used to treat subjects in need. In certain embodiments, the subject is a mammal (such as a human being) or a non-human mammal. In one embodiment, when applied to a subject (such as a human being), the composition or the compound is applied as a pharmaceutical composition, and the pharmaceutical composition includes, for example, a compound provided herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art, including, for example, aqueous solutions (such as water or physiological buffered saline) or other solvents or vehicles (such as ethylene glycol, glycerol, oils (such as olive oil) or injectable organic esters). In one embodiment, when such pharmaceutical compositions are used for human administration, particularly invasive administration routes (i.e., avoiding the transport or diffusion routes through the epithelial barrier, such as injection or implantation), aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of a medicament or selectively target one or more cells, tissues or organs. Pharmaceutical compositions can be in dosage unit form, such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized agents for reconstruction, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0402] A pharmaceutically acceptable carrier may contain physiologically acceptable agents, such as agents that function to stabilize, increase the solubility of a compound (such as the compounds provided herein), or increase the absorption of a compound. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier (including physiologically acceptable reagents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymeric matrix, into which, for example, the compounds provided herein may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0403] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0404] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (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) dihydric alcohols, such as propylene glycol; (11) polyhydric alcohols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0405] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral (e.g., in the form of an aqueous or non-aqueous solution or suspension, tablet, capsule (including spray capsule and gelatin capsule), bolus, powder, granule, paste for applying to the tongue); absorption through the oral mucosa (e.g., sublingual); anus, rectum or vagina (e.g., as vaginal suppository, cream or foam); parenteral (including intramuscular, intravenous, subcutaneous or intrathecal, e.g., as a sterile solution or suspension); intranasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment or spray applied to the skin, or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for such routes can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 and patents cited therein.

[0406] The preparation can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the subject being treated, the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally speaking, in percent, the range of this amount will be about 1% to about 99%, about 5% to about 70%, or about 10% to about 30% of the active ingredient.

[0407] The method for preparing these preparations or compositions includes the step of combining active compound (such as compound provided herein) with carrier and optionally one or more auxiliary components. In general, the preparation is prepared by uniformly and intimately combining compound provided herein with liquid carrier or finely divided solid carrier or both, and then shaping the product as required.

[0408] Formulations suitable for oral administration provided herein can be in the form of capsules (including spray capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and gum arabic or tragacanth), lyophilized agents, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or as a mouthwash, etc., each containing a predetermined amount of a compound provided herein as an active ingredient. The composition or compound can also be administered in the form of a pill, a granule, or a paste.

[0409] To prepare solid dosage forms for oral administration (capsules (including spray capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or two pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) wetting agents, Such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution delay agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including spray capsules and gelatin capsules), tablets and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols.

[0410] Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0411] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including spray capsules and gelatin capsules), pills and granules, can be optionally scored or prepared into coatings and shells, such as enteric coatings and other coatings well-known in the field of pharmaceutical formulation. They can also be formulated to provide slow or controlled release of the active ingredient therein, for example, using different proportions of hydroxypropyl methylcellulose to provide the desired release curve, other polymer matrices, liposomes and / or microspheres. It can be sterilized by filtering, for example, through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions can also optionally contain an opacifier and can be a composition that releases one or more active ingredients only in a certain part of the gastrointestinal tract or in a certain part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. If appropriate, the active ingredient can also be in a microencapsulated form with one or more of the above-mentioned excipients.

[0412] Liquid dosage forms that can be used for oral administration include pharmaceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0413] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming and emulsifying agents.

[0414] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0415] Formulations for rectal, vaginal or urethral administration may be presented as suppositories which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0416] Formulations of pharmaceutical compositions for oral administration may be presented as mouthwashes, oral sprays or oral ointments.

[0417] Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, wire or other intravascular device. Delivery via such devices may be particularly suitable for delivery to the bladder, urethra, ureter, rectum or intestine.

[0418] Formulations suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations, which contain such carriers as are known in the art.

[0419] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.

[0420] In addition to the active compound, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0421] In addition to the active compound, the powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0422] Transdermal patches have the additional advantage of being able to deliver the compounds provided herein to the body in a controlled manner. Such dosage forms may also be prepared by dissolving or dispersing the active compound in a suitable medium. Penetration enhancers may also be used to increase the flux of the compound through the skin. The rate of this flux may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0423] Also provided herein are ophthalmic formulations, eye ointments, powders, solutions, etc. Exemplary ophthalmic formulations are described in US Publications Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and US Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulations have properties similar to or are compatible with tears, aqueous humor or vitreous humor. The route of administration is topical administration (e.g., topical administration such as eye drops, or administration via an implant).

[0424] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to a route of administration other than enteral and topical administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0425] Pharmaceutical compositions suitable for parenteral administration include a combination of one or more active compounds with one or more of the following: pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile powders that can be reconstituted into sterile injectable solutions or dispersions before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0426] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0427] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including absorption delaying agents such as aluminum monostearate and gelatin.

[0428] In some cases, to prolong the action of a drug, it is necessary to slow down the absorption of a drug administered subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a pharmaceutical form for parenteral administration is accomplished by dissolving or suspending the drug in an oily vehicle.

[0429] Injectable reservoir forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled according to the ratio of the drug to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by embedding the drug in a liposome or microemulsion compatible with body tissues.

[0430] For use in the methods provided herein, the active compound can be provided per se, or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (eg, 0.5% to 90%) active ingredient with a pharmaceutically acceptable carrier.

[0431] The method of introduction can also be provided by a rechargeable or biodegradable device. In recent years, various slow-release polymer devices have been developed and tested in vivo for controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), both biodegradable and non-degradable, can be used to form implants that continuously release compounds at specific target sites.

[0432] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0433] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or combination of compounds employed, or the esters, salts or amides thereof, the route of administration, the time of administration, the rate of excretion of the compound or compounds employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound or compounds employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0434] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a doctor or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than the desired level in order to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the subject's weight, sex, age and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the subject's illness, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound provided herein. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th edition, 1814-1882, which is incorporated herein by reference).

[0435] In general, a suitable daily dose of an active compound for use in the compositions and methods provided herein will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[0436] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments, the active compound can be administered twice or three times daily. In certain embodiments, the active compound will be administered once a day.

[0437] In certain embodiments, provided herein are compounds that can be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds, so that while administering the second compound, the previously administered therapeutic compound is still effective in vivo (for example, two compounds are effective in the subject at the same time, which may include the synergistic effect of the two compounds). For example, different therapeutic compounds can be administered simultaneously or successively in the same preparation or in a separate preparation. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours or a week. Therefore, the subject receiving such treatment may benefit from the combined effect of different therapeutic compounds.

[0438] In certain embodiments, the combined administration of a compound provided herein with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy relative to each separate administration of a compound provided herein (e.g., a compound of Formula I or Ia) or one or more additional therapeutic agents. In certain such embodiments, the combined administration provides an additional effect, wherein the additional effect refers to the sum of the individual effects of the separate administration of a compound provided herein and one or more additional therapeutic agents.

[0439] Also provided herein is the use of a pharmaceutically acceptable salt of a compound provided herein in the compositions and methods provided herein. In certain embodiments, the expected salt provided herein includes but is not limited to alkylammonium salts, dialkylammonium salts, trialkylammonium salts or tetraalkylammonium salts. In certain embodiments, the expected salt provided herein includes but is not limited to L-arginine salts, benthamine salts (benenthamine), benzathine penicillin salts, betaine salts, calcium hydroxide, choline salts, dimethylethanolamine salts (deanol), diethanolamine salts, diethylamine salts, 2- (diethylamino) ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucosamine salts, hydrabamine penicillin salts (hydrabamine), 1H-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4- (2- hydroxyethyl) morpholine salts, piperazine salts, potassium salts, 1- (2- hydroxyethyl) pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts and zinc salts. In certain embodiments, contemplated salts provided herein include, but are not limited to, Na salts, Ca salts, K salts, Mg salts, Zn salts, or other metal salts.

[0440] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be derived from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental to such solvent.

[0441] Pharmaceutically acceptable anionic salts include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camphorsulfonate, carbonate, chloride, citrate, decanoate, edetate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate, naphthenate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, chlortetracycline and toluenesulfonate.

[0442] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0443] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0444] Now that the disclosure has been generally described, it will be more readily understood by reference to the following examples, which are intended merely to illustrate certain aspects and embodiments provided herein and are not intended to limit the disclosure.

[0445] 5. Examples

[0446] General synthetic methods

[0447] The compounds provided herein can be prepared by a variety of synthetic methods, as further described and illustrated herein. Those skilled in the art will appreciate that the following general synthetic methods are representative and not limiting. Racemic compounds can be enriched for enantiomers by chiral, preparative, SFC or HPLC separation. Stereoisomers without upper or lower wedge annotations are shown in Table 1. 3 The center represents an unquantified mixture of configurations at the position. Stereo sp drawn with upper or lower wedge annotation 3 The center represents the stereo enrichment of the drawn configuration. Stereo sp drawn with an upper or lower wedge 3 The center is further annotated with “or1”, indicating stereoenrichment of a single unknown configuration.

[0448]

[0449]

[0450]

[0451] Method A

[0452]

[0453] Nitropyridine I can be reduced using Fe metal conditions to give aminopyridine type II. This transformation can also be achieved by using Raney nickel and hydrazine; or in the case where the substrate contains an isoxazole moiety, the yield can be improved by using SnCl2 conditions. Intramolecular ring closure of II can be achieved using C-H insertion cross-coupling conditions to give type III compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.

[0454] Method B

[0455]

[0456] The use of sodium hydroxide in tetrahydrofuran can convert the nitrile Form IV to the primary amide Form V. Alternative hydroxide sources include, but are not limited to, lithium hydroxide, potassium hydroxide, cesium hydroxide, or tetraalkylammonium hydroxides (eg, Triton B).

[0457] Method C

[0458]

[0459] Nitrile IV is reacted with sodium hydroxide in methanol to give Type VI carboxylic acid. Lithium hydroxide, potassium hydroxide, cesium hydroxide or tetraalkylammonium hydroxide (such as Triton B) can be used as a substitute for sodium hydroxide in this transformation. Type VI carboxylic acid can be reacted with Type VII amine in the presence of an amide coupling reagent to give Type VIII amide. Suitable amide coupling reagents include, but are not limited to, HATU, EDCI, TBTU, CDI and T3P.

[0460] Method D

[0461]

[0462] Halides IX can be coupled with stannane X using Stille coupling conditions to give Type II compounds. Various additives including, but not limited to, LiCl or CuI can be optionally used to promote the reaction. Intramolecular ring closure of halide II can be achieved using CH insertion cross-coupling conditions to give compound III. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.

[0463] Method E

[0464]

[0465] Nitropyridines XI can be reduced with Fe metal to afford aminopyridines XII. This transformation can also be accomplished using Raney nickel and hydrazine or, in the case of substrates containing an isoxazole moiety, using SnCl 2The intramolecular ring closure of compound XII can be achieved using a two-step one-pot borylation / Suzuki cross-coupling condition to afford compound III.

[0466] Method F

[0467]

[0468] Thioether XIII can be converted to a mixture of sulfoxide XIV and sulfone XV using m-chloroperbenzoic acid. The products can be separated and isolated using chromatographic methods.

[0469] Method G

[0470]

[0471] Nitropyridine I can be reduced under iron metal conditions to give an aminopyridine intermediate, which can be converted to bromide XII using NBS. The initial iron reduction step can also be accomplished by using Raney nickel and hydrazine; or in the case of substrates containing an isoxazole moiety, by using SnCl 2 The intramolecular ring closure of compound XII can be achieved using a two-step one-pot borylation / Suzuki cross-coupling condition to afford compound III.

[0472] Method H

[0473]

[0474] Ester XVI is reacted with aqueous lithium hydroxide in an organic solvent to give Type VI carboxylic acid. Sodium hydroxide, potassium hydroxide, cesium hydroxide or tetraalkylammonium hydroxide (such as Triton B) can be used as a substitute for lithium hydroxide in this transformation. Type VI carboxylic acid can be reacted with Type VII amine in the presence of an amide coupling reagent to give Type VIII amide. Suitable amide coupling reagents include, but are not limited to, HATU, EDCI, TBTU, CDI and T3P.

[0475] Method I

[0476]

[0477] Deprotection of SEM ether XVII with an acid can provide pyrazole XVIII. Suitable acids include, but are not limited to, TFA and HCl.

[0478] Method J

[0479]

[0480] Ketone XIX can be reduced to alcohol XX using a reducing agent such as sodium borohydride in an alcoholic solvent such as methanol.

[0481] Method K

[0482]

[0483] Halides IX can be coupled with boronate esters XXI under Suzuki coupling conditions to afford aminopyridines XXII after base-promoted Boc deprotection. Bromination of the aminopyridine ring with NBS followed by intramolecular ring closure using C-H insertion cross-coupling conditions can afford macrocycles III. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.

[0484] Method L

[0485]

[0486] MOM ether XXIII can be deprotected under acidic conditions, and the exposed alcohol can be oxidized using Dess-Martin periodinane to obtain ketone XXIV. Suitable acids include, but are not limited to, TFA and HCl. Intramolecular ring closure of XXIV can be performed using CH insertion cross-coupling conditions to obtain macrocycle XXV. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.

[0487] Method M

[0488]

[0489] Weinreb amide XXVII can be converted to ketone XXVIII by reaction with Grignard reagent XXVII.

[0490] As used in General Methods A, B, C, D, E, F, G, H, I, J, K, L and M, each A is independently O, N, S, NR, if valency permits. g8 , CR g9 or C(R g9 ) 2 , where each R g8 and R g9 are independently H or C 1-6 Alkyl. Each R g1 Each R is independently H, methyl or hydroxymethyl. g2 are independently H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl. Each R g3 are independently H, CN, halogen, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO 2 -、C1-4 Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 wherein, if the valence permits, the heteroaryl, cycloalkyl, heterocyclyl or alkyl is further substituted with 0, 1, 2 or 3 C 1-4 Alkyl or halogen substituted. Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted; each R g4 and R g5 are independently substituted or unsubstituted C 1-4 Alkyl; or R g4 and R g5 Together with its intermediate nitrogen, it forms C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted. Each R g6 and R g7 are independently substituted or unsubstituted C 1-4 Alkyl. Z is CR 5 or N and R 5 is H or F. T is -CH 2 -, -O-, -CH(OH)-, or -C(=O)-.

[0491] Analytical methods

[0492] Collect LCMS data using one of the following methods:

[0493]

[0494]

[0495]

[0496] Synthesis Example

[0497] Intermediates

[0498] Synthesis of 5-ethyl-1-methyl-1H-pyrazole-3-carboxaldehyde

[0499]

[0500] To a mixture of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (4.50 g, 20.5 mmol) in i-PrOH (50 mL) were added potassium vinyl trifluoroborate (6.05 g, 45.19 mmol), Pd(dppf)Cl 2 (1.5 g, 2.05 mmol) and TEA (4.16 g, 41.1 mmol). The mixture was degassed and heated with N 2 Purge three times. The mixture was stirred at 80 ° C for 12 h. The mixture was concentrated. The residue was purified by silica gel flash column chromatography (0→3% MeOH / DCM) to give 1-methyl-5-vinyl-1H-pyrazole-3-carboxylic acid methyl ester (3.40 g, yield: 99.6%) as a light yellow solid. LC / MS ESI (m / z): 167.1 [M+H] + .

[0501] To a solution of methyl 1-methyl-5-vinyl-1H-pyrazole-3-carboxylate (3.40 g, 7.58 mmol) in MeOH (30 mL) was added Pd / C (220 mg, 0.1 mmol, 10 wt%). The mixture was degassed and heated to 40 ℃ for 1 h. 2 Purge three times. The mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was concentrated to give 5-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (3.2 g, 95% yield) as a yellow solid. LC / MS (ESI) (m / z): 169.1 [M+H] + .

[0502] To a stirred solution of 5-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (3.20 g, 19.0 mmol) in THF (40 mL) was added DIBAL-H (1.5 M in THF, 19 mL, 29 mmol) at -60 °C. The reaction was stirred at -60 °C for 2 h. The mixture was quenched with a saturated aqueous solution of Rochelle salt (100 mL) and extracted with EtOAc (90 mL x 3). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by silica gel column chromatography (10→100% EtOAc / PE) to give 5-ethyl-1-methyl-1H-pyrazole-3-carbaldehyde (2.5 g, 95.1% yield) as a light yellow oil. LC / MS (ESI) (m / z): 139.1 [M+H] + .

[0503] Synthesis of 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile

[0504]

[0505] To a stirred solution of 1-ethyl-1H-pyrazole-3-carbonitrile (3.30 g, 27.3 mmol) in MeCN (20 mL) was added TFA (3.11 g, 27.3 mmol) at 0°C. Then a solution of NIS (7.98 g, 35.3 mmol) in MeCN (20 mL) was added dropwise at 0°C. The reaction was stirred at 25°C for 16 h. The mixture was washed with NaHCO 3 The mixture was quenched with saturated aqueous solution (30 mL) and partially concentrated to remove MeCN. The mixture was extracted with EtOAc (100×3 mL). The combined organic phases were washed with brine (50 mL×2) and purified by anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (15→20% EtOAc / PE) to give 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile (3.70 g, yield: 55.0%) as a clear oil. LC / MS (ESI) m / z: 248 [M+H] + .

[0506] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0507]

[0508] Synthesis of 1-cyclobutyl-1H-pyrazole-3-carbonitrile

[0509]

[0510] A mixture of 1H-pyrazole-3-carbonitrile (5.00 g, 53.7 mmol) and NaH (1.93 g, 80.6 mmol, 60% in mineral oil) in DMF (50 mL) was stirred at 0 ° C under N2 for 0.5 h. A solution of bromocyclobutane (10.9 g, 80.6 mmol) in DMF (100 mL) was added and the reaction was stirred at room temperature for 16 h. The mixture was quenched with NH4Cl (50 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with H 2 O (40 mL × 3), brine (40 mL × 2), and anhydrous Na 2 SO 4 Dried and concentrated. The residue was purified by silica gel flash column chromatography (50→100% EtOAc / PE) to give 1-cyclobutyl-1H-pyrazole-3-carbonitrile (3.50 g, 44.3% yield) as a clean oil. LC / MS (ESI) (m / z): 148 [M+H] + .

[0511] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0512]

[0513]

[0514] Synthesis of (2-chloro-6-methylpyridin-3-yl)boronic acid

[0515]

[0516] To a solution of 3-bromo-2-chloro-6-methylpyridine (5 g, 24.22 mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexane, 18 mL, 29.06 mmol) at -70 °C. The mixture was stirred at -70 °C for 1 h. Triisopropyl borate (5.47 g, 29.06 mmol) was then added dropwise and the mixture was stirred at 20 °C for 3 hours. The reactants were quenched with aqueous NaOH (5%, 30 mL). The aqueous layer was separated and acidified to pH 3 with aqueous HCl (1 M), followed by extraction with EtOAc (50 mL x 3). The combined organic layers were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to give (2-chloro-6-methylpyridin-3-yl)boronic acid (1.6 g, 38% yield). LC / MS (ESI) (m / z): 172 [M+H] + .

[0517] Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol

[0518]

[0519] To a solution of 3,5-dibromo-1-methyl-1H-pyrazole (1.00 g, 4.17 mmol) in THF (10 mL) was added n-BuLi (1.6 M in hexanes, 3.13 mL, 5.00 mmol) at -78 °C. The mixture was stirred at -78 °C for 15 min. A solution of cyclopropanecarboxaldehyde (0.311 mL, 4.168 mmol) in THF (10 mL) was added and the reaction was stirred at -78 °C for 2 h. The solution was heated at 0 °C with NH 4 The mixture was quenched with a saturated aqueous solution of Cl. It was then extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→30% EtOAc / PE) to give (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (330 mg, yield: 34%) as a yellow oil. LC / MS (ESI) (m / z): 231 [M+H] + .

[0520] Synthesis of 5-cyano-1-methylpyrazole-3-carboxylic acid ethyl ester

[0521]

[0522] A solution of (E)-ethyl 2-(2-methylhydrazinylidene)acetate (50.0 g, 384 mmol), prop-2-enenitrile (38.2 mL, 576 mmol), benzoyl peroxide (232 g, 960 mmol) and iodine (19.4 g, 76.8 mmol) in MeCN (750 mL) was stirred at 80 °C for 16 h. The residue was diluted with EtOAc (300 mL) and washed with NaHCO 3 Saturated aqueous solution (200 mL) and Na 2 S 2 O 3 The organic phase was washed with brine and then with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (30→60% EtOAc / PE) to give ethyl 5-cyano-1-methylpyrazole-3-carboxylate (20.0 g, yield: 29.1%) as a yellow solid. LC / MS (ESI) (m / z): 180 [M+H] + .

[0523] Synthesis of 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole

[0524]

[0525] To a mixture of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (330 mg, 1.428 mmol) and TFA (4 mL) was added TES (2.306 mL, 14.280 mmol) at 25 °C. The mixture was degassed three times and heated with N 2 The mixture was concentrated and washed with NaHCO 3 The saturated aqueous solution was diluted and then extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL) and washed with anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (205 mg, yield: 66.7%) as a yellow oil. LC / MS (ESI) (m / z): 215 [M+H] + .

[0526] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0527]

[0528]

[0529]

[0530] Synthesis of 5-(Hydroxymethyl)-2-methylpyrazole-3-carbonitrile

[0531]

[0532] To a stirred solution of ethyl 5-cyano-1-methylpyrazole-3-carboxylate (10.0 g, 55.8 mmol) and MeOH (3.5 g, 112 mmol) in THF (100 mL) was added LiBH 4 (55.8 mL, 112 mmol, 2 M in THF). The reaction was stirred at 25 °C for 16 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous Cl (100 mL) and then extracted with EtOAc (100 mL). The organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give 5-(hydroxymethyl)-2-methylpyrazole-3-carbonitrile (3.60 g, yield: 47.0%) as a white solid. LC / MS (ESI) (m / z): 138 [M+H] + .

[0533] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0534]

[0535]

[0536] Synthesis of Ethyl 5-Cyclobutyl-1H-pyrazole-3-carboxylate

[0537]

[0538] To a solution of ethyl 4-cyclobutyl-2,4-dioxobutanoate (8.3 g, 41.69 mmol) in EtOH (40 mL) was added hydrazine (2.4 g, 62.54 mmol, 85% in water) and the reaction was stirred at 80 °C for 2 h. The mixture was concentrated, diluted with AcOH (7 mL), and the solution was stirred at 25 °C for 8 h. The mixture was concentrated and washed with NaHCO 3 The mixture was diluted with saturated aqueous solution and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine and purified by anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→30% EtOAc / PE) to give ethyl 5-cyclobutyl-1H-pyrazole-3-carboxylate (6.9 g, yield: 85.1%) as a yellow oil. LC / MS ESI (m / z): 195 [M+H] +

[0539] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0540]

[0541] Synthesis of 5-cyclopropyl-2,4-dioxopentanoic acid ethyl ester

[0542]

[0543] To a solution of 1-cyclopropylpropan-2-one (1.50 g, 15.3 mmol) and diethyl oxalate (1.70 g, 15.3 mmol) in THF (20 mL) was added t-BuOK (15.3 mL, 15.3 mmol, 1 M in THF) at 0°C, and the mixture was stirred at 25°C for 3 h. The reaction was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×2) and dried over anhydrous Na 2 SO 4 Drying and concentration gave ethyl 5-cyclopropyl-2,4-dioxopentanoate (1.80 g, crude material) as a brown oil. LC / MS (ESI) (m / z): 199 [M+H] + .

[0544] Synthesis of 5-(Cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole

[0545]

[0546] To a solution of 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (185 mg, 0.860 mmol) in dioxane (8 mL) was added DMEDA (0.009 mL, 0.086 mmol), NaI (1.29 g, 8.601 mmol) and CuI (8.19 mg, 0.043 mmol). The mixture was degassed and heated with N 2 Purge three times and then stir in a sealed tube at 110 ° C for 16 h. The mixture is filtered and the filtrate is concentrated. The residue is purified by silica gel flash column chromatography (0→50% EtOAc / PE) to give 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole (187 mg, yield: 83%) as a yellow oil. LC / MS (ESI) (m / z): 263 [M+H] + .

[0547] Synthesis of 5-Formyl-2-Methylpyrazole-3-carbonitrile

[0548]

[0549] To a stirred solution of 5-(hydroxymethyl)-2-methylpyrazole-3-carbonitrile (1.00 g, 7.29 mmol) in DCM (10 mL) was added DMP (4.64 g, 10.9 mmol) at 0°C. The reaction was stirred at 25°C for 16 h. The mixture was washed with NaHCO 3 The mixture was quenched with saturated aqueous solution (50 mL) and extracted with DCM (50 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→25% EtOAc / PE) to give 5-formyl-2-methylpyrazole-3-carbonitrile (860 mg, yield: 87.3%) as a yellow oil. LC / MS (ESI) (m / z): 136 [M+H] + .

[0550] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0551]

[0552] Synthesis of 1-(Cyclopropylmethyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester

[0553]

[0554] Ethyl 4-formyl-1H-pyrazole-3-carboxylate (1.00 g, 5.95 mmol) and Cs 2 CO 3A solution of (2.91 g, 8.93 mmol) in DMF (5 mL) was cooled to -10 °C. (Bromomethyl)cyclopropane (1.19 g, 8.93 mmol) was added and the reaction was stirred at -10 °C for 2 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with H 2 O (30 mL × 3), brine (50 mL × 2), and anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→30% EtOAc / PE) to give ethyl 1-(cyclopropylmethyl)-4-formyl-1H-pyrazole-3-carboxylate (800 mg, 61.0% yield) as a yellow solid. LC / MS (ESI): m / z 223 [M+H] + .

[0555] To ethyl 1-(cyclopropylmethyl)-4-formyl-1H-pyrazole-3-carboxylate (1.40 g, 6.30 mmol) in CHCl 3 m-CPBA (1.63 g, 9.45 mmol) was added to the solution in 4% ethyl acetate (28 mL). The reaction mixture was stirred at 60 °C for 2 h. The mixture was treated with Na 2 S 2 O 3 The mixture was quenched with saturated aqueous solution (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were washed with NaHCO 3 The mixture was washed with saturated aqueous solution (30 mL) and then with anhydrous Na 2 SO 4 The residue was dissolved in ethanol (30 mL) and aqueous HCl (5 M, 30 mL). The mixture was stirred at room temperature for 10 min and then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine and purified by anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE) to give ethyl 1-(cyclopropylmethyl)-4-hydroxy-1H-pyrazole-3-carboxylate (1.10 g, 83.0% yield) as a white solid. LC / MS ESI (m / z): 211 [M+H] + .

[0556] Synthesis of 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine

[0557]

[0558] To 1-ethyl-1H-pyrazol-4-ol (500 mg, 4.46 mmol), (2-chloropyridin-3-yl)boronic acid (1.40 g, 8.92 mmol) and A mixture of molecular sieves in DCM (20 mL) was added with Cu(OAc) 2 (810mg, 4.46mmol) and TEA (1.2mL, 8.91mmol). The reaction mixture was stirred at 25 °C for 18h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc / PE) to give 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine (45.0mg, 4.50% yield) as a yellow oil. LCMS (ESI): m / z: 224[M+H] + .

[0559] Synthesis of Ethyl 1-(Cyclopropylmethyl)-3-(Methylthio)-1H-pyrazole-4-carboxylate

[0560]

[0561] DIEA (3.08 mL, 18.6 mmol) was added to a solution of 2-cyano-3,3-bis(methylthio)acrylate (1.35 g, 6.21 mmol) and (cyclopropylmethyl)hydrazine (535 mg, 6.21 mmol) in i-PrOH (40 mL). The reaction mixture was stirred overnight in a sealed tube at 85 ° C. The mixture was concentrated. The residue was purified by silica gel flash column chromatography (0 → 100% EtOAc / PE) to give 5-amino-1-(cyclopropylmethyl)-3-(methylsulfanyl)-1H-pyrazole-4-carboxylic acid ethyl ester (850 mg, 54.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 256 [M + H] + .

[0562] To a solution of 5-amino-1-(cyclopropylmethyl)-3-(methylsulfanyl)-1H-pyrazole-4-carboxylic acid ethyl ester (600 mg, 2.35 mmol) in THF (24 mL) was added 3-methylbutyl nitrate (1.27 mL, 9.40 mmol). The reaction mixture was refluxed for 2 h. The residue was purified by silica gel flash column chromatography (0→100% EtOAc / PE) to give 1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 89.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 241 [M+H] + .

[0563] Synthesis of 4-(Cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

[0564]

[0565] To a solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (5.50 g, 0.0200 mol) in THF (50 mL) was added i-PrMgCl.LiCl (1.3 M in THF, 15.5 mL, 0.0200 mol) at 0°C. The mixture was stirred at 0°C for 1 h. A solution of cyclopropanecarboxaldehyde (1.65 mL, 0.0200 mol) in THF (10 mL) was added and stirring was continued at 0°C for 1 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (30 mL×2) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel flash column chromatography (0→50% EtOAc / PE) to give 4-(cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.35 g, 52.4%) as a yellow oil. LC / MS ESI (m / z): 246 [M+H] + .

[0566] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0567]

[0568]

[0569] Synthesis of (2-bromopyridin-3-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

[0570]

[0571] To a solution of 2-bromo-3-iodopyridine (3.57 g, 12.6 mmol) in THF (10 mL) was added i-PrMgCl (9.67 mL, 12.6 mmol, 1.3 M in THF) at 0°C and the mixture was stirred at 0°C for 0.5 h. Then a solution of 1-ethylpyrazole-4-carbaldehyde (1.3 g, 10.472 mmol) in THF (10 mL) was added and the reaction was stirred at 0°C for 1 h and then at 50°C for 12 h. The reaction was washed with NH 4 The solution was quenched with saturated aqueous Cl solution (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with anhydrous Na 2 SO4 Dry, filter, and concentrate. Purify the residue by silica gel column chromatography (10→100% EtOAc / PE) to obtain (2-bromopyridin-3-yl)(1-ethyl-1H-pyrazol-4-yl)methanol as a yellow solid (1.97 g, yield: 66.7%). LC / MS (ESI) (m / z): 282 [M+H] + .

[0572] Synthesize the following intermediates using a similar protocol (with m / z (ESI) values):

[0573]

[0574]

[0575] Synthesis of (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanone

[0576]

[0577] Add MnO 2 (523 mg, 6.02 mmol) to a solution of (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (200 mg, 0.602 mmol) in DCM (30 mL). Stir the reaction mixture at 20 °C for 16 h. Filter the mixture and concentrate the filtrate. Purify the residue by silica gel flash column chromatography (30→50% EtOAc / PE) to obtain (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanone as a white solid (142 mg, yield: 71.4%). LC / MS (ESI) (m / z): 331 [M+H] + .

[0578] Synthesize the following intermediates using a similar protocol (with m / z (ESI) values):

[0579]

[0580]

[0581] Synthesis of 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

[0582]

[0583] To a mixture of 4-(cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.35 g, 9.58 mmol) and TFA (7 mL) was added TES (11.2 g, 95.9 mmol). The reaction was stirred at room temperature for 1 h. The mixture was concentrated and the residue was washed with NaHCO 3 The mixture was diluted with saturated aqueous solution (25 mL) and then extracted with EtOAc (35 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.00 g, yield: 91.3%) as a yellow solid. LC / MS (ESI) (m / z): 230 [M+H] + .

[0584] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0585]

[0586] Synthesis of 3-Formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

[0587]

[0588] at -15 °C in N 2 To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (5.30 g, 23.7 mmol) in THF (25 mL) was added dropwise a 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (35.6 mL, 35.6 mmol, 1 M in hexane) under an atmosphere. After stirring for 1 h under the same conditions, DMF (3.671 mL, 47.5 mmol) was added dropwise at -15 °C, and the mixture was stirred at the same temperature for 1 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (50 mL) and extracted with EtOAc (80 mL×3). The combined organic phases were washed with brine (50 mL×2) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→10% EtOAc / PE) to give 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (3.00 g, yield: 50.3%) as a yellow oil. LC / MS (ESI) (m / z): 252 [M+H]+

[0589] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0590]

[0591]

[0592] Synthesis of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid

[0593]

[0594] To a solution of methyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (500 mg, 3.20 mmol) and 2-bromo-3-fluoropyridine (1.13 g, 6.41 mmol) in DMF (10 mL) was added Cs 2 CO 3 (5.22 g, 16.0 mmol). The mixture was stirred at 60 °C for 48 h. The mixture was concentrated and washed with H 2 O (10 mL) and then acidified with aqueous HCl (4 M) at 0°C. The mixture was filtered and washed with H 2 O (10 mL) to wash the filter cake to obtain a white solid. The white solid was dried in vacuo to obtain 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid (680 mg, yield: 71.3%) as a white solid. LC / MS (ESI) (m / z): 298 [M+H] + .

[0595] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0596]

[0597] Synthesis of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile

[0598]

[0599] 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile (90 mg, 0.25 mmol) and K were added at 0 °C. 2 CO 3To a solution of iodomethane (69 mg, 0.49 mmol) in DMF (1 mL) was added dropwise iodomethane (39 mg, 0.27 mmol). The reaction was stirred at 25 °C for 16 h. The mixture was concentrated and diluted with EtOAc (15 mL), washed with brine (10 mL), and washed with Na 2 SO 4 Dried and concentrated. The residue was purified by silica gel column chromatography (0→25% EtOAc / PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (60 mg, yield: 64.5%) in the form of a yellow oily mixture. LC / MS (ESI) (m / z): 311 [M+H] + .

[0600] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0601]

[0602]

[0603] Synthesis of (1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazol-4-yl)methanol

[0604]

[0605] To a solution of ethyl 1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazole-4-carboxylate (1.00 g, 4.16 mmol) in THF (19 mL) was added DIBAL-H (1 M in THF, 12.48 mL, 12.48 mmol) at -70 °C. The reaction was stirred at 0 °C for 1 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (25 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE) to give (1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazol-4-yl)methanol (800 mg, 97.0% yield) as a white solid. LC / MS (ESI) (m / z): 199 [M+H] + .

[0606] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0607]

[0608] Synthesis of 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

[0609]

[0610] To a stirred solution of 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile (2.00 g, 8.10 mmol) in THF (20 mL) at 0°C was added i-PrMgCl (1 M in THF, 6.20 mL, 8.10 mmol). After stirring at 0°C for 0.5 h, a solution of 2-chloronicotinaldehyde (2.23 g, 16.2 mmol) in THF (20 mL) was added dropwise at 0°C. The reaction was stirred at 25°C for 0.5 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (20 mL×3) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (40→50% EtOAc / PE) to give 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (930 mg, yield: 44.0%) as a white solid. LC / MS (ESI) m / z: 263 [M+H] + .

[0611] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0612]

[0613]

[0614] Synthesis of (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanone

[0615]

[0616] To a solution of (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanol (1.8 g, 6.08 mmol) in DCM (10 mL) and MeOH (1 mL) was added MnO 2(2.64g, 30.4mmol). The reactant was stirred at 45 °C for 12h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0→5% MeOH / DCM) to give (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanone (1.1g, 61.1% yield) as a yellow solid. LC / MS (ESI) (m / z): 294.1[M+H] + .

[0617] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0618]

[0619] Synthesis of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile

[0620]

[0621] At 0°C in N 2 To a mixture of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid (730 mg, 2.45 mmol) in THF (20 mL) was added oxalyl chloride (1.84 mL, 3.67 mmol) and DMF (0.020 mL, 0.245 mmol) under atmospheric pressure, and the mixture was stirred at 60° C. for 2.5 h. Then, NH 4 OH (4 mL, 8.57 mmol) and the mixture was stirred under N 2 The reaction mixture was stirred at room temperature for 12 h. 4 The mixture was quenched with saturated aqueous solution of Cl (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (30 mL×2) and washed with anhydrous Na 2 SO 4 Drying and concentration gave 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxamide (710 mg, crude material) as a yellow oil. LC / MS (ESI) (m / z): 297 [M+H] - .

[0622] To a mixture of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxamide (710 mg, 2.39 mmol) in THF (20 mL) was added TEA (0.830 mL, 5.97 mmol) and TFAA (1.16 mL, 8.36 mmol). The reaction was stirred at 25 °C for 1 h. The mixture was washed with NH 4The mixture was quenched with saturated aqueous solution of Cl (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (20 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→30% EtOAc / PE) to give 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (365 mg, yield: 54.7%) as a colorless oil. LC / MS (ESI) (m / z): 279 [M+H] +

[0623] Synthesis of 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid

[0624]

[0625] A mixture of 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.00 g, 3.27 mmol) and concentrated HCl (10 mL) was stirred at 80 °C for 4 h. The mixture was washed with H 2 O (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid (900 mg, crude) as a yellow oil. LC / MS (ESI) m / z: 326 [M+H] + .

[0626] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0627]

[0628]

[0629] Synthesis of 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile

[0630]

[0631] To a solution of 1-cyclobutyl-4-iodo-1H-pyrazole-3-carbonitrile (1.70 g, 6.23 mmol) in THF (50 mL) was added i-PrMgCl.LiCl (1.3 M in THF, 4.80 mL, 6.23 mmol) at 0°C. After stirring at 0°C for 1 h, a solution of 2-chloronicotinaldehyde (1.77 g, 12.45 mmol) in THF (50 mL) was added at 20°C. The reaction was stirred at 20°C for 1 h. The mixture was washed with NH 4 The solution was quenched with aqueous Cl solution (25 mL) and extracted with EtOAc (45 mL×3). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (50% EtOAc in PE) to give 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (1.10 g, 49.0% yield) as a white oil. LC / MS (ESI) (m / z): 289 [M+H] + .

[0632] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0633]

[0634] Synthesis of 3-((2-bromopyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0635]

[0636] To a stirred solution of 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (1.00 g, 3.42 mmol) in THF (10 mL) was added NaH (120 mg, 5.13 mmol, 60% in mineral oil) at 0°C, and the mixture was stirred at 0°C for 30 min. Then MOMCl (410 mg, 5.13 mmol) was added dropwise at 0°C, and the mixture was stirred at 25°C for 16 h. The reaction was washed with NH 4 The solution was quenched with saturated aqueous Cl (100 mL) and extracted with DCM (30 mL). The organic phase was washed with anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→25% EtOAc / PE) to give 3-((2-bromopyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (761 mg, yield: 65.9%) as a yellow oil. LC / MS (ESI) (m / z): 337 [M+H] + .

[0637] Synthesis of 1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0638]

[0639] To a solution of ethyl 1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole-5-carboxylate (5.30 g, 14.16 mmol) and tributyl(1-ethoxyvinyl)stannane (7.67 g, 21.3 mmol) in toluene (30 mL) was added Pd(PPh 3 ) 4 (820 mg, 0.710 mmol). 2 Degas three times and stir at 100 ° C for 16 h. The mixture was diluted with saturated aqueous KF solution (20 mL) and ethyl acetate (20 mL) and continued to stir at room temperature for 1 h. The mixture was filtered and the filtrate was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL×2) and washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated. The residue was diluted with THF (20 mL) and aqueous HCl (1 M, 20 mL), and the mixture was stirred at room temperature for 1 h (this acidic hydrolysis step can be skipped to isolate the enol ether intermediate). The mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL × 2) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel flash column chromatography (0→8% MeOH / DCM) to give ethyl 1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (1.60 g, yield: 39%) as a yellow oil. LC / MS ESI (m / z): 291 [M+H] + .

[0640] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0641]

[0642] Synthesis of (3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanol

[0643]

[0644] at -78 °C in N 2 To a solution of ethyl 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (5.30 g, 17.8 mmol) in THF (70 mL) was slowly added diisobutylaluminum hydride (1 M in hexanes, 19.5 mL, 19.5 mmol) under atmosphere. The reaction was stirred at 25 °C for 16 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (30 mL) and potassium sodium tartrate (30 mL), and then extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (50 mL×2) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE) to give (3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanol (4.50 g, yield: 90.3%) as a colorless oil. LC / MS ESI (m / z): 257 [M+H] + .

[0645] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0646]

[0647] Synthesis of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile

[0648]

[0649] To a solution of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (872 mg, 2.59 mmol) in DCM (10 mL) was added Et 3 SiH (1.21 g, 10.4 mmol) and TFA (887 mg, 7.78 mmol). The mixture was stirred at 0 °C for 1 h and then concentrated. The residue was dissolved in DCM (20 mL) and washed with NaHCO 3 The combined organic layers were washed with anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (50→100% EtOAc / PE) to give 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (562 mg, 67.7% yield) as a yellow oil. LC / MS (ESI) (m / z): 320 [M+H] + .

[0650] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0651]

[0652] Synthesis of 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-N,N-dimethyl-1H-pyrazole-3-carboxamide

[0653]

[0654] To a solution of 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid (447 mg, 1.44 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (353 mg, 4.32 mmol), HATU (877 mg, 2.31 mmol) and DIEA (0.310 mL, 1.87 mmol). The mixture was stirred at 20 °C for 16 h. The reactant was diluted with EtOAc (30 mL) and washed with water (25 mL x 3). The organic layer was washed with brine (25 mL x 2) and purified by anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (80→100% EtOAc / PE) to give 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (250 mg, yield: 51.4%) as a colorless oil. LC / MS (ESI) (m / z): 337 [M+H] + The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0655]

[0656] Synthesis of Sodium 4-(Cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate

[0657]

[0658] To a solution of 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (1.14 g, 4.97 mol) in THF (30 mL) was added LDA (2.0 M in THF, 4.97 mL, 9.94 mol) at -78°C. After stirring at -78°C for 0.5 h, a solution of dimethyl carbonate (670 mg, 7.46 mol) in THF (10 mL) was added dropwise at -78°C, and the reaction was stirred at room temperature for 4 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (30 mL×3) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel flash column chromatography (0→5% MeOH / DCM) to give methyl 4-(cyclopropylmethyl)-1-(N,N-dimethylsulfamoyl)-1H-imidazole-2-carboxylate (410 mg, yield: 28.7%) as a yellow gum. LC / MS ESI (m / z): 288 [M+H] + .

[0659] To a solution of methyl 4-(cyclopropylmethyl)-1-(N,N-dimethylsulfamoyl)-1H-imidazole-2-carboxylate (400 mg, 1.39 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 5 mL, 20 mmol). The reaction was stirred at 50 °C for 2 h. The mixture was concentrated to give methyl 4-(cyclopropylmethyl)-1H-imidazole-2-carboxylate (250 mg, crude) directly as a yellow gum. LC / MS ESI (m / z): 181 [M+H] + .

[0660] To a solution of methyl 4-(cyclopropylmethyl)-1H-imidazole-2-carboxylate (250 mg, 1.39 mmol) and 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole (580 mg, 2.78 mmol) in DMF (5 mL) was added Cs 2 CO 3 (1.81 g, 5.57 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with H 2 O (25 mL × 3), brine (30 mL × 2), and anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give methyl 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (540 mg, 97.2% over two steps) as a yellow solid. LC / MS (ESI) (m / z): 401 [M+H] + .

[0661] To a solution of methyl 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (360 mg, 0.900 mmol) in MeOH (5 mL) was added aqueous NaOH (2M in water, 1.80 mL, 3.60 mmol) at room temperature. The mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated to give sodium 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (340 mg, crude) as a white solid. LC / MS (ESI) (m / z): 387 [M+H] + .

[0662] Synthesis of Ethyl 3-(Cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

[0663]

[0664] At 0°C in N 2 To a stirred solution of ethyl 5-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate (1.30 g, 6.63 mmol) in THF (15 mL) was added NaH (401 mg, 10.0 mmol, 60% in mineral oil) under atmosphere. After stirring at 0°C for 1 h, a solution of SEMCl (1.34 g, 8.03 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at 0°C for 2 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (15 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (20 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (10→25% EtOAc / PE) to give ethyl 3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (1.77 g, 81.0% yield) as a white solid. LC / MS (ESI) (m / z): 325 [M+H] + .

[0665] Synthesis of (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyrazin-2-amine

[0666]

[0667] At 0°C in N 2 To a solution of (R)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (500 mg, 1.88 mmol) and 3,5-dibromopyrazin-2-amine (470 mg, 2.26 mmol) in THF (5 mL) was added NaHMDS (1.4 mL, 2.82 mmol, 2.0 M in THF), and the mixture was stirred at 70 °C overnight. The reaction was washed with NH 4 The solution was quenched with saturated aqueous Cl solution (10 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give (R)-5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyrazin-2-amine (570 mg, yield: 69.2%) as a yellow oil. LC / MS (ESI) m / z: 438 [M+H] + .

[0668] To a solution of (R)-5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyrazin-2-amine (550 mg, 1.26 mmol) in toluene (5 mL) were added hexamethyldistanane (494 mg, 1.51 mmol) and Pd(PPh 3 ) 4 (72.5 mg, 0.0630 mmol) and stirred at 25 °C. The mixture was degassed and heated with N 2 The mixture was purged three times and stirred at 100°C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→20% EtOAc / PE) to give (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyrazin-2-amine (570 mg, yield: 95.6%) as a yellow solid. LC / MS (ESI) m / z: 476 [M+H] + .

[0669] Synthesis of (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol

[0670]

[0671] To 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine (35.0 mg, 0.160 mmol), (3R)-5-fluoro-3-methyl-1,3-dihydro-2,1-benzoxaborol-1-ol (31.0 mg, 0.180 mmol) and Na 2 CO 3 To a solution of (33.0 mg, 0.310 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl 2 (11.5 mg, 0.0160 mmol). The mixture was degassed three times and heated with N 2 Purge, and then stir at 80 ° C for 16h. The mixture is filtered, and the filtrate is concentrated. The residue is purified by silica gel flash column chromatography (0→50% EtOAc / PE) to give (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol (20.0 mg, 39.0% yield) as a yellow oil. LCMS (ESI): m / z: 328 [M+H] + .

[0672] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0673]

[0674]

[0675]

[0676]

[0677] Synthesis of 5-((2-chloro-6-methylpyridin-3-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile

[0678]

[0679] To a solution of N'-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonylhydrazide (400 mg, 0.95 mmol) in dioxane (5 mL) was added (2-chloro-6-methylpyridin-3-yl)boronic acid (250 mg, 1.43 mmol) and K 2 CO 3 (72.5 mg, 0.0630 mmol), then degassed and heated with N 2 The mixture was stirred at 100°C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL x 3) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→20% EtOAc / PE) to give 5-((2-chloro-6-methylpyridin-3-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (120 mg, yield: 34.8%) as a yellow oil. LC / MS (ESI) m / z: 363 [M+H] + .

[0680] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0681]

[0682] Synthesis of 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

[0683]

[0684] at -20 °C in N 2 To a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (3.00 g, 15.1 mmol) in THF (30 mL) was added TMPMgCl·LiCl (1 M in heptane, 21.5 mL, 21.5 mmol) under atmosphere, and the mixture was stirred at -20°C for 1 h. Then a solution of 2-bromopyridine-3-carboxaldehyde (3.30 g, 17.9 mmol) in THF (10 mL) was added at -20°C. The mixture was stirred at -20°C for 1 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (50 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (40 mL×2) and dried over anhydrous Na 2SO 4 The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (4.00 g, 54.0% yield) as a colorless oil. LCMS (ESI): m / z: 409 [M+H] + .

[0685] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0686]

[0687] Synthesis of (R)-3-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile

[0688]

[0689] To 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (165 mg, 0.591 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborolan-1(3H)-ol (147 mg, 0.887 mmol), K 3 PO 4 (376 mg, 1.77 mmol) and BI-DIME (39.1 mg, 0.118 mmol) in toluene (10 mL) and H 2 Pd was added to the solution in O (2 mL) 2 (dba) 3 (54.1 mg, 0.0590 mmol). The mixture was washed with N 2 Degassing three times and stirring at 100 ° C for 3.5h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→8% MeOH / DCM) to give (R)-3-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (155 mg, yield: 77.5%) as a yellow solid. LC / MS ESI (m / z): 339 [M+H] + .

[0690] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0691]

[0692]

[0693] Synthesis of 3-(3-iodo-1-methyl-1H-pyrazole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

[0694]

[0695] To a solution of 3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (1.29 g, 2.80 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.38 g, 5.61 mmol) at 0°C and stirred at 0°C for 1 h. The reaction was washed with saturated aqueous NaHCO (5 mL) and Na 2 S 2 O 3 The combined organic phase was washed with brine (20 mL x 2) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (30→50% EtOAc / PE) to give 3-(3-iodo-1-methyl-1H-pyrazole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (878 mg, yield: 68.6%) as a yellow oil. LC / MS (ESI) (m / z): 458 [M+H] + .

[0696] Synthesis of 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile and 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

[0697]

[0698] To a stirred solution of 3-(2,4-dibromothiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (500 mg, 1.01 mmol) and methylboronic acid (92 mg, 1.52 mmol) in dioxane (20 mL) was added K 2 CO 3 (420 mg, 3.04 mmol) and Pd(PPh 3 ) 4 (117 mg, 0.10 mmol). The mixture was degassed and heated to 40 ℃ with N 2Purge three times, then stir at 100 °C for 12 h. Filter the reaction and wash the filter cake with EtOAc (30 mL). Wash the filtrate with water (15 mL) and brine (15 mL). The combined organic phases were purified by anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→30% EtOAc / PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile (100 mg, yield: 23%) as a white solid mixture. LC / MS(ESI)(m / z):427[M+H] + .

[0699] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0700]

[0701] Synthesis of 3-(2-chloronicotinoyl)-1H-pyrazole-5-carbonitrile

[0702]

[0703] To a solution of 3-(2-chloronicotinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (960 mg, 2.65 mmol) in DCM (6 mL) was added TFA (3 mL, 40.4 mmol). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was washed with EtOAc (10 mL) and NaHCO 3 The mixture was diluted with saturated aqueous solution (20 mL). The mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (20 mL×2) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel flash column chromatography (0→10% MeOH / DCM) to give 3-(2-chloronicotinoyl)-1H-pyrazole-5-carbonitrile (583 mg, yield: 94.7%) as a yellow solid. LC / MS ESI (m / z): 233 [M+H] + .

[0704] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0705]

[0706] Synthesis of 5-((2-chloropyridin-3-yl)methyl)-3-ethyl-N,N-dimethyl-1H-pyrazole-1-carboxamide

[0707]

[0708] To a solution of 2-chloro-3-((3-ethyl-1H-pyrazol-5-yl)methyl)pyridine (165 mg, 0.744 mmol) and TEA (0.0600 mL, 0.433 mmol) in toluene (10 mL) was added dimethylnitrocarbonyl chloride (0.0690 mL, 0.744 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was added to water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and purified by anhydrous Na 2 SO 4 The residue was purified by silica gel flash column chromatography (0→100% EtOAc in PE followed by 0→10% MeOH in DCM) to give a mixture of regioisomers. The regioisomers were separated by SFC (ChiralPak IB, 100×4.6 mm ID, 5 μm; 40% MeOH + 0.05% DEA in CO 2 5-[(2-chloropyridin-3-yl)methyl]-3-ethyl-N,N-dimethylpyrazole-1-carboxamide (100 mg, yield: 45.9%) was obtained as a white solid. LC / MS ESI (m / z): 293 [M+H] + .

[0709] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0710]

[0711] Synthesis of 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0712]

[0713] A mixture of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile (100 mg, 0.20 mmol) and TFA (5 mL) was stirred at 25 ° C for 3 h. The reaction mixture was concentrated. The residue was dissolved in MeCN (3 mL) and NH 3 The solution was stirred at 25 °C for 0.5 h. The mixture was washed with H 2 O (20 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (30 mL×3) and dried over anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (0→30% EtOAc / PE) to give 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1H-pyrazole-5-carbonitrile (30 mg, crude material) as a yellow oily mixture. LC / MS (ESI) (m / z): 297 [M+H] + .

[0714] 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1H-pyrazole-5-carbonitrile (90 mg, 0.25 mmol) and K were added at 0 °C. 2 CO 3 To a mixture of iodomethane (69 mg, 0.49 mmol) in DMF (1 mL) was added dropwise iodomethane (39 mg, 0.27 mmol). The reaction was stirred at 25 °C for 16 h and then concentrated. The residue was diluted with EtOAc (15 mL), washed with brine (10 mL), and purified by Na 2 SO 4 Dried and concentrated. The residue was purified by silica gel column chromatography (0→25% EtOAc / PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (60 mg, yield: 64.5%) in the form of a yellow oily mixture. LC / MS (ESI) (m / z): 311 [M+H] + .

[0715] Synthesis of 3-cyano-5-((2,4-dibromothiazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide

[0716]

[0717] To a solution of 5-((2,4-dibromothiazol-5-yl)methyl)-1H-pyrazole-3-carbonitrile (550 mg, 1.58 mmol) in THF (10 mL) was added dimethylcarbamoyl chloride (340 mg, 3.16 mmol), TEA (0.659 mL, 4.74 mmol) and DMAP (96.5 mg, 0.790 mmol). The mixture was degassed and heated with N 2 Purged three times, then stirred at 70 °C for 3 h. The mixture was washed with H 2 O (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (10→50% EtOAc / PE) to give 3-cyano-5-((2,4-dibromothiazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (600 mg, yield: 90.6%) as a yellow oil. LC / MS (ESI) m / z: 418 [M+H] + .

[0718] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0719]

[0720]

[0721] Synthesis of 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile

[0722]

[0723] 3-(2-Chloronicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-Chloronicotinoyl)-1-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.810 mmol), (R)-5,7-difluoro-3-methylbenzo[c][1,2]oxaborolan-1(3H)-ol (270 mg, 1.22 mmol) and Na 2 CO 3(387 mg, 3.65 mmol) was added to a mixture of 1,4-dioxane (9 mL) and water (3 mL) with Pd(dppf)Cl 2 (89.0 mg, 0.120 mmol). 2 Degas three times and stir at 100 ° C for 16h. The mixture is filtered and the filtrate is concentrated. The residue is purified by silica gel flash column chromatography (0→8% MeOH / DCM) to give 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (70.0 mg, yield: 15.1%) as a white solid mixture. LC / MS ESI (m / z): 369[M+H] + .

[0724] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0725]

[0726] Synthesis of 1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0727]

[0728] To a solution of ethyl 1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylate (2.60 g, 8.90 mmol) in DMF (15 mL) at 0°C was added imidazole (2.72 g, 39.9 mmol) and tert-butylchlorodimethylsilane (4.02 g, 26.7 mmol). The reactants were stirred at room temperature for 1 h. The mixture was poured into water (50 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (30 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→20% EtOAc / PE) to give ethyl 1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (3.30 g, yield: 91.3%) as a clear oil. LC / MS ESI (m / z): 407 [M+H] + .

[0729] Synthesis of (Z)-N'-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonylhydrazide

[0730]

[0731] To a solution of 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (1.50 g, 5.97 mmol) in dioxane (50 mL) was added 4-methylbenzene-1-sulfonylhydrazide (1.10 g, 5.91 mmol), and the reactants were stirred at 80 ° C for 3 hours. The reactants were concentrated. The residue was purified by silica gel flash column chromatography (20→40% EtOAc / PE) to give (Z)-N'-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonylhydrazide (500 mg, 99.8% yield) as a yellow oil. LC / MS(ESI)(m / z):420[M+H] + .

[0732] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0733]

[0734] Synthesis of 1-(cyclopropylmethyl)-4-((3-(2,4-difluoro-6-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile

[0735]

[0736] To a solution of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (850 mg, 2.66 mmol) in 1,4-dioxane (9 mL) and water (3 mL) were added 5,7-difluoro-3-methylbenzo[c][1,2]oxaborolan-1(3H)-ol (732 mg, 3.98 mmol), Na 2 CO 3 (844 mg, 7.96 mmol) and X-phos G 3 Pd (112 mg, 0.130 mmol). 2 The mixture was degassed three times and stirred at 100 °C for 2 h. 2 O (30 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine (30 mL×2) and dried over anhydrous Na2 SO 4 The residue was purified by flash column chromatography on silica gel (30→100% EtOAc / PE) to give 1-(cyclopropylmethyl)-4-((3-(2,4-difluoro-6-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile (950 mg, 90.0% yield) as a black oil. LC / MS (ESI) (m / z): 398 [M+H] + .

[0737] Synthesis of 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide

[0738]

[0739] To a solution of 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carboxylic acid (330 mg, 0.762 mmol), dimethylamine (93.42 mg, 1.142 mmol) and DIEA (344.54 mg, 2.666 mmol) in DMF (4 mL) was added HATU (347.52 mg, 0.914 mmol) at 0 °C and the reaction was stirred at 25 °C under N 2 The reaction was stirred for 2 h under a 4% CO atmosphere. 2 O (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to give a residue. The residue was purified by silica gel column chromatography (0→3% MeOH / DCM) to give 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (312 mg, yield: 89%) as a yellow oil. LC / MS (ESI) (m / z): 460 [M+H] + .

[0740] Synthesis of (R)-4-bromo-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide

[0741]

[0742] To a solution of (R)-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (88.0 mg, 0.222 mmol) in THF (4 mL) was added dropwise a solution of NBS (39.5 mg, 0.222 mmol) in THF (1 mL) at 0°C, and the mixture was stirred at 0°C for 30 min. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by preparative TLC (100% EtOAc) to give (R)-4-bromo-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (100 mg, yield: 95.0%) as a yellow solid. LC / MS ESI (m / z): 475 [M+H] + .

[0743] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0744]

[0745] Synthesis of 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile

[0746]

[0747] To a solution of 1-(cyclopropylmethyl)-4-((1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-3-carbonitrile (264 mg, 0.650 mmol) in THF (9 mL) was added HCl (3 mL). The reaction was stirred at 20 °C for 1 h. The mixture was washed with NaHCO 3 The mixture was diluted with saturated aqueous solution and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (15 mL×2) and purified by anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE) to give 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (160 mg, yield: 65.0%) as a yellow solid. LC / MS (ESI): m / z=378 [M+H] + .

[0748] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0749]

[0750] Synthesis of 1-cyclobutyl-4-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide

[0751]

[0752] To a solution of 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (240 mg, 0.567 mmol) in MeOH (5 mL) at 0 °C was added NaBH 4 (23.58 mg, 0.623 mmol) and heated at 0 °C under N 2 The reaction was stirred under atmosphere for 0.5 h. The reaction was quenched with aqueous HCl (1 M, 5 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue. The residue was purified by silica gel column chromatography (0→2% MeOH / DCM) to give 1-cyclobutyl-4-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (181 mg, yield: 75.1%) as a yellow oil. LC / MS (ESI) (m / z): 426 [M+H] + .

[0753] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0754]

[0755] Synthesis of (R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

[0756]

[0757] To a solution of (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol (25.0 mg, 0.0760 mmol) in THF (15 mL) was added NaH (4.60 mg, 0.120 mmol, 60% mineral oil), and the mixture was stirred for 0.5 h. Then 5-bromo-3-fluoro-2-nitropyridine (20.0 mg, 0.0900 mmol) was added. The reaction was stirred at 25 °C for 18 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were purified by anhydrous Na 2 SO 4 The mixture was dried, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc / PE) to give (R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (26.0 mg, 64.0% yield) as a yellow solid. LCMS (ESI): m / z: 528 [M+H] + .

[0758] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0759]

[0760]

[0761]

[0762] Synthesis of (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

[0763]

[0764] To a solution of (R)-1-ethyl-4-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carbonitrile (320 mg, 0.910 mmol) and 5-bromo-3-fluoro-2-nitropyridine (303 mg, 1.37 mmol) in THF (10 mL) was added t-BuOK (1 M in THF, 1.37 mL, 1.37 mmol) at -70 °C. The reaction was stirred at -70 °C for 10 min. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×2) and dried over anhydrous Na 2 SO 4 Drying and concentration gave (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (500 mg, crude) as a white solid. LC / MS (ESI) (m / z): 551 [M+H] + .

[0765] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0766]

[0767]

[0768] Synthesis of (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

[0769]

[0770] At 0°C in N 2 To a stirred solution of (R)-1-ethyl-4-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile (584 mg, 1.65 mmol) in THF (10 mL) was added NaH (198 mg, 4.96 mmol, 60% in mineral oil) under atmosphere. After stirring at 0°C for 1 h, a solution of 5-bromo-3-fluoro-2-nitropyridine (365 mg, 1.65 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at 0°C for 1 h and NH 4 The solution was quenched with saturated aqueous Cl solution (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with anhydrous Na2 SO 4 The filtrate was dried and concentrated to give a crude substance (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (916 mg) as a yellow oil. LC / MS (ESI) (m / z): 554.1 [M+H] + .

[0771] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0772]

[0773]

[0774] Synthesis of 3-(2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2-[(1R)-1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile

[0775]

[0776] At 0°C in N 2 To a solution of 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (70 mg, 0.190 mmol) in THF (5 mL) was added NaH (15.2 mg, 0.380 mmol, 60% in mineral oil) and the mixture was stirred at 0° C. for 0.5 h. 5-Bromo-3-fluoro-2-nitropyridine (83.9 mg, 0.380 mmol) was then added and the reaction was stirred at room temperature under N 2 The mixture was stirred for 12 h. 4 The mixture was quenched with saturated aqueous Cl solution (10 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→10% MeOH / DCM) to give 3-(2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2-[(1R)-1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (60.0 mg, yield: 55.5%) as a yellow solid mixture. LC / MS ESI (m / z): 569 [M+H] + .

[0777] Synthesis of 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0778]

[0779] At 0°C in N 2 To a stirred solution of 3-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (1.67 g, 4.03 mmol) in THF (30 mL) was added NaH (242 mg, 6.04 mmol, 60% in mineral oil) under atmosphere. After stirring at 0°C for 1 h, a solution of 3,5-dibromopyrazin-2-amine (1.20 g, 4.84 mmol) in THF (10 mL) was added dropwise. The reaction was stirred at 70°C for 1 h. The reaction was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (100 mL) and extracted with EtOAc (100 mL). The organic phase was purified by Na 2 SO 4 Drying and concentration to dryness gave 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (800 mg, 34% yield) as a yellow oil. LC / MS (ESI) (m / z): 586 [M+H] + .

[0780] Synthesis of 3-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-5-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide and 5-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-3-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide

[0781]

[0782] at -78 °C in N 2 To a mixture of 3-cyano-5-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide and 5-cyano-3-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (110 mg, 0.267 mmol) and 5-bromo-3-fluoro-2-nitropyridine (70.9 mg, 0.321 mmol) in THF was added potassium tert-butoxide (1 M in THF, 0.401 mL, 0.401 mmol). The reaction was stirred at -78 °C for 1 h. The reaction mixture was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (7 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE) to give 5-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-3-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide and 3-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-5-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide (110 mg, yield: 67.2%) as a yellow oily mixture. LC / MS(ESI)(m / z): 612[M+H] + .

[0783] Synthesis of (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)oxy)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylic acid ethyl ester

[0784]

[0785] at -70 °C in N 2 To a solution of (R)-1-(cyclopropylmethyl)-4-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1H-pyrazole-3-carboxylic acid ethyl ester (550 mg, 1.29 mmol) and 5-bromo-3-fluoro-2-nitropyridine (314 mg, 1.42 mmol) in THF (22 mL) was added t-BuOK (1 M in THF, 2.59 mL) under atmospheric pressure. After stirring for 15 min, the mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (25 mL×2) and dried over anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→100% EtOAc / PE, V / V) to give (R)-ethyl 4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)oxy)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate (400 mg, 49.0% yield) as a white solid. LC / MS (ESI) (m / z): 626 [M+H] + .

[0786] The following intermediates were synthesized using a similar protocol (with m / z (ESI) values):

[0787]

[0788] Synthesis of 3-{1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-3-methyl-1H-pyrazole-5-carbonyl}-1H-pyrazole-5-carbonitrile

[0789]

[0790] To a solution of 3-(1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (584 mg, 1.00 mmol) in THF (8 mL) was added TBAF (2.00 mL, 4.00 mmol) at room temperature. The reaction was stirred at 40 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×2), the combined organic phases were washed with brine (20 mL×3), and the mixture was purified by anhydrous Na2 SO 4 The residue was purified by flash column chromatography on silica gel (0→8% MeOH / DCM) to give 3-{1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-3-methyl-1H-pyrazole-5-carbonyl}-1H-pyrazole-5-carbonitrile (223 mg, yield: 65.7%) as a white solid. LC / MS ESI (m / z): 340 [M+H] + .

[0791] Synthesis of 3-(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl]-1-methyl-1H-pyrazole-3-carbonitrile

[0792]

[0793] To a stirred solution of 5-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile and 3-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (76.0 mg, mixture, 0.220 mmol) in THF (5 mL) was added NaH (10.3 mg, 0.260 mmol, 60% in mineral oil) at 0°C and the mixture was stirred at 0°C under N 2 5-Bromo-3-fluoro-2-nitropyridine (61.8 mg, 0.280 mmol) in THF (5 mL) was then added and the reaction was stirred at 50° C. for 12 h. The mixture was washed with NH 4 The mixture was quenched with saturated aqueous solution of Cl (10 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (10 mL×2) and washed with anhydrous Na 2 SO 4The residue was purified by flash column chromatography on silica gel (0→10% MeOH / DCM) to give 3-(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (45.0 mg, yield: 37.7%) as a yellow solid. 5-[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl]-1-methyl-1H-pyrazole-3-carbonitrile was not isolated. LC / MS ESI (m / z): 554[M+H] + .

[0794] Compound

[0795] Embodiment 1 (method A):

[0796] Name: (19R)-22-amino-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carbonitrile

[0797] NMR: 1H NMR(400MHz,MeOD)δ7.60(s,1H),7.55(dd,J=10.1,2.5Hz,1H),7.49(d,J=1.6Hz,1H),7.29 –7.16(m,1H),7.08(d,J=2.6Hz,1H),6.46(s,1H),5.45(d,J=6.3Hz,1H),4.09(d,J=6.3Hz, 1H),4.02(s,1H),3.94(s,3H),3.80(d,J=15.8Hz,1H),3.04(d,J=15.8Hz,1H),1.82(d,J=6 .2Hz,3H),1.17–1.07(m,1H),0.57–0.41(m,2H),0.31(d,J=4.8Hz,1H),0.20–0.07(m,1H).

[0798] LCMS: Method N; t R :1.19min; m / z:470[M+H] +

[0799] To (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (100 mg, 0.17 mmol) in EtOH (5 mL) and H 2 Iron powder (96.2 mg, 1.72 mmol) and NH 4 Cl (184 mg, 3.44 mmol). The reaction was stirred at 70 °C for 1 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , 50% EtOAc / PE) to give (R)-4-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (60 mg, 63% yield) as a yellow solid. LC / MS (ESI) (m / z): 550 [M+H] + .

[0800] To a solution of (R)-4-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (60 mg, 0.11 mmol) in 2-methyl-2-butanol (2 mL) was added KOAc (27 mg, 0.27 mmol), Pd(OAc) and 4-((3-(2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (60 mg, 0.11 mmol) in 2-methyl-2-butanol (2 mL). 2 (6.0 mg, 0.026 mmol) and cataCXiumA (19 mg, 0.052 mmol), and in N 2 The reaction was stirred at 120°C for 12 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Gemini 5um C18 250×21.2 mm; 20→95% MeCN / H 2 O+0.1% FA) to obtain the target compound (22 mg, 43% yield). LC / MS (ESI) (m / z): 470 [M+H] + .

[0801] The following compounds were prepared in a similar manner:

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817] Embodiment 5 (method B):

[0818]

[0819] Name: (R)-22-amino-3-ethyl-16-fluoro-10-methyl-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxamide

[0820] NMR: 1H NMR (400MHz, DMSO) δ7.70(d,J=10.0Hz,1H),7.52–7.45(m,2H),7.42(s,1H),7.24(s,1H),7.16–7.10(m,2H),6.31(d,J=1.6Hz,1H),6.16(s,2H), 5.39–5.29(m,1H),4.23(d,J=14.9Hz,1H),4.14–3.98(m,2H),3.85(s,3 H), 2.62 (d, J = 14.5Hz, 1H), 1.71 (d, J = 6.2Hz, 3H), 1.29 (t, J = 7.2Hz, 3H).

[0821] LCMS: Method F; t R :0.71min; m / z:462[M+H] +

[0822] At room temperature, (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ] To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carbonitrile (20 mg, 0.045 mmol) in THF (1.0 mL) was added a solution of NaOH (5.0 mg, 0.14 mmol) in water (2.0 mL). The reaction was stirred at 100 °C in a sealed tube for 12 h. The mixture was extracted with EtOAc (2 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Gemini 5um C18 250×21.2 mm; 5→95% MeCN / H 2 O+0.1% FA) to obtain the target product (10 mg, 48% yield). LC / MS (ESI) (m / z): 462 [M+H] + .

[0823] The following compounds were prepared in a similar manner:

[0824]

[0825] Embodiment 7 (method C):

[0826]

[0827] Name: N,N-dimethyl-(R)-22-amino-3-ethyl-16-fluoro-10-methyl-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxamide

[0828] NMR: 1H NMR (400MHz, DMSO) δ7.73(s,1H),7.69(d,J=10.6Hz,1H),7.46(s,1H),7.12(d,J=7.0Hz,2H),6.32(s,1H),6.14(s,2H),5.35(d,J=6.0Hz,1H),4 .05(q,J=7.2Hz,2H),3.86(s,3H),3.72(d,J=15.0Hz,1H),3.20(s,3H), 3.05(s,3H),2.67(s,1H),1.71(d,J=6.1Hz,3H),1.28(t,J=7.2Hz,3H).

[0829] LCMS: Method F; t R :1.10min; m / z:490[M+H] +

[0830] To (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ] To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carbonitrile (10 mg, 0.023 mmol) in MeOH (2 mL) was added NaOH (2M in water, 0.015 mL, 0.09 mmol) and the reaction was stirred at 80°C for 12 h. The mixture was concentrated directly to give the crude material (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxylic acid (8 mg, 76% yield). LC / MS (ESI) (m / z): 463 [M+H] + .

[0831] To the crude material (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ] To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxylic acid (8.0 mg, 0.017 mmol) in DMF (1.0 mL) was added dimethylamine hydrochloride (0.003 mL, 0.04 mmol), DIEA (0.009 mL, 0.05 mmol) and HATU (11 mg, 0.028 mmol). The reactants were stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with Na 2 SO 4 The residue was purified by preparative HPLC (column: Gemini 5um C18 250×21.2 mm; 5→95% MeCN / H 2 O+0.1% FA) to obtain the target product (1.6 mg, 19% yield). LC / MS (ESI) (m / z): 490 [M+H] + .

[0832] The following compounds were prepared in a similar manner:

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841] Example 49 (Method D):

[0842]

[0843] Name: (R)-23-amino-17-fluoro-4-methyl-20-methyl-7-oxo-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 ] Hexadecene-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecene-3-carbonitrile

[0844] NMR: 1H NMR (400MHz, TFA salt,MeOD)δ8.85(dd,J=4.9,1.7Hz,1H),8.49(dd,J=8.0,1.6Hz,1H),7.66(ddd,J=8.6,6.3,3.8Hz,3H),7.41(dd,J=10.0 ,2.6Hz,1H),7.15(td,J=8.5,2.7Hz,1H),6.59(d,J=1.7Hz,1H),5.00(q,J=6.3Hz,1H),4.18(s,3H),1.80(d,J=6.3Hz,3H).

[0845] LCMS: Method Q; t R :1.11min; m / z:441[M+H] +

[0846] To a mixture of 3-(2-bromonicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (300 mg, 1.0 mmol), (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyridin-2-amine (635 mg, 1.30 mmol) in DMF (10 mL) was added AsPh 3 (157 mg, 0.510 mmol), CuI (19.6 mg, 0.100 mmol) and Pd 2 (dba) 3 (94.0 mg, 0.100 mmol). The mixture was degassed three times and heated with N 2 The reaction was stirred at 100 °C for 16 h. The mixture was cooled and filtered. The filtrate was washed with H 2Dilute with O (15 mL) and extract with EtOAc (40 mL × 3). Wash the combined organic solution with water (15 mL × 3) and brine (20 mL × 2), and dry over anhydrous Na 2 SO 4 dry, filter and concentrate. Purify the residue by flash column chromatography on silica gel (0→50% EtOAc / PE) to obtain (R)-3-(2-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (100 mg, 18.6% yield). LCMS (ESI): m / z: 521 [M+H] + .

[0847] To a mixture of (R)-3-(2-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (100 mg, 0.200 mmol) in 2-methyl-2-butanol (5 mL), add KOAc (56.5 mg, 0.580 mmol), butyl-di-1-adamantylphosphine (27.5 mg, 0.0800 mmol) and palladium(II) acetate (8.60 mg, 0.0400 mmol). Degas the mixture three times and purge with N 2 and seal the reaction tube. Stir the reactant at 120 °C for 16 h. Purify the residue directly by flash column chromatography on silica gel (0→60% EtOAc / PE) and further by preparative HPLC (column: YMC-Actus Triart C18 150×20 mm×5 μm; 10→95% MeCN / H 2 O + 0.1% TFA) to obtain the target product trifluoroacetate (26.0 mg, 23% yield). Separate the free base form by solid-phase or liquid-phase acid-base extraction with a basic medium such as an aqueous solution of NaHCO 3 1H NMR (400 MHz, free base, MeOD) δ 8.79 (dd, J = 4.9, 1.7 Hz, 1H), 8.28 (dd, J = 8.0, 1.7 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.6, 5.7 Hz, 1H), 7.57 (dd, J = 8.0, 4.9 Hz, 1H), 7.42 (dd, J = 10.1, 2.7 Hz, 1H), 7.12 (td, J = 8.5, 2.7 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 4.71 (q, J = 6.3 Hz, 1H), 4.13 (s, 3H), 1.75 (d, J = 6.3 Hz, 3H). LCMS (ESI): m / z: 441 [M+H] +.

[0848] The following compounds were prepared in a similar manner:

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855] Example 23 (Method E):

[0856]

[0857] Name: (19R)-22-amino-3-(cyclopropylmethyl)-14,16-difluoro-N,N,10,19-tetramethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decene-5-carboxamide

[0858] NMR: 1H NMR (400MHz, MeOD) δ7.99(s,1H),7.41(d,J=1.6Hz,2H),6.98(s,1H),6.54(d,J=1.6Hz,1H),5.41(d,J=5.9Hz,1H),3.97(m,4H),3.12(m,7H ), 2.59(dd,J=6.6,1.9Hz,2H),1.80(d,J=6.3Hz,3H),0.93(s,1H),0.39(ddd,J=12.6,8.6,4.4Hz,2H),0.14(s,1H),0.03(d,J=3.8Hz,1H).

[0859] LCMS: Method U;t R :1.25min; m / z:534[M+H] +

[0860] To a solution of (R)-4-bromo-5-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (65.0 mg, crude material) and iron powder (50.0 mg, 0.890 mmol) in EtOH (5 mL) and H 2 NH 4 Cl (48.0 mg, 0.890 mmol). The reactant was stirred at 80 ° C for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0 → 55% EtOAc / PE) to give (R) -5- ((3- (2- (1- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl) -4,6-difluorophenyl) -1-methyl -1H- pyrazol-4-yl) methyl) -4-bromo-3- (cyclopropylmethyl) -N, N- dimethyl -1H- pyrazole -1- carboxamide (45.0 mg, 56.0% yield, over two steps) as a light yellow oil. LC / MS (ESI) (m / z): 692 [M + H] + .

[0861] To (R)-5-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-bromo-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (45.0 mg, 0.0650 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (33.0 mg, 0.130 mmol), CsF (2 M in H 2 To a mixture of 1,4-dihydro-1,4-dihydro-2-nitropropene (2-nitropropene, 0.100 mL, 0.195 mmol) and cataCXium A (9.00 mg, 0.0260 mmol) in MeOH (10 mL) was added Pd(OAc) 2 (3.00 mg, 0.0130 mmol). The suspension was degassed and heated to 40 ℃ with N 2 The reaction mixture was stirred at 70°C in a sealed tube for 2 h. The mixture was concentrated and purified by preparative HPLC (column: YMC-TAC18 250×21.2 mm×5 μm; 5→95% MeCN / H 2 The residue was purified by HPLC (HPLC-MS / MS / ESI): 534[M+H] + .

[0862] The following compounds were prepared in a similar manner:

[0863]

[0864]

[0865] Embodiment 2 (method F):

[0866]

[0867] Name: (R)-3-(Cyclopropylmethyl)-16-fluoro-5-methylsulfonyl-10-methyl-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decen-22-ylamine

[0868] NMR: 1H NMR(400MHz,MeOD)δ7.73(s,1H),7.55(d,J=10.2Hz,1H),7.47(s,1H),7.24–7.12 (m,1H),7.07(t,J=8.0Hz,1H),6.52(s,1H),5.49(d,J=6.2Hz,1H),4.17–4.08(m,2 H),4.06–3.97(m,1H),3.93(s,3H),3.33(s,3H),2.94(d,J=15.2Hz,1H),1.83(d,J =6.2Hz,3H),1.12(m,1H),0.47(m,J=28.5Hz,2H),0.33–0.24(m,1H),0.10(m,1H).

[0869] LCMS: Method U;t R :0.88min; m / z:523[M+H] +

[0870] At 0°C, (R)-3-(cyclopropylmethyl)-16-fluoro-10-methyl-19-methyl-5-(methylthio)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18] To a solution of pentacosa-1(25),2(6),4,8,11,13,15,17,21,23-decen-22-ylamine (50.0 mg, 0.100 mmol) in DCM (2 mL) was added m-CBPA (21 mg, 0.100 mmol). The reaction was stirred at 0° C. for 30 min. The mixture was washed with Na 2 S 2 O 3 The mixture was quenched with saturated aqueous solution (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was dried, filtered, and concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250×20 mm×5 μm; 5→95% MeCN / H 2 O + 0.1% FA) to give the sulfone product (1.00 mg, 2.0% yield, white solid, LC / MS ESI (m / z): 523 [M+H] + ) and sulfoxide product (6.7 mg, 13% yield, LC / MS ESI (m / z): 507 [M+H] + ).

[0871] The following compounds were prepared in a similar manner:

[0872]

[0873] Example 41 (Method G):

[0874] Name: N,N-dimethyl-(R)-22-amino-3-(cyclopropylmethyl)-16-fluoro-10-methyl-19-methyl-20-oxa-4,6,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decene-5-carboxamide

[0875] NMR: 1H NMR (400MHz, DMSO) δ7.87(s,1H),7.73(d,J=10.2Hz,1H),7.33(s,1H),7.11(d,J=6.5Hz,2H),6.32(s,1H),6.04(s,2H),5.42(d ,J=15.5Hz,2H),3.90(s,3H),3.86(s,1H),3.25(s,3H),3.07(s,3H),2.35(dd,J=20.5,6.4Hz,2H),1.73(d,J=6.2Hz,3H),0.94–

[0876] 0.89(m,1H),0.37–0.28(m,2H),0.14–0.03(m,2H).

[0877] LCMS: Method U;t R :0.80min; m / z:516[M+H] +

[0878] To a solution of (R)-1-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (80.0 mg, 0.140 mmol) in EtOH (5 mL) and water (1 mL) was added iron powder (40.0 mg, 0.700 mmol) and NH 4 Cl (70.0 mg, 1.40 mmol). The reactant was stirred at 80 ° C for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0 → 50% EtOAc / PE) to give (R) -1- ((3- (2- (1- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl) -4-fluorophenyl) -1-methyl -1H- pyrazol-4-yl) methyl) -4- (cyclopropylmethyl) -N, N- dimethyl -1H-imidazole -2-carboxamide (70.0 mg, yield: 92.1%) as a brown solid. LC / MS (ESI) (m / z): 596 [M + H] + .

[0879] To a stirred solution of (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (40 mg, 0.060 mmol) in MeCN (4 mL) at 0°C was added a solution of N-bromosuccinimide (10 mg, 0.060 mmol) in MeCN (1 mL). The reaction was stirred at 0°C for 1 h. The mixture was poured into NaHCO 3 The solution was added to a saturated aqueous solution (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×2) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel (0→50% EtOAc / PE) to give (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-bromo-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (40.0 mg, yield: 88.9%) as a brown solid. LC / MS (ESI) (m / z): 674 [M+H] + .

[0880] To a solution of (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-bromo-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (50 mg, 0.070 mmol) in MeOH (8 mL) was added B 2 Pin 2 (60 mg, 0.22 mmol), cataCXium A (10 mg, 0.040 mmol), CsF (2 M in H 2 O, 0.07 mL, 0.150 mmol) and Pd(OAc) 2 (10 mg, 0.020 mmol). 2 Degas three times and stir at 80°C overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (5% MeOH / DCM) and purified by preparative HPLC (column: YMC TAC18 250×21.2 mm 5 μm, 5→95% MeCN / H 2O (containing 0.1% FA)) was further purified to obtain the target product (1.5 mg, yield: 0.40%). LC / MS (ESI) (m / z): 516 [M+H] + 。

[0881] Example 39 (Method H):

[0882]

[0883] Name: N,N-dimethyl-(R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaene-5-carboxamide

[0884] NMR: 1H NMR (400 MHz, DMSO) δ 8.25 (d, J = 3.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.37 (ddt, J = 13.3, 7.8, 3.6 Hz, 3H), 7.10 (dd, J = 8.5, 5.8 Hz, 1H), 6.92 (ddd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 2H), 6.11 (d, J = 1.4 Hz, 1H), 4.88 (d, J = 4.9 Hz, 1H), 4.00 (dd, J = 14.4, 6.2 Hz, 1H), 3.85 (dd, J = 14.5, 7.3 Hz, 1H), 2.93 (s, 3H), 2.83 (s, 3H), 1.55 (d, J = 6.2 Hz, 3H), 1.01 (m, J = 16.7, 9.4 Hz, 1H), 0.26 (m, J = 12.4, 8.5, 4.8 Hz, 2H), 0.12 (m, J = 9.0, 4.2 Hz, 1H), -0.00 (m, J = 9.5, 4.7 Hz, 1H).

[0885] LCMS: Method Y2; t R : 1.79 min; m / z: 515 [M+H] +

[0886] To (R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2 ,6 .0 8 , 13 .0 14 , 19 ] Ethyl hexacosyl-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylate (65.0 mg, 0.126 mmol) in THF (2 mL), EtOH (2 mL) and H 2 Lithium hydroxide hydrate (26.0 mg, 0.630 mmol) was added to the solution in 4% HCl (2 mL). The reaction was stirred at room temperature overnight. The mixture was adjusted to pH 5 with aqueous HCl (1 M) and extracted with EtOAc (10 mL×3). The combined organic phases were purified by Na 2 SO 4 Drying and concentration gave (20R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 ] Hexacosyl-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylic acid (45.0 mg, crude material). LC / MS (ESI) (m / z): 488 [M+H] + .

[0887] At 0°C, (20R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 ] To a solution of hexadecene-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylic acid (25.0 mg, 0.0500 mmol), dimethylamine hydrochloride (4.60 mg, 0.100 mmol) and DIEA (0.03 mL, 0.200 mmol) in DMF (1 mL) was added HATU (23.3 mg, 0.0600 mmol). The reactants were stirred at room temperature for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Azzota C18 30×250 mm×10 μm, 15→95% MeCN / H2 O (containing 0.1% FA)) to obtain the target product (8.00 mg, 30.0% yield, over two steps). LC / MS (ESI) (m / z): 515 [M+H] + .

[0888] Embodiment 77 (method I):

[0889]

[0890] Name: (R)-23-amino-15,17-difluoro-20-methyl-7-oxo-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 ] Hexadecene-1(25),2,5,8,10,12,14,16,18,22(26),23-undecene-3-carbonitrile

[0891] NMR: 1H NMR (400MHz, DMSO-d6) δ14.84(s,1H),8.96(dd,J=4.9,1.6Hz,1H),8.34(s,1H),7.75(dd,J=8.0,4.9Hz,1H),7.71(s,1H ), 7.44 (d, J = 9.8Hz, 1H), 7.32 (t, J = 9.2Hz, 1H), 6.28 (s, 1H), 6.17 (d, J = 1.9Hz, 1H), 4.64 (s, 1H), 1.58 (d, J = 6.2Hz, 3H).

[0892] LCMS: Method U;t R :0.83min; m / z:445[M+H] +

[0893] To (R)-23-amino-15,17-difluoro-20-methyl-7-oxo-4-{[2-(trimethylsilyl)ethoxy]methyl}-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19To a solution of hexacosyl-1(25),2,5,8,10,12,14,16,18,22(26),23-undecene-3-carbonitrile (55 mg, 0.096 mmol) in DCM (3 mL) was added TFA (1.0 mL, 13 mmol) and the reaction was stirred at 25 °C for 4 h. The mixture was washed with NaHCO 3 The saturated aqueous solution was quenched and extracted with DCM (20 mL x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (0→5% MeOH / DCM) and then by preparative HPLC (column: YMC Triart C18 250×20 mm I.D., 5 um, 5→95% MeCN / H 2 O (containing 0.1% FA)) was further purified to obtain the target product (9.9 mg, yield: 23.3%). LC / MS ESI (m / z): 445 [M+H] + .

[0894] Example 78 (Method J):

[0895]

[0896] Name: (7S,20R)-23-amino-17-fluoro-7-hydroxy-4-methyl-20-methyl-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 ] Hexadecene-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecene-3-carbonitrile

[0897] NMR: 1H NMR (400MHz, MeOD) δ8.56–8.48(m,1H),7.96–7.88(m,1H),7.65(d,J=1.7Hz,1H),7.45–7.30(m,3H),6.96(td,J=8. 5, 2.7Hz, 1H), 6.72 (d, J = 1.6Hz, 1H), 6.43 (s, 1H), 4.97 (td, J = 6.2, 4.4Hz, 1H), 4.08 (s, 3H), 1.79 (d, J = 6.3Hz, 3H).

[0898] LCMS: Method R; t R :0.76min; m / z:443[M+H]+

[0899] At 25°C, (R)-23-amino-17-fluoro-4-methyl-20-methyl-7-oxo-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 ] A solution of hexacosyl-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecene-3-carbonitrile (100 mg, 0.227 mmol) in MeOH (5 mL) was added with NaBH 4 (17.0 mg, 0.454 mmol). After stirring at 25°C for 1 h, the reaction was washed with NH 4 The mixture was quenched with saturated aqueous Cl solution (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Gemini 5um C18 250×21.2 mm; 5→95% CH 3 CN / H 2 O+0.1% FA) to obtain the target product (50 mg, yield: 50%). LC / MS (ESI) (m / z): 443 [M+H] + .

[0900] The following compounds were prepared in a similar manner:

[0901]

[0902] Example 80 (Method K):

[0903]

[0904] Name: (R)-22-amino-14,16-difluoro-4-methyl-10,19-dimethyl-7-oxo-20-oxa-9-thia-4,5,11,23-tetraazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ]pentacosa-1(24),2,5,8(12),10,13,15,17,21(25),22-decene-3-carbonitrile

[0905] NMR: 1H NMR(400MHz,MeOD)δ7.70(d,J=1.8Hz,1H),7.34(ddd,J=9.6,2.4,1.2Hz,1H),7.05(td,J=9.0,2.5Hz,1 H), 6.40 (d, J = 1.9Hz, 1H), 4.90 (dd, J = 6.1, 1.6Hz, 1H), 4.13 (s, 3H), 2.86 (s, 3H), 1.72 (d, J = 6.3Hz, 3H).

[0906] LCMS: Method U;t R :1.29min; m / z:479[M+H] +

[0907] To a solution of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (50 mg, 0.16 mmol) in toluene (0.6 mL), t-BuOH (0.3 mL) and H 2 To the mixture in 2% CO (0.2 mL), (R)-tert-butyl(3-(1-(3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethoxy)pyridin-2-yl)carbamate (115 mg, 0.24 mmol), Pd(dppf)Cl 2 (12 mg, 0.02 mmol) and Na 2 CO 3 (51 mg, 0.48 mmol). The reaction was degassed and heated to 40 ℃ with N 2 The mixture was purged three times and stirred at 80°C for 8 h. The mixture was cooled to 25°C and filtered using EtOAc (50 mL) to rinse the filter cake. The filtrate was washed with water (15 mL), washed with brine (15 mL), and washed with Na 2 SO 4 The mixture was dried and concentrated to give tert-butyl (R)-(3-(1-(2-(5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-2-methylthiazol-4-yl)-3,5-difluorophenyl)ethoxy)pyridin-2-yl)carbamate and tert-butyl N-{3-[(1R)-1-{2-[5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-1,3-thiazol-4-yl]-3,5-difluorophenyl}ethoxy]pyridin-2-yl}carbamate (80 mg, crude material) as a white solid mixture. LC / MS(ESI)(m / z): 581[M+H] + .

[0908] To tert-butyl (R)-(3-(1-(2-(5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-2-methylthiazol-4-yl)-3,5-difluorophenyl)ethoxy)pyridin-2-yl)carbamate and tert-butyl N-{3-[(1R)-1-{2-[5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-1,3-thiazol-4-yl]-3,5-difluorophenyl}ethox...

Claims

1. A compound of formula (I), or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein Q is CH or N; Z is CR 5 or N; L is -CH 2 -, C=O or -O-; X is a 5-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene group is surrounded by 1, 2 or 3 R 2 replace; Y is a 5-membered or 6-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered or 6-membered heteroarylene group is surrounded by 0, 1 or 2 R 3 replace; R 1 Selected from the group consisting of H, methyl and hydroxymethyl; Each R 2 are independently selected from the group consisting of: H, CN, halogen, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO 2 -、C 1-4 Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 Heterocyclic group; provided that, when L is -CH 2 -, at least one R 2 for -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -; and wherein the heteroaryl, cycloalkyl, heterocyclyl or alkyl group is further allowed to be substituted by 0, 1, 2 or 3 C 1-4 Alkyl or halogen substitution; Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substitution; Each R ° independently H or C 1-4 alkyl; Each R 3 are independently selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl; and R 4 and R 5 are each independently H or F.

2. A compound of formula (I), or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, wherein Q is CH or N; Z is CR 5 or N; L is -CH 2 -, C=O, -CH(OH)-, or -O-; X is a 5-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene group is surrounded by 1, 2 or 3 R 2 replace; Y is a 5-membered or 6-membered heteroarylene group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered or 6-membered heteroarylene group is surrounded by 0, 1 or 2 R 3 replace; R 1 Selected from the group consisting of H, methyl and hydroxymethyl; Each R 2 are independently selected from the group consisting of: H, CN, halogen, -SC 1-4 Alkyl, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO 2 -、C 1-4 Alkoxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C 3-6 Heterocyclyl; provided that, when L is -CH 2 -, at least one R 2 for -CO-C 1-4 Alkyl, 5-membered heteroaryl, -SC 1-4 Alkyl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -; and wherein the heteroaryl, cycloalkyl, heterocyclyl, alkoxy or alkyl group is further allowed to be substituted by 0, 1, 2 or 3 C 1-4 Alkyl, Si(C 1-4 alkyl) 3 or halogen substitution; Each R n Independently H, C 1-4 Alkyl, halo-C 1-4 Alkyl or C 3-6 Cycloalkyl, or two R n The group and its central nitrogen form C 3-6 Heterocycloalkyl, the heterocycloalkyl is optionally substituted with one or more C 1-4 Alkyl or halogen substituted; Each R ° are independently H or C 1-4 alkyl; Each R 3 are independently selected from the group consisting of: H, halogen, CN, C 1-4 Alkoxy, halo-C 1-4 Alkyl and C 1-4 Alkyl; and R 4 and R 5 are each independently H or F.

3. The compound according to claim 1 or 2, which is a compound of formula (IA): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2, which is a compound of formula (IA-1): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or 2, which is a compound of formula (IB): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or 2, which is a compound of formula (IB-1): or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 or 2, which is a compound of formula (IC): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 or 2, which is a compound of formula (IC-1): or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 or 2, which is a compound of formula (ID): or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 or 2, which is a compound of formula (ID-1): or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 or 2, which is a compound of formula (ID-1-1): or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1 to 11, wherein X is a 5-membered heteroaryl selected from the group consisting of 3*,4-substituted pyrazolylene, 4*,5-substituted pyrazolylene, 4,5*-substituted pyrazolylene, 1*,5-substituted pyrazolylene, 4*,5-substituted imidazolylene, 1*,5-substituted imidazolylene or 4*,5-substituted triazolylene, wherein * represents the point of attachment of X or Y to the L group bonded to X and Y.

13. The compound of claim 12, wherein X is a 5-membered heteroarylene group selected from the group consisting of: wherein * represents the point of attachment of X to the L group bonded to X and Y.

14. The compound of claim 13, wherein X is And the R at the ** position 2 for -CO-C 1-4 Alkyl, -SC 1-4 Alkyl, CN, 5-membered heteroaryl, C 1-4 Alkyl-SO- or C 1-4 Alkyl-SO 2 -.

15. The compound of claim 13, wherein X is 16. The compound of any one of claims 1 to 15, wherein Y is selected from the group consisting of 1*,5-substituted pyrazolylene, 3*,4-substituted pyrazolylene, 2,3*-substituted pyridylene, 3*,4-substituted pyridylene, 3,4*-substituted pyridylene, 4,5*-substituted 1,3-thiazolylene, 4*,5-substituted 1,2,3-triazolylene, 1*,5-substituted 1,2,4-triazolylene, 1,5*-substituted 1,2,4-triazolylene and 4*,5-substituted 1,3-thiazolylene, wherein * represents the point of attachment to the L group bonded to X and Y.

17. The compound of claim 16, wherein Y is wherein * represents the point of attachment of Y to the L group bonded to X and Y.

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

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

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

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

22. A compound as described in any one of claims 1 to 21, wherein R 1 It is methyl.

23. A compound as described in any one of claims 1 to 22, wherein R 4 For F.

24. The compound of any one of claims 1 to 23, wherein one R 2 Is it 1, 2 or 3 Cs? 1-4 Alkyl-substituted 5-membered heteroaryl.

25. A compound as described in any one of claims 1 to 23, wherein each R 2 Independently selected from the group consisting of: CN, -CH 2 -cyclopropyl, -CH 2 CH 2 OCH 3 , -CO 2 Et, methyl, ethyl, -C(=O)-N(CH 3 ) 2 、-C(=O)-N(CH 3 ) i Pr, -C(=O)-N(CH 3 )Et, -C(=O)-NH 2 、-C(=O)-N(CH 3 )(CH 2 CF 3 )、-C(=O)-N(CH 3 )(cyclopropyl), -C(=O)-CH 3 、-C(=O)-N(CH 3 )-OCH 3 、-CH 2 -O(CH 2 ) 2 -Si(CH 3 ) 3 、-CH 2 -cyclobutyl, CH 2 -cyclopropyl, (CH 2 ) 2 -OCH 3 , -SO-CH 3 and-SO 2 -CH 3 .

26. A compound as described in any one of claims 1 to 23, wherein each R 2 Independently selected from the group consisting of H, fluorine, chlorine, CN, methyl and ethyl.

27. A compound as described in any one of claims 1 to 26, wherein each R 3 Independently selected from the group consisting of H, fluorine, chlorine, CN, methyl and ethyl.

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

29. A compound of Table 1, Table 1A, Table 1B or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

38. The method of claim 37, wherein the cancer is a solid tumor; and the solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitzoid tumor, and neuroblastoma.

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

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

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

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

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

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

45. The method of claim 37, wherein the cancer is bile duct cancer.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

65. The method of claim 64, wherein the ALK fusion is with one of the fusion partners selected from the group consisting of: EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B.

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

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

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

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

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

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

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

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

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

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

76. The method of any one of claims 31 to 75, wherein the subject has received one prior cancer therapy.

77. The method of any one of claims 31 to 75, wherein the subject has received at least two prior cancer therapies.

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

79. The method of claim 78, wherein the IC of the compound for inhibiting mutant or non-mutant ROS1 or ALK is 50 Not exceeding the IC of compounds for inhibition of wild-type tropomyosin receptor kinase A, B or C 50 One fifth of.

80. A method for selectively inhibiting ROS1 but not TRK, wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound as described in any one of claims 1 to 29 or a pharmaceutical composition as described in claim 30.

81. A method for selectively inhibiting ALK but not TRK, wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound as described in any one of claims 1 to 29 or a pharmaceutical composition as described in claim 30.

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

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

84. The method of claim 83, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, lopatinib, cabozantinib, foreitinib, talentinib, mesartinib, masitinib, or ensartinib.

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

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

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

88. The method of claim 87, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, lopatinib, cabozantinib, foreitinib, talentinib, mesartinib, masitinib, or ensartinib.

Images