Phenylaminopyrimidineamide autophagy inhibitor and method of use thereof

Abstract

To provide compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancers.SOLUTION: SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority under U.S. applications No. 62 / 846,251, No. 62 / 846,258, No. 62 / 911,728, and No. 62 / 711,730, filed on 10 May 2019, the contents of each of these applications being incorporated herein by reference in their entirety.

[0002] Sequence List This application includes an electronically submitted sequence listing in ASCII format, the entirety of which is incorporated herein by reference. The ASCII copy, created on 5 May 2020, is named DCP-079WO_SL.txt and has a size of 27,196 bytes. [Background technology]

[0003] Autophagy (literally meaning "self-eating") is a process that allows cells to regenerate organelles, proteins, stored lipids, glucagon, and other substances under stress for the purpose of producing nutrients. These cellular contents are regenerated by phagocytosis into vesicles called autophagosomes. The autophagosomes then fuse with lysosomes, which break down the contents of the autophagosome for the recycling of nutrients back into the cell. Tumor cells tend to activate autophagy because they have high metabolic demands, experience cellular stress, and are often in a hypoxic environment with limited blood flow and nutrient supply. Furthermore, chemotherapy and targeted therapies have been shown to induce autophagy as a mechanism of treatment resistance, and combinations of chemotherapy regimens with autophagy inhibition (by genetic loss of functional mutations in autophagy genes or by pharmacological means) have been shown to suppress tumor growth and induce widespread apoptosis in tumor cells more effectively than monotherapy.

[0004] Mutant Ras protein drives approximately 30% of all human cancers, including 95% of pancreatic cancers and 45% of colorectal cancers, and treating these mutant Ras cancers is currently an area of ​​high unmet medical need. Mutant Ras cancers are highly proliferative and depend on basal levels of autophagy for survival, suggesting that inhibiting autophagy in these "autophagy-addicted" cancers is a viable therapeutic approach.

[0005] Currently, the most widely used autophagy inhibitors are the well-known antimalarial drugs chloroquine and hydroxychloroquine. These antimalarial drugs are thought to block autophagy by sequestering within the lysosomal compartment and increasing the pH of these lysosomes, thereby inactivating proteases that break down and regenerate nutrients. These antimalarial drugs have multiple mechanisms of action beyond inhibiting lysosomes and are known to induce retinopathy in patients. Therefore, there is a need for more targeted drugs that selectively block autophagy and do not exhibit the toxicity of these antimalarial drugs. ULK1 kinase is the autophagy initiation protein and is a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stress, including nutrient deficiency and energy depletion. Nutrient deficiency activates ULK kinase activity through mTORC1 inhibition, and energy depletion activates AMP-activated protein ULK kinase activity is activated through activation by the protein kinase AMPK. Importantly, kinase corpus mutants of ULK kinase block the initiation of standard autophagy, suggesting that small molecule inhibitors of ULK kinase activity can block autophagy.

[0006] Further mechanistic studies have shown that ULK1 gene deletion inhibits autophagy in cancer cells and mitigates the upregulation of FOX3A turnover and the pro-apoptotic protein PUMA. In addition to classical activation of standard autophagy, ULK1 kinase activity has been shown to be required for Bcl-2-L-13 mediated mitophagy (autophagy of damaged mitochondria). ULK1 and ULK2 kinases have also been demonstrated to rewire cancer cell glucose metabolism. ULK inhibitors may also find utility in blocking these standard protumoral activities of ULK.

[0007] Autophagy is also upregulated in cancer host cells and tissues. Autophagy in pancreatic stellate cells has been shown to support tumor growth. Pancreatic stellate cells have been shown to support pancreatic cancer tumor metabolism via autophagy-alanine secretion. Inhibition of host tissue autophagy has been shown to lead to depletion of circulating arginase (an amino acid necessary for tumor metabolism and growth) via increased hepatic-mediated arginase secretion. Activation of ULK1 kinase has also been shown to inactivate the STING pathway in immune cells via inhibitory phosphorylation of STING, mediating a negative feedback mechanism to limit the interferon-mediated innate immune cell response. Thus, autophagy is activated not only in tumor cells (cancer cell-autonomous) but also in other cells within the tumor microenvironment or host tissues (cancer is called non-autonomous) to support tumor survival and growth.

[0008] Mutant Ras cancers are dependent on autophagy. In pancreatic cancer, mutant Ras primarily signals via the MAPKAP pathway. Mutant Ras activates RAF kinase, then MEK kinase, and finally ERK kinase: mutant Ras → RAF → MEK → ERK. Despite mutant Ras signaling via the MAPKAP pathway, inhibitors of this pathway have shown little to no clinical benefit in clinical trials when used as monotherapies. Inhibition of the MAPKAP pathway has recently been reported to induce autophagy as a compensatory survival mechanism. When MEK inhibitors were combined with the autophagy inhibitor hydroxychloroquine, synergistic activity was observed, resulting in regression of numerous mutant Ras or mutant BRAF cancers. Similarly, when ERK inhibitors were combined with the autophagy inhibitors hydroxychloroquine or chloroquine, synergistic activity was observed, leading to inhibition of mutant Ras pancreatic cancer. Genetic depletion of RAF kinases (CRAF and BRAF) has been demonstrated to result in synergistic antitumor activity in mutant Ras cancer cell lines when autophagy is also genetically depleted. In combination, recent publications highlight that dual inhibition of the MAPKAP and autophagy pathways in mutant Ras cancer is a promising treatment regimen for patients with mutant Ras cancer. Furthermore, other targeted therapies and chemotherapy agents have been shown to activate tumor autophagy as a resistance mechanism, and therefore there is a rationale for combining such targeted therapies or chemotherapy agents with autophagy inhibitors.

[0009] Mutations in the gene encoding the LRRK2 kinase are a cause of Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) and sporadic Parkinson's disease patients. The most common LRRK2 mutation in Parkinson's disease is LRRK2 G2019S. These mutations in LRRK2 are gain-of-function mutations that cause overactivation of LRRK2 signaling. Autophagy is a process used by brain neurons to maintain health and homeostasis. Autophagy is a process in which cells undergo cellular aging. Autophagy is a process that identifies, localizes, and destroys organelles and structural elements, and in the case of proteins known to aggregate, particularly in neurons, autophagy maintains neuronal health by eliminating such toxic protein aggregates. LRRK2 activity suppresses autophagy, and the LRRK2 G2019S gain-of-function mutant further suppresses autophagy and is associated with the aggressive form of Parkinson's disease.

[0010] Increased LRRK2 kinase activity is also associated with colitis and immunoinflammatory diseases, including Crohn's disease and inflammatory bowel disease. In the gastrointestinal tract, LRRK2 is present in antigen-presenting cells, including dendritic cells. LRRK2 activity has been shown to be important in Dectin-1-mediated innate immune responses, such as activation of the NFκB pathway and increased TNF-alpha production in dendritic cells of Crohn's disease patients.

[0011] LRRK2 inhibitors are sought after for the treatment of neurodegenerative diseases, including Parkinson's disease, as well as for the treatment of gastrointestinal diseases, including Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0012] There is a need for new targeted therapies that can be used in combination with autophagy inhibitors, MAPKAP pathway inhibitors, chemotherapeutic agents, and / or other targeted therapies. [Overview of the Initiative]

[0013] This specification describes compounds that are autophagy inhibitors, pharmaceutical compositions, and their use as agents in the treatment of disorders such as cancer, processes for their preparation, and pharmaceutical compositions containing them as active ingredients. Such pharmaceutical compositions may contain the compounds as the sole activator or in combination with other activators, in the presence of pharmaceutically acceptable excipients. In one embodiment, the compounds described are inhibitors of ULK kinase activity, including ULK1 and ULK2 activity.

[0014] For example, the compounds provided herein are of the following formula (I)

Chemical Formula

[0015] Next, the features and other details of this disclosure will be described in more detail. The specific terms used in the specification, examples, and appended claims are summarized here. These definitions should be read in a manner that is understandable to those skilled in the art in light of the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0016] definition As used herein, the term “alkyl” refers to saturated linear or branched hydrocarbons. Exemplary alkyl groups are, but are not limited to, C1 Examples of alkyl groups include linear or branched hydrocarbons with 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, known as C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0017] As used herein, the term “alkenyl” refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, linear or branched groups of 2 to 6 or 3 to 4 carbon atoms, referred herein as C2-C6 alkenyls and C3-C4 alkenyls, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0018] As used herein, the term “alkoxy” refers to a linear or branched alkyl group (alkyl-O-) bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1 to 6 or 2 to 6 carbon atoms, referred herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0019] As used herein, the term “alkoxyalkyl” refers to an oxygen-bonded linear or branched alkyl group (alkyl-O-alkyl-) bonded to a second linear or branched alkyl group. Examples of alkoxyalkyl groups, though not limited to those specified, are referred to herein as C1-C6 alkoxy-C1-C6 alkyl groups, each containing 1 to 6 carbon atoms independently. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, and 2-isopropoxyethyl.

[0020] As used herein, the term “alkynyl” refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, linear or branched groups of 2 to 6 or 3 to 6 carbon atoms, referred herein as C2-C6 alkynyls and C3-C6 alkynyls, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0021] As used herein, the term "cyano" refers to the radical-CN.

[0022] As used herein, the terms “cycloalkyl” or “carbocyclic group” refer to saturated or partially unsaturated hydrocarbon groups of, for example, 3 to 6 or 4 to 6 carbon atoms, respectively, which are referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0023] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group bonded to oxygen (cycloalkyl-O-). Examples of cycloalkoxy groups include, but are not limited to, Although not necessarily so, as used herein, the term "C3-C6 cycloalkoxy group" refers to a cycloalkoxy group having 3 to 6 carbon atoms. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

[0024] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0025] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 5- or 6-membered ring system containing one or more heteroatoms, for example, 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the aforementioned heteroaryl ring may be linked to adjacent radicals via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, or pyrimidine.

[0026] The term "heterocyclyl" or "heterocyclic group" is recognized in the art and refers to a saturated or partially unsaturated 4- to 10-membered ring structure, including monocyclic, bridged-ring, or fused-ring structures, the ring structure of which contains 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be linked to adjacent radicals via carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran.

[0027] As used herein, the term "lactam" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkane-2-one structure, or an analog having a heteroatom that replaces one or more carbon atoms of an unsaturated or ring. "Alpha-lactam" refers to a lactam consisting of a 3-membered ring. "Beta-lactam" refers to a lactam consisting of a 4-membered ring. "Gamma-lactam" refers to a lactam consisting of a 5-membered ring. "Delta-lactam" refers to a lactam consisting of a 6-membered ring. "Epsilon-lactam" refers to a lactam consisting of a 7-membered ring.

[0028] As used herein, the term "oxo" refers to the radical =O.

[0029] "Combination therapy" is a treatment that includes the administration of two or more therapeutic agents, such as a compound of Formula I and a MAPKAP pathway inhibitor, to a patient in need of treatment.

[0030] As used herein, the terms "disease", "disorder", and "condition" are used interchangeably.

[0031] "Individual", "patient", or "subject" are used interchangeably herein and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered to mammals such as humans, but can also be administered to other mammals that require veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0032] "MAPKAP pathway inhibitor" is an inhibitor of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and This includes ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996). The terms "MAPKAP pathway inhibitor" and "MAPKAP kinase inhibitor" are used interchangeably herein.

[0033] "Pharmacologically or pharmacologically acceptable" includes molecular entities and compositions that, when administered appropriately to animals or humans, do not produce adverse reactions, allergic reactions, or other adverse reactions. For administration to humans, formulations must meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics standards.

[0034] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to all solvents, dispersions, coatings, isotonic and absorption retardants, etc., that are compatible with pharmaceutically active substances. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0035] As used herein, the term “pharmaceutical composition” means a composition comprising at least one compound disclosed herein, which is formulated with one or more pharmaceutically acceptable carriers.

[0036] As used herein, the term “pharmaceutically acceptable salts” refers to salts of any acidic or basic groups that may be present in the compounds used in the composition. The compounds in this composition, which are inherently basic, can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but are not limited to, salts containing pharmacochemically acceptable anions, namely malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbicates, succinates, maleates, gentisates, fumarates, glucons, glucarons, sugarates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition, which are inherently acidic, can form base salts having a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present composition, including a basic or acidic moiety, can also form pharmaceutically acceptable salts with a variety of amino acids. Compounds of the present disclosure may contain both an acidic group and a basic group, for example, one amino group and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a base salt.

[0037] The compounds of this disclosure may contain one or more chiral centers and therefore exist as stereoisomers. As used herein, the term “stereoisomer” comprises all enantiomers or diastereomers. These compounds may be designated by the symbols “(+)”, “(-)”, “R”, or “S”, depending on the configuration of substituents around the stereogenic carbon atom, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center. The compounds described herein encompass various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)”, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center.

[0038] In this specification, “therapeutically effective dose” includes the amount of the compound in question that elicits a biological or medical response in a tissue, system, or animal (e.g., mammal or human), as determined by researchers, veterinarians, physicians, or other clinicians. The compounds described herein are administered in therapeutically effective doses to treat a disorder.

[0039] As used herein, “to treat” includes any effect that results in improvement, reduction, regulation, or elimination of, for example, a condition, disease, or disorder.

[0040] This disclosure also includes isotope-labeled compounds that are identical to those enumerated herein, except that one or more atoms are substituted by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and36 Examples include Cl. For instance, the compounds of this disclosure may have one or more H atoms substituted with deuterium.

[0041] The individual enantiomers and diastereomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or they may be prepared by the preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers in a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture may also be separated into its component enantiomers by well known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms an heterogeneous mixture of stereoisomers during the creation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0042] compound In this specification, compounds represented by formula I, [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof In the formula, W is CH or N, X is CH or N, and Y is C(R 3 ) or N, R 1is selected from the group consisting of halogens, cyanos, C1-C5 alkyls, and C3-C5 cycloalkyls, and each C1-C5 alkyl and C3-C5 cycloalkyl may optionally be substituted with 1, 2, or 3 independently generated fluorines, R 2 R is selected from the group consisting of H, halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, and C1-C5 alkoxy-C2-C5 alkyl, and each of the C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy in the formula may be optionally substituted with 1, 2, or 3 independently generated fluorine or cyano, 3 and R 33 Each generation is independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, and each C1-C6 alkyl and C1-C6 alkoxy may optionally be substituted with fluorine of one or more independent generations, R 4 B, D, NR 6 R 9 , NR 6 -(C(R 10 )2) p -NR 9 R 9 , C(O)-NR 6 R 9 Selected from the group consisting of C(O)-B, C(O)-D, and CN, where B is selected from N-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional ring nitrogen or oxygen, and B is R 7 It may be optionally substituted on one or more available carbons by R 9 D may be optionally substituted on the nitrogen available by R, and D is selected from C-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional cyclic nitrogen or oxygen, and D is R 7 It may be optionally substituted on one or more available carbons by R 9 It may be optionally substituted on nitrogen available by R 5Each generation is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with fluorine of one or more independent generations, R 7 Each generation independently produces H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 9 R 9 Selected from the group consisting of, each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with one or more independently generated fluorines, or two R 7 However, they bond together with the atoms they are bonded to to form an oxo, R 6 and R 9 Each generation independently involves H, C1-C6 alkyl, and C 3- C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 SO2R 5 Selected from the group consisting of , and D, each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with one or more independently generated fluorine, R 10 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and each C1-C3 alkyl and C3-C5 cycloalkyl may optionally be substituted with fluorine of one or more independent generations, or two R 10 However, they bond together with the carbon they are attached to to form a C3-C5 cycloalkyl group, where Z is selected from the group consisting of a 4-membered lactam ring bonded via a nitrogen atom, or a 6- to 10-membered lactam ring bonded via a nitrogen atom, and the lactam ring atom is optionally oxygen or NR if the lactam ring is a 6- to 10-membered ring. 6 It may also be that the available carbon atoms on the 4-membered lactam ring or 6-10 membered lactam are R 36 It is arbitrarily substituted by R 36Each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 36 are joined together with the carbon to which they are attached to form a C3-C6 cycloalkyl, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, p is 2 or 3, provided that both X and Y are not N.

[0043] In some embodiments, W is N. In some embodiments, X is CH and Y is N. In some embodiments, X is CH and Y is C(R 3 ).

[0044] In some embodiments, Z is selected from the following,

Chemical formula

[0045] In some embodiments, Z is selected from the following,

Chemical formula

[0046] In some embodiments, Z is selected from the group consisting of.

Chemical formula

[0047] In some embodiments, Z is selected from the following,

Chemical formula

[0048] In some embodiments, Z is selected from the group consisting of.

Chemical formula

[0049] In some embodiments, R 4 is B.

[0050] In some embodiments, R 4 is selected from the group consisting of,

Chemical formula

[0051] In some embodiments, R 4 is selected from the group consisting of. [ka]

[0052] In some embodiments, R 4 The group is selected from the following: [ka]

[0053] In some embodiments, R 4 The group is selected from the following: [ka]

[0054] In some embodiments, R 4 It is D.

[0055] In some embodiments, R 4 The group is selected from the following: [ka]

[0056] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0057] In some embodiments, R 1 R is selected from the group consisting of halogens, C1-C5 alkyls, and C3-C5 cycloalkyls, and the C1-C5 alkyl may optionally be substituted with 1, 2, or 3 generated fluorines. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is a halogen. In some embodiments, R 1 It is Bromo. In this embodiment, R 1 It is cyclopropyl.

[0058] In some embodiments, R 2 is selected from the group consisting of H, C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl, and C2-C5 alkynyl, and each C1-C5 alkyl may optionally be substituted with 1, 2, or 3 independently generated fluorine. In some embodiments, R 2 C 1-2 Alkyl and C 3-4 Selected from the group consisting of cycloalkyls. In some embodiments, R 2 The group is selected from chloro and bromo.

[0059] In some embodiments, R 2 R is selected from the group consisting of C1-C5 alkyl, H, and C3-C4 cycloalkyl. In some embodiments, R 2 R is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl. In some embodiments, R 2 The group is selected from chloro and bromo.

[0060] In some embodiments, n is 3.

[0061] In some embodiments, the compound is a compound represented by the following formula II, [ka] or a pharmaceutically acceptable salt thereof, where n is 2, 3, or 4, R 1 is selected from the group consisting of halogens, cyanos, C1-C5 alkyls, and C3-C5 cycloalkyls, and each C1-C5 alkyl and C3-C5 cycloalkyl may optionally be substituted with 1, 2, or 3 independently generated fluorines, R 2R4 is selected from the group consisting of halogens, C1-C2 alkyls, and C3-C4 cycloalkyls, and R4 is selected from the group consisting of the following: [ka] R 6 and R 9 Each generation independently involves H, C1-C6 alkyl, C3-C6 cycloalkyl, and C(=O)R 5 SO2R 5 Selected from the group consisting of , and D, each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with one or more independently generated fluorine, R 5 Each generation is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with fluorine of one or more independent generations, R 7 Each generation independently involves H, C1-C6 alkyl, and C3 Selected from the group consisting of -C6 cycloalkyl groups, each C1-C6 alkyl and C3-C6 cycloalkyl group may optionally be substituted with one or more independently generated fluorine groups, or two R groups 7 However, they bond together with the atoms they are bonded to to form an oxo, and D is selected from C-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional ring nitrogen or oxygen, and D is R 7 It may be optionally substituted on one or more available carbons by R 9 It may be optionally substituted on the nitrogen available by, and Z is selected from the group consisting of the following: [ka] R 34 Each occurrence of H and R is independent. 36 Selected from, R 36Each generation is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl groups, and each C1-C5 alkyl and C3-C6 cycloalkyl group may optionally be substituted with fluorine in one or more independent generations, or two R groups. 36 However, they bond together with the carbon atoms they are attached to to form a C3-C6 cycloalkyl group.

[0062] In some embodiments, R 1 R is selected from the group consisting of halogens, C1-C5 alkyls, and C3-C5 cycloalkyls, where the C1-C5 alkyl may be optionally substituted with 1, 2, or 3 generated fluorines and C3-C5 cycloalkyls. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 It is cyclopropyl.

[0063] In some embodiments, R 2 R is selected from the group consisting of H, C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, R 2 The group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro.

[0064] In some embodiments, R 4 The group is selected from the following: [ka]

[0065] In some embodiments, R 4 The group is selected from the following: [ka]

[0066] Several embodiments, each R 6 and R 9 The elements are independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, and each of the C1-C6 alkyl and C3-C6 cycloalkyl elements is optionally substituted with one or more independently generated fluorine atoms.

[0067] In some embodiments, R 7 H is H.

[0068] In some embodiments, R 34 Each generation is independently selected from the group consisting of H and C1-C5 alkyl groups, and the C1-C5 alkyl groups may optionally be substituted with fluorine from one, two, or three independent generation. In some embodiments, two R 34 These atoms bond with the carbon atoms they are attached to to form a C3-C6 cycloalkyl group.

[0069] In some embodiments, Z is selected from the group consisting of the following: [ka]

[0070] In some embodiments, Z is selected from the group consisting of the following: [ka]

[0071] In some embodiments, n is 3.

[0072] In one embodiment, the compound is represented by a formula selected from the group consisting of the following: [ka] In the formula, R 1Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0073] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is H, and n is 3. be.

[0074] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0075] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0076] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, where n is 3.

[0077] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. , R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3.

[0078] In one embodiment, the compound is represented by a formula selected from the group consisting of the following: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl. Re, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0079] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0080] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0081] In some embodiments, R 1 Each occurrence is CF2H, and R 2Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0082] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each occurrence n is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0083] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3.

[0084] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0085] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0086] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. , R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0087] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0088] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0089] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0090] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0091] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0092] In some embodiments, R 1 Each occurrence is CF3, R 2 Each occurrence is independent Selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0093] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0094] In some embodiments, the compound is represented by a formula selected from the following: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, where n is 3.

[0095] In some embodiments, R 1 Each occurrence is bromo, R 2Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each occurrence is independently H and C1-C3 alcohol Selected from Kill, n is 3.

[0096] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0097] In some embodiments, R1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups. n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0098] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0099] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0100] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0101] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0102] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 9 R is selected from the group consisting of C1-C3 alkyl, H, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is CF2H, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 The C1-C3 alkyl group and H are selected.

[0103] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 This group consists of bromo, chloro, CF3, CF2H, and cyclopropyl. Selected from, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 9 R is selected from the group consisting of C1-C3 alkyl, H, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is CF2H, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 The C1-C3 alkyl group and H are selected.

[0104] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 9 R is selected from the group consisting of C1-C3 alkyl, H, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is CF2H, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 The C1-C3 alkyl group and H are selected.

[0105] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 9 R is selected from the group consisting of C1-C3 alkyl, H, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is CF2H, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 The C1-C3 alkyl group and H are selected.

[0106] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 9R is selected from the group consisting of C1-C3 alkyl, H, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 9 R is selected from C1-C3 alkyl and H. In some embodiments, R 1 is CF2H, and R 2 C1 -Selected from the group consisting of C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 The C1-C3 alkyl group and H are selected.

[0107] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. In some embodiments, R 1 is CF2H, and R 2 The group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro.

[0108] In some embodiments, the compound is represented by the following formula: [ka] In the formula, R 1 R is selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl. 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. In some embodiments, R 1 is CF3, and R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. In some embodiments, R 1 is bromo, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. In some embodiments, R 1 is CF2H, and R 2 The group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro.

[0109] In some embodiments, the compound is represented by the following formula: [ka] or a pharmaceutically acceptable salt thereof, where n is 2, 3, or 4, R 1 is selected from the group consisting of halogens, cyanos, C1-C5 alkyls, and C3-C5 cycloalkyls, and each C1-C5 alkyl and C3-C5 cycloalkyl may optionally be substituted with 1, 2, or 3 independently generated fluorines, R 2 R is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 4 The group is selected from the following: [ka] R6 and R 9 Each generation independently involves H, C1-C6 alkyl, C3-C6 cycloalkyl, and C(=O)R 5 SO2R 5 Selected from the group consisting of , and D, each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with one or more independently generated fluorine, R 5 Each generation is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with fluorine of one or more independent generations, R 7 Each generation is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with fluorine of one or more independent generations, or two R 7 However, they bond together with the atoms they are bonded to to form an oxo, and D is selected from C-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional ring nitrogen or oxygen, and D is R 7 It may be optionally substituted on one or more available carbons by R 9 It may be optionally substituted on the nitrogen available by, and Z is selected from the group consisting of the following: [ka] R 34 Each occurrence of H and R is independent. 36 Selected from, R 36 Each generation is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl groups, and each C1-C5 alkyl and C3-C6 cycloalkyl group may optionally be substituted with fluorine in one or more independent generations, or two R groups. 36 However, they bond together with the carbon atoms they are attached to to form a C3-C6 cycloalkyl group.

[0110] In some embodiments, R1 R is selected from the group consisting of halogens, C1-C5 alkyls, and C3-C5 cycloalkyls, where the C1-C5 alkyl may be optionally substituted with 1, 2, or 3 generated fluorines and C3-C5 cycloalkyls. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 It is cyclopropyl.

[0111] In some embodiments, R 2 R is selected from the group consisting of H, C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, R 2 The group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro.

[0112] In some embodiments, R 4 The group is selected from the following: [ka]

[0113] In some embodiments, R 4 The group is selected from the following: [ka]

[0114] Several embodiments, each R 6 and R 9 The elements are independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, and each of the C1-C6 alkyl and C3-C6 cycloalkyl elements is optionally substituted with one or more independently generated fluorine atoms.

[0115] In some embodiments, R 7 H is H.

[0116] In some embodiments, R 34 The group is selected from H and C1-C5 alkyl groups, and the C1-C5 alkyl groups may optionally be substituted with 1, 2, or 3 independently generated fluorines. In some embodiments, two R 34 These atoms bond with the carbon atoms they are attached to to form a C3-C6 cycloalkyl group.

[0117] In some embodiments, Z is selected from the group consisting of the following: [ka]

[0118] In some embodiments, Z is selected from the group consisting of the following: [ka]

[0119] In some embodiments, n is 3.

[0120] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0121] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each occurrence is independent of C1-C Selected from 2-alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0122] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0123] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0124] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, where n is 3.

[0125] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each occurrence is independent Selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3.

[0126] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation independently involves C1-C2 alkyl and C3 -Selected from the group consisting of C4 cycloalkyl and halogens, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0127] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0128] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0129] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0130] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation independently involves C1-C2 alkyl, C3- Selected from the group consisting of C4 cycloalkyl and halogens, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, where n is 3.

[0131] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3.

[0132] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0133] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0134] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation independently involves C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro Selected from the following, each R 34 H is , and n is 3.

[0135] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0136] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0137] In some embodiments, R 1 Each occurrence is bromo, R 2Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0138] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0139] In some embodiments, R 1 Each occurrence is bromo, R 2Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0140] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0141] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 9 Each generation is selected from H and C1-C3 alkyl groups, R 34Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 9 Each generation is selected from H and C1-C3 alkyl groups, and each R 34 H is , and n is 3.

[0142] In some embodiments, the compound is represented by a formula selected from the following: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, R 9 Each generation is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, where n is 3.

[0143] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation independently involves C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro Selected from, R 6 Each generation is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, R 9 Each generation is independently selected from H and C1-C3 alkyl groups, and n is 3.

[0144] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 34 Each generation is selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0145] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. , R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R34 H is , and n is 3.

[0146] In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0147] In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 34 Each generation is independently selected from the group consisting of H and C1-C2 alkyl groups, where n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, and each R 34 H is , and n is 3.

[0148] In some embodiments, the compound is represented by a formula selected from the following group: [ka] In the formula, R 1 Each generation is independently selected from the group consisting of bromo, chloro, CF3, CF2H, and cyclopropyl, R 2 Each generation is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, R 6Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3.

[0149] In some embodiments, R 1 Each occurrence is bromo, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF3, R 2 Each generation is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence is CF2H, and R 2 Each generation independently involves C1-C2 alkyl and C3-C4 cyclo Selected from Rukil, Bromo, and Chrollo, R 6 Each generation is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl groups, where n is 3. In one embodiment, the compounds described herein are selected from the following group: 1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-cyclo Ropropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidine-4-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl) Peridine-2-one, (R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)pyrrolidine-3-carbonitride, 1-(3-((2-((4-(4-cyclopropylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-bromo-2-((2-isopropyl-4-(4-methyl Lupiperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one,4-(3-cyclopropyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1-methylpiperazine-2-one, 1-(3-((5-bromo-2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl) Pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(1-methylpiperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl )amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2 -((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-(2-fluoroethyl)piperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(piperidine-4-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl, (S)piperidine-2-one, 1-(3-((2-((4-(4-acetylpiperazine-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, (S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)- 5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)pyrrolidine-3-carbonitride, 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-isopropylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-isopropyl Ropyru-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-cyclobutylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino )-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(piperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(1,4-Diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl (L)piperidine-2-one, 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl (L)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-bromo-2- ((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl, )pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1] Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, rac-(R)-3-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[ 1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(tri Fluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)morpholine-3-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azepan-2-one, 4 -(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl. Pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidine-4-yl)amino )propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-ox Sazepan-3-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl )phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl )-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl )amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, rac-4-(3- ((2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-ethyl Lu-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((5-Cyclopropyl-2-((2-Ethyl-4-(4-Methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, n, 4-(3-((2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5- (Trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2 -((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, rac-(R)-4-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine -2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 3-(3-((2-((4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(3-((2-((4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazine (1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridine-3-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyridine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((4-(4-cyclopropylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-5,5-Dimethylpyrrolidine-2-one, 1-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-(( 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((5-(4-methylpiperazine, (R)-4-(3-((( 2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1] Heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3- Oxazinan-2-one, 4-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]Heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((2-((2-(methoxymethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-ethyl -6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitride, 3-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,. 3-Oxazinan-2-one, (S)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1-methylpiperazine-2-yl)acetonitrile, (R (Tylpiperazine-2-yl)acetonitrile, (S)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)piperazine-2-yl)acetonitrile, (R)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl) Mino)phenyl)piperazin-2-yl)acetonitrile, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4 -(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitride, 4-(3-((2-((2-ethyl-4-(1-methylpiperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1] Octane-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1] Nonane-9-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, (S)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidine-1-yl (L)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(1-methylpyrrolidine-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethynyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(tri Fluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((Ethinyl-d5)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((Ethyl-d5)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine. (4-yl)amino)propyl)-1,4-oxazepan-5-one, 5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzonitrile, 2-methyl-2-(5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl) Ropannitrile, 2-(5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)acetonitrile, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((difluoromethyl (Tyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-bromo-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl) Limidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 3-(3-((2-(( 2-Ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl (L)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diaze Pan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methyl, Tylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1 ]Octane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]Octane-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2 .2.1]Heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, (R)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2( 1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, (S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 1-(3- ((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl -4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine Radin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-, 4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diaze Pan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl- 4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitride, 2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octa (3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitride, 2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitride, 2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]Heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitride, 2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]Heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitriel, (R)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitriel, (S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl )amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitri, 2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitri, 2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitri Lu, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidine-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidine-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1- Il)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl. (Ropil)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclo Ropropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl) (L)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3- Tyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitride, 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]Octane-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5. -(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl )amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino) Pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octa (3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1] Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine (1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 8-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonane-9-one, 4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5 -(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3 ,8-Diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-Diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-Diazabicyclo[3.2.1] Octane-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl) Amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane. -3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(tri Fluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3 -Dimethylazetidine-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2 -((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]Heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylpyrrolidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S )-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylpyrrolidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1] Octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylpyrrolidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolol[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl Pyrrolidine-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl. (L)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylpyrrolidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl )amino)-5-chloropyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)pyrimidine- 4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-bromopyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)pyrrolidine-2-one, 4-(3-((2- ((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-ethyl-4-(2-(pyrrolidine-1-yl)ethyl)phenyl )amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-((dimethylamino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine -4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-methoxy-N-(1-methylpiperidine-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzamide, 4-(3-((2-((4-(4-((diethylamino)piperidine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-3-one, (S)-4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((, 2-Ethyl-4-(2-(pyrroridine-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-((dimethylamino)methyl)piperidine-1-yl )-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-((dimethylglycyl)piperazine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(3,3-dimethylpiperazine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine -4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,5,5-tetramethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan -5-one, 4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 1-(3-((2-((2-chloro-4-(3,4-Dimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azepan-2-one, 3-(3-((2-((4-(Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl) (L)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(Octahydro-2H-pyrido[1,2-a]pyrazine-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl )phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-bromo-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3 -Oxazepan-2-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((4-(1R,5S)-8-methyl-3,8-Diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl, )amino)propyl)azepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyridine-4-yl)amino)propyl)pyrrolidine-2-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl) Mino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-(4-(methylsulfonyl)piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-(dimethylglycyl)piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1 ,4-Oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2 -((2-ethyl-4-(2-(pyrroridine-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-fluoro-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-((1,1-Dioxidethiomorpholino(methyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-((4-methylpiperazine-1-yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((4-(3-(diethylamino)propyl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl (Tyl)pyridine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-chloro-4-(3,4-dimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((2 -(2-hydroxypropan-2-yl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-((2-(2-hydroxypropan-2-yl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((1-hydroxyethyl)- 4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-Diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-, ( (2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-(( 2-(1-hydroxyethyl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-(( 2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1-hydroxyethyl)-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3- (3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-((1-hydroxyethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-((1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3- Oxazinan-2-one, 3-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2 -yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinane-2-one, 3-(3-((2-((2-((1-hydroxyethyl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinane-2- On, 3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl. )amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2- ((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-( 1-Hydroxyethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)- 1,4-Oxazepan-3-one, 4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((2-((2-(1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1] Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((difluoromethoxy)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(triflu Oromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(((Methoxymethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1 ,3-Oxazinan-2-one, 4-(3-((2-((4-(1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-( These are 3-((2-((4-(3-((dimethylamino)methyl)azetidine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, as well as pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

[0150] Treatment method The compounds described herein may act as autophagy inhibitors useful for treating disorders in patients in need. These disorders may include, for example, tumors, such as solid tumors. The disorders may also include cancer.

[0151] Examples of disorders include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, and metastatic bone cancers. Examples include cancers to the bone, papillary thyroid carcinoma, non-small cell lung cancer, and colorectal cancer. Cancers treated by the methods described herein may be metastatic cancers.

[0152] In some embodiments, the compounds described herein are useful for treating cancers caused by RAS mutations. In some embodiments, the cancer is caused by a KRAS mutation. In some embodiments, the cancer has additional mutations in tumor suppressor proteins, including mutations in TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, these additional mutations occur in one or more of TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer.

[0153] In some embodiments, the determination of cellular inhibition of autophagy by the compounds described herein is determined by monitoring the autophagic flux, for example, by monitoring the inhibition of the autophagy-mediated clearance of the mCherry / GFP-LC3 fusion protein. In some embodiments, the determination of cellular inhibition of autophagy by the compounds described herein is determined by monitoring the accumulation of autophagic proteins such as p62 or LC-3. In some embodiments, the determination of cellular inhibition of autophagy by the compounds described herein is determined by a decrease in the clearance of luciferase-tagged LC3 protein. In some embodiments, the determination of cellular inhibition of autophagy by the compounds described herein is determined by monitoring the decrease in cellular autophagosomes, for example, by measuring fluorescent puncta using the autophagosome marker Cyto-ID.

[0154] In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined in host tissues, including immune cells.

[0155] In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in host tissues, including immune cells. In some embodiments, in vivo inhibition of the autophagic flux by the compounds described herein can be used as a pharmacodynamic model for monitoring the kinetics and extent of such ULK inhibition. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in pancreatic cancer animals. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in lung cancer animals. In some embodiments, in vivo inhibition of ULK kinase is determined in colorectal cancer animals. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of the autophagic flux in tumor cells or non-tumor host tissues by monitoring the inhibition of autophagosome formation, or by the accumulation of autophagic proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is This is determined in host tissues, including immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition.

[0156] In some embodiments, the inhibition of autophagy and antitumor activity by the compounds described herein is evaluated in xenograft studies using human RAS mutant cell lines in immunodeficient mice, such as SCID or nude mice. In some embodiments, the inhibition of autophagy and antitumor activity by the compounds described herein is evaluated in xenograft studies using human RAS mutant patient-derived tumor xenografts (PDX) in immunodeficient mice, such as SCID or nude mice. In some embodiments, the xenograft study includes evaluation of the compounds described herein in a pancreatic cancer model. In some embodiments, the inhibition of autophagy and antitumor activity by the compounds described herein is evaluated in a syngeneic mouse genetic engineering model (GEM) of mutant RAS cancer. In some embodiments, the inhibition of autophagy and antitumor activity by the compounds described herein is evaluated in a KPC model (LSL-Kras G12D / + LSL-Trp53 R172H / + It is evaluated in a mouse GEM-mediated orthotopic pancreatic cancer model known as a variant of the Pdx-1-Cre or KPC model.

[0157] In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with MEK inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAF inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with ERK inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAS G12C direct inhibitors.

[0158] In some embodiments, the inhibition of autophagy and antitumor activity by the compounds described herein is evaluated in immunonormal mouse cancer models, and the immunomodulatory components of the ULK inhibitors are evaluated for their mechanism of action. In some embodiments, the immunonormal mouse model is the KPC model (LSL-Kras G12D / + LSL-Trp53R172H / + This is a mouse GEM-associated orthotopic pancreatic cancer model known as a variant of the Pdx-1-Cre or KPC model. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a MEK inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a RAF inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with an ERK inhibitor. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with a RAS G12C direct inhibitor.

[0159] In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced innate immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced adaptive immune response. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced activity of antigen-presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced antitumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced antitumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced activity of effector T cells, including cytotoxic T cells.

[0160] In one embodiment, the Specified herein provides a method for treating a disorder described herein, comprising administering a therapeutically effective amount of the compound described herein to a patient in need, and during or after the administration process (for example, at individual points in time, for example, the most effective treatment of the intended compound) The method includes detecting the involvement of the compound with ULK kinase (in the first week, two weeks later, or the month following administration), wherein the detection includes contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the level of phospho-ATG13 in the sample. In some embodiments, the intended method includes optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay before administration of the compound, and comparing the level of phospho-ATG13 in a sample obtained before administration with the level of phospho-ATG13 in a sample obtained during or after the administration process. In some embodiments, phospho-ATG13 is p-S318ATG13.

[0161] In one embodiment, provided herein is a method for treating a disorder described herein, comprising administering a therapeutically effective amount of the compound described herein to a patient in need thereof, and detecting the involvement of the compound with ULK kinase during or after the administration (for example, at individual time points, e.g., the first week, two weeks after, or the month following the administration of the compound intended), wherein the detection includes contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG14 antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the level of phospho-ATG14 in the sample. In some embodiments, the intended method includes optionally contacting a sample obtained from the patient before administration of the compound (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG14 antibody ELISA assay, and comparing the level of phospho-ATG14 in the sample obtained before administration with the level of phospho-ATG14 in the sample obtained during or after the administration. In some embodiments, phospho-ATG14 is p-ATG14 Ser29.

[0162] In one embodiment, provided herein is a method for treating a disorder described herein, comprising administering a therapeutically effective amount of the compound described herein to a patient in need thereof, and detecting the involvement of the compound with ULK kinase during or after the administration (for example, at individual time points, e.g., the first week, two weeks after, or the month following the administration of the compound intended), wherein the detection includes contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the level of p62 in the sample. In some embodiments, the intended method includes optionally contacting a sample obtained from the patient before administration of the compound (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay, and comparing the level of p62 in the sample obtained before administration with the level of p62 in the sample obtained during or after the administration.

[0163] In one embodiment, provided herein is a method for treating a disorder described herein, comprising administering a therapeutically effective amount of the compound described herein to a patient in need thereof, and detecting the involvement of the compound with ULK kinase during or after the administration (for example, at individual time points, e.g., the first week, two weeks after, or the month following administration of the compound intended), wherein the detection includes contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p-beclin antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the level of p-beclin in the sample. In some embodiments, the intended method includes optionally contacting a sample obtained from the patient before administration of the compound (including, but not limited to, tumor, blood, saliva, or tissue) with a p-beclin antibody ELISA assay, and comparing the level of p-beclin in the sample obtained before administration with the level of p-beclin in the sample obtained during or after the administration.

[0164] The compounds provided herein may be administered to patients (animals and humans) requiring such treatment in doses that would provide optimal pharmacokinetic efficacy. The dose required for any particular use will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the patient's age and condition, any concomitant medications or special diets followed by the patient, and other factors that a person skilled in the art would recognize. It will be understood that the appropriate dose is ultimately left to the discretion of the attending physician. To treat the clinical conditions and diseases described above, the compounds provided herein may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally, in dose units containing conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0165] Treatment can be continued for as long or as short a period as desired. The composition may be administered, for example, in regimens of 1 to 4 or more times a day. Preferred treatment durations can be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinitely. The treatment period can be terminated when the desired results are achieved.

[0166] Combination therapy The compounds described herein, for example, the compounds of formula I as defined herein, can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein, such as cancer. For example, a pharmaceutical composition comprising the compounds described herein, for example, the compounds of formula I as defined herein, one or more additional therapeutic agents, and pharmaceutically acceptable excipients is provided in this disclosure. In some embodiments, the compounds of formula I as defined herein and one additional therapeutic agent are administered. In some embodiments, the compounds of formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, the compounds of formula I as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, the compounds of formula I as defined herein and additional therapeutic agents can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example, a pharmaceutical composition comprising the compounds of formula I as one therapeutic agent and one or more additional therapeutic agents such as MAPKAP pathway inhibitors or chemotherapeutic agents. For example, the compound of formula I as defined herein and additional therapeutic agents can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more drugs in combination therapy can be administered simultaneously, but this is not required. For example, the administration of the first drug (or combination of drugs) may precede the administration of the second drug (or combination of drugs) by only a few minutes, hours, days, or weeks. Thus, two or more drugs can be administered to each other within a few minutes, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks or longer. In some cases, even longer intervals are possible. In many cases, it is desirable, but not required, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0167] Combination therapy may also include two or more doses of one or more drugs used in combination with different order of constituent drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times consecutively in any combination, such as in the order XYX, XXY, YXY, YYX, XXYY.

[0168] In some embodiments, one compound may be administered in combination with the compounds provided herein. One or more additional therapeutic agents may be MAPKAP pathway inhibitors. Examples of such MAPKAP pathway inhibitors include MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.

[0169] Examples of MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts. Examples of ERK inhibitors include, but are not limited to, urixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and their pharmaceutically acceptable salts. Examples of RAF inhibitors include, but are not limited to, LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and their pharmaceutically acceptable salts. Examples of Ras inhibitors include, but are not limited to, AMG-510, MRTX849, and their pharmaceutically acceptable salts.

[0170] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiotherapy, antitubulins, DNA alkylating agents, DNA synthesis inhibitors, DNA insertion agents, anti-estrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, PARP inhibitors, cell cycle regulatory kinase inhibitors, thalidomide, lenalidomide, antibody-drug conjugates (ADCs), immunotherapies including immunomodulators, targeted therapies, cancer vaccines, and CAR-T cell therapies.

[0171] In one embodiment, additional therapeutic agents include, but are not limited to, antitubulin agents (e.g., paclitaxel, paclitaxel protein-binding particles for injectable suspensions containing nab-paclitaxel, eribulin, docetaxel, ixabepyrone, vincristine, auristatin, or meitansinoids), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, and temozolomide), DNA insertion agents or DNA topoisomerase inhibitors (e.g., anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin; including camptothecins such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, and 5-azacitadine (5-aza). The chemotherapeutic agent may include cytadine, gemcitabine, and methotrexate.

[0172] In some embodiments, additional therapeutic agents include, but are not limited to, kinase inhibitors such as erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, loxo292, lalotrectinib, and quizartinib. Antiestrogens including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; antiandrogens including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate; steroids including but not limited to prednisone and dexamethasone; PARP inhibitors including but not limited to neraparib, olaparib, talazoparib, and rucaparib; and topoi including but not limited to irinotecan, camptothecin, exatecan, and topotecan. Topoisomerase II inhibitors, including but not limited to somerase I inhibitors, anthracyclines, etoposide, phosphate etoposide, and mitoxantrone; histone deacetylase (HDAC) inhibitors, including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors, including but not limited to DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to bortezomib and carfilzomib, thalidomide, lenalidomide, and pomalidomide; trastuzumab, adtrastuzumab, pertuzumab, cetol This may include, but is not limited to, biological agents including ximab, panitumumab, ipilimumab, and tremelimumab; anti-PD-1 including pembrolizumab, nivolumab, pizilizumab, and cemiprimab; anti-PD-L1 including atezolizumab, avelumab, durvalumab, and BMS-936559; anti-angiogenic agents including bevacizumab and aflibercept; payloads of DM1, DM4, MMAE, MMAF, or camptothecin; antibody-drug conjugates (ADCs) including brentuximab vedotin and trastuzumab emtansine; radiotherapy; and therapeutic vaccines including, but not limited to, siplücel-T.

[0173] In some embodiments, the additional therapeutic agents include anti-PD-1 or anti-PDL-1 therapeutic agents including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab; anti-TIM3 (anti-HAVcr2) therapeutic agents including but not limited to TSR-022 or MBG453; anti-LAG3 therapeutic agents including but not limited to relatrimab, LAG525, or TSR-033; anti-4-1BB (anti-CD37, anti-TNFRSF9) CD40 agonist therapeutic agents including but not limited to SGN-40, CP-870, 893, or RO7009789; and anti-CD37 agonist agents including but not limited to Hu5F9-G4. 47 Therapeutic agents, anti-CD20 therapies, anti-CD38 therapies; STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazole; anthracyclines including but not limited to doxorubicin or mitoxantrone; hypomethylating agents including but not limited to azacitidine or decitabine; and other immunomodulatory agents including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone.

[0174] In some embodiments, additional therapeutic agents are selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0175] In some embodiments, additional therapeutic agents include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatanib, Nilotinib, Decatanib, Panitumumab, Amrubicin, Olegobomab, Lep-etu, Noratexed, AZD2171, Batabulin, Ofatumumab, Zanolimumab, Edtecalin, Tetrandrin, Lubitecan, Tesmilifen, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY 317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Taranpanel, Atracenta Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)-ethyl ]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugate estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazine methyl)-indolyl]-quinolone, batalanib, AG-013736, AVE-0005, acetate of [D-Ser(But)6,Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 Oi4-(C2H4O2) x(wherein x=1~2.4)], goserelin acetate, leuprorelin acetate, triptrelyn pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EG F antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambutyl, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevec, hydroxyurea, idarubicin, ifosfamide, i Matinib, leuprolide, levamisol, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoin Calcium acid, phenylalanine mustard, uracil mustard, estramustine, altoretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668 EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody), and Erbitux, Paclitaxel without Cremofol, Epithilone BB) BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifene, Pipendoxifene, ERA-923, Alzoxifene, Fulvestran T, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prednisone, Cetuximab, Granulocyte Macro Phage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone Ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine The following are selected from the group consisting of dramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, sspegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0176] Pharmaceutical compositions and kits Another aspect of the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include formulations suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but in any particular case the most appropriate mode of administration depends on the degree and severity of the condition being treated, as well as the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0177] Exemplary pharmaceutical compositions may be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid forms containing one or more of the compounds described herein as active ingredients mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. The active ingredients may be formulated, for example, with ordinary non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other forms suitable for use. The active substance compound is contained in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0178] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as conventional tablet components like corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or rubber, and other pharmaceutical diluents, such as water, to form the compounds provided herein, or their non-toxic drugs. Solid pre-formulation compositions containing a homogeneous mixture of scientifically acceptable salts can be formed. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredients are uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0179] For solid dosage forms for oral administration (capsules, tablets, pills, sugars, powders, granules, etc.), the composition in question is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (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 retarding agents. (1) an agent, e.g., paraffin; (2) an absorption enhancer, e.g., a quaternary ammonium compound; (3) a wetting agent, e.g., acetyl alcohol and glycerol monostearate; (4) an absorbent, e.g., kaolin and bentonite clay; (5) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (6) a coloring agent. In the case of capsules, tablets, and pills, the composition may also include a buffering agent. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol.

[0180] Tablets may be prepared by compression or molding with one or more adjuncts as optional. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of the composition to be prepared, moistened with an inert liquid diluent, using a suitable machine. Tablets, and other solid dosage forms such as sugars, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology.

[0181] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the composition of interest, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0182] The suspension may contain, in addition to the target composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar and tragacanth, and mixtures thereof.

[0183] Formulations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but become liquid at body temperature, and thus melt in the body cavity and release the active agent.

[0184] Dosage forms for transdermal administration of the composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0185] The ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0186] The powders and sprays may contain, in addition to the target composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0187] The compositions and compounds of this disclosure may be administered by aerosol alternatively. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposure of the drug to shear, which may result in the degradation of compounds contained in the composition of interest. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of interest together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition of interest, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0188] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include a composition of interest combined with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, and may contain antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0189] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0190] In another embodiment, an enteric pharmaceutical preparation is provided comprising the disclosed compounds and enteric-coated materials, as well as pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The intestines are part of the digestive tract (intestines) between the stomach and the large intestine, and include the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5.

[0191] Therefore, enteric-coated materials do not dissolve up to a pH of, for example, about 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or about 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate acetate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate, cellulose succinate acetate, cellulose succinate acetate, cellulose hexahydrophthalate acetate, cellulose propionic acid phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionic acid acetate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl methacrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric-coated dispersions (e.g., Eudragit). Examples include L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or readily determinable in vitro. The foregoing is a list of possible materials, but those skilled in the art who are interested in this disclosure will recognize that it is not exhaustive and that there are other enteric-coated materials that serve the purposes described herein.

[0192] Advantageously, this specification provides, for example, kits for use by purchasers who require treatment for cancer. Such kits include appropriate dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, reduce, or prevent inflammation. The instructions instruct the purchaser or healthcare professional to administer the dosage forms according to the dosage forms known to those skilled in the art. Such kits may be advantageously packaged and sold in single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of relatively rigid material covered with a foil of generally preferably transparent plastic material. During the packaging process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and the sheet of relatively rigid material is sealed against the plastic foil with the side of the foil opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed in a recess between the plastic foil and the sheet. Preferably, the sheet is strong enough so that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess, thereby forming an opening within the sheet at the location of the recess. The tablet or capsule can then be removed through this opening.

[0193] For example, memory aids (memory) on the kit in the form of numbers next to tablets or capsules. It may be desirable to provide a memory aid, where the number corresponds to the day of the regimen on which the designated tablet or capsule should be taken. Another example of such memory aids is a calendar printed on a card, for example, "Week 1, Monday, Tuesday" ...and so on...the second week, Monday, Tuesday, ...and so on. Other types of memory aids will be readily apparent. The "daily dose" may be a single tablet or capsule or multiple tablets or capsules taken on a given day. Also, the daily dose of the first compound may consist of one tablet or capsule, the daily dose of the second compound may consist of multiple tablets or capsules, and vice versa. The memory aids should reflect this. [Examples]

[0194] The compounds described herein can be prepared by a number of methods based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of the synthetic methods described below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedure, can be selected to be standard conditions for the reaction unless otherwise specified. Those skilled in the art of organic synthesis will understand that the functionalities present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be obvious to those skilled in the art, and alternative methods will therefore be shown. The starting materials for the examples are commercially available or readily prepared by standard methods from known materials.

[0195] The following abbreviations are used in this disclosure and have the following definitions: “ADP” is adenosine diphosphate, “Boc” is t-butyl carbonate, “CDI” is carbodiimidazole, “conc” is concentrated, “Cs2CO3” is cesium carbonate, “CuI” is copper(I) iodide, “DBU” is 1,8-diazabicyclo[5.4.0]undeca-7-ene, “DCC” is N,N'-dicyclohexylcarbodiimide, “DCE” is dichloroethane, “DCM” is dichloromethane, “DIEA” is N,N-diisopropylethylamine, “DMA” is N,N-dimethylacetamide, “DMAP” is 4-(dimethylamino)pyridine, “DMF” is N,N-dimethylformamide, and “dppf” is 1,1'-bis(diphenylphosphino)ferrocene. "DMEM" is Dulbecco's modified Eagle medium, "DMSO" is dimethyl sulfoxide, "DPPA" is diphenyl phosphoryl azide, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, "Et2O" is diethyl ether, "siRNA" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is time (plural possible), "HBTU" is (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), "H2" is hydrogen gas, "HCl" is hydrochloric acid, "Hex" is hexane, "H2O" is water, "HOBt" is hydroxybenzotriazole, and "IC 50" is the 50% inhibitory concentration, "K2CO3" is potassium carbonate, "K3PO4" is potassium phosphate, "LiMHDS" is lithium bis(trimethylsilyl)amide, "MeCN" is acetonitrile, "MeOH" is methanol, "Me4tBuXPhos" is di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is minutes (plural possible), and "MS" is mass spectrometry. "MTBE" is methyl tert-butyl ether, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, "Na2SO4" is sodium sulfate, "NH4Cl" is ammonium chloride, "NaSMe" is sodium thiomethoxide, "NBS" is N-bromosuccinimide, "NMR" is nuclear magnetic resonance, "PBS" is phosphate-buffered saline, "Pd / C" is palladium carbon, and "Pd2(dba)3" is tris(dibenzyledenacetone) dipalladium Pd(OAc)2 is palladium(II) acetate, Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(O), prep-HPLC is preparative high-performance liquid chromatography, PyBOP is benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, rt is room temperature, also known as ambient temperature, understood to be the range of normal laboratory temperatures from 15 to 25°C, satd. is saturated, and T "3P" is n-propanephosphonic anhydride, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, "THF" is tetrahydrofuran, "TMS" is trimethylsilyl, "Tris" is tris(hydroxymethyl)aminomethane, "Xantphos" is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "X-Phos" is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and "ZnCl2" is zinc chloride.

[0196] general chemistry The exemplary compounds described herein are available by general synthetic methods shown in the following schemes, intermediate preparations, and accompanying examples. [ka]

[0197] Scheme 1 shows exemplary preparations of amines DIi, DI-ii, and DI-iii. Amine R, which can be aliphatic or heterocyclic, in the presence of a base (e.g., Cs2CO3 or K2CO3). 4 When AI is treated with -H, compound BI is obtained. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, a commercially available boronic acid ester / boronic acid / trifluoroborate is used to R 2a Further treatment of BI, where Br is present, yields compound CI. Intermediate CI can be reduced under mild reducing conditions, for example, with zinc or iron metals accompanied by ammonium chloride, R2b The intermediate CI may be selectively converted to an amine DIi that is an alkenyl, alkynyl, or cycloalkyl. The intermediate CI can be completely reduced to DI-iii by palladium-catalyzed hydrogenation. 2a Intermediate BI, where is Cl, Br, alkyl, CN, or alkoxy, is mild It may be reduced to DI-ii under reducing conditions, for example, by zinc or iron metal accompanied by ammonium chloride.

[0198] In Scheme 1, the example of X includes N and CH, and the example of Y includes N, CH, and CF, but both X and Y do not include N, and R 2 Examples include alkyl and cycloalkyl, and R 4 Examples include N-bonded alkyls and N-bonded heterocyclines having any suitable substituent as illustrated by the table of intermediates below. [ka]

[0199] Scheme 2 shows exemplary preparations of amines D-II-i, D-II-ii, and D-II-iii. A-II (commercial starting material) and amine R under reductive amination conditions (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH). 4 Compound B-II is obtained by the reaction of -H. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, R 2a Compound C-II is obtained by further treatment of B-II, which is Br, with a commercially available boronic acid ester / boronic acid / trifluoroborate. Intermediate C-II is reduced under mild reducing conditions, for example, with zinc or iron metal accompanied by ammonium chloride. 2b The intermediate C-II can be selectively converted to an amine D-II-i which is an alkenyl, alkynyl, or cycloalkyl amine. The intermediate C-II can be completely reduced to D-II-iii by palladium-catalyzed hydrogenation. 2aIntermediate B-II, which is Cl, Br, alkyl, CN, or alkoxy, may be reduced to D-II-ii under mild reducing conditions, for example, by zinc or iron metal with ammonium chloride.

[0200] In Scheme 2, the example of X includes N and CH, and the example of Y includes N, CH, and CF, but both X and Y do not include N, and R 2 Examples include alkyl and cycloalkyl, R 4 Examples include N-linked alkyls and N-linked heterocyclines having any suitable substituents as illustrated by the table of intermediates below. [ka]

[0201] Scheme 3 shows exemplary preparations of amines D-III-i, D-III-ii, and D-III-iii. Reduction of A-III-i with a reducing agent such as DIBAL yields the aldehyde A-III-ii. Another method for preparing A-III-ii is to reduce A-III-i to the corresponding alcohol, followed by mild oxidation conditions such as using MnO2. A-III-ii and amine R under reductive amination conditions (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH). 4 Compound B-III is obtained by the reaction of -H. Another method for preparing B-III is to reduce A-III-I to an alcohol, and then convert the alcohol to the sulfonate A-III-iii. A-III-iii and amine R in the presence of a base such as triethylamine, Hünig base, or cesium carbonate. 4 Reaction with -H yields B-III. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, R is obtained with a commercially available boronic acid ester / boronic acid / trifluoroborate. 2aFurther treatment of B-III, where Br is present, yields compound C-III. Intermediate C-III is reduced under mild reducing conditions, for example, with zinc or iron metal accompanied by ammonium chloride, R 2b However, it may be selectively converted to amine D-III-iii, which is an alkenyl, alkynyl, or cycloalkyl. The intermediate C-III can be completely reduced to D-III-ii by palladium-catalyzed hydrogenation. 2a Intermediate B-III, where Cl, Br, alkyl, CN, or alkoxy is present, can be reduced to D-III-i under mild reducing conditions, for example, by a zinc or iron metal containing ammonium chloride.

[0202] In Scheme 3, example X includes N and CH, example Y includes N, CH, and CF, but both X and Y do not include N, example R includes methyl and ethyl, and R 2 Examples are Includes alkyl and cycloalkyl, R 4 Examples are illustrated in the table of intermediates below, as well as by the examples of LGs including mesylates and tosylates, and include N-bonded alkyls and N-bonded heterocyclines with suitable substituents. [ka]

[0203] Scheme 4 shows an exemplary preparation of amine D-IV. Amide B-IV is obtained by the reaction of A-III-i with various amines in the presence of a catalytic amount of DMAP and optionally with an amide coupling reagent (e.g., CDI, DCC, EDC, HOBt, HBTU, PyBOP, or T3P). In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, commercially available boronic acid esters / boronic acid / trifluoroborates are used for R 2a Further treatment of B-IV, where Br is present, yields compound C-IV. Intermediate C-IV is reduced under mild reducing conditions, for example, by a zinc or iron metal containing ammonium chloride, R 2bIt may be selectively converted to amine D-IV-i, which is an alkenyl, alkynyl, or cycloalkyl. The intermediate C-IV can be completely reduced to D-IV-iii by palladium-catalyzed hydrogenation. 2a Intermediate B-IV, which is Cl, Br, alkyl, CN, or alkoxy, may be reduced to D-IV-ii under mild reducing conditions, for example, with a zinc or iron metal containing ammonium chloride.

[0204] In scheme 4, example X includes N and CH, example Y includes N, CH, and CF, but both X and Y do not include N, example R includes methyl and ethyl, and R 2 Examples include alkyl and cycloalkyl, R 4 Examples include -C(O)-alkyl and -C(O)-heterocyclyl, where the alkyl and heterocyclyl moieties are N-bonded to any suitable substituent as exemplified in the table below. [ka]

[0205] Scheme 5 shows an exemplary preparation of amine DV. BV reacts with a boronic ester / boronic acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to obtain compound CV. Many boronic esters / boronic acid / trifluoroborates are commercially available, and some cannot be readily prepared from their corresponding carboxylic acids (see Scheme 7). Intermediate CV can be converted to amine DV by standard reducing conditions, for example, by hydrogenation with a palladium catalyst, or by mild reducing conditions involving zinc metal and ammonium chloride.

[0206] In Scheme 5, the example of X includes N and CH, the example of Y includes N, CH, and CF, and R 2 Examples include alkyl and cycloalkyl, R 4 Examples include C-bonded heterocyclyls and heteroaryls having any suitable substituent as illustrated in the table of intermediates below. [ka]

[0207] Scheme 6 shows an exemplary preparation of D-VI from C-VI-i, where C-VI-i contains R 4 It contains a nitrogen protecting group, such as a Boc group. C-VI-i can be deprotected under acidic conditions to provide an amine salt. Further treatment of the salt with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH (reductive amination conditions) yields C-VI. The intermediate C-VI can be converted to aniline D-VI by standard reducing conditions, for example by palladium-catalyzed hydrogenation, or by mild reducing conditions involving zinc metal and ammonium chloride.

[0208] In Scheme 6, the example of X includes N and CH, and the example of Y includes N, CH, and CF, but both X and Y do not include N, and R 2 Examples include alkyl and cycloalkyl, and R 4 Examples include heterocyclyls having any suitable substituent as illustrated by the following table of intermediates. [ka]

[0209] Scheme 7 shows exemplary preparations of boronic acids / boronic esters T that are not commercially available. These compounds can be readily prepared from substituted carboxylic acids. The starting carboxylic acid can be activated with 2-hydroxyisoindoline-1,3-dione in the presence of a coupling reagent (e.g., DCI or Et3N / HATU) to obtain Q. Intermediate Q can be converted to boronic ester T by nickel-catalyzed decarboxylation boronation with a [B2pin2Me]Li complex pre-mixed with methyllithium and B2pin2 (Science, 356, 1045 (2017), JACS, 138, 2174 (2016)).

[0210] In scheme 7, examples of m include 0, 1, and 2, and R 4 Examples include alkyl, cycloalkyl, and heterocyclyl compounds having any suitable substituent as illustrated by the table of intermediates below. [ka]

[0211] Scheme 8 shows exemplary preparations of LI-1 and LI-2. Commercially available 2,4-dichloro-5-iodopyrimidine reacts with TMSCF2H in a solvent such as NMP or DMF in the presence of CuI and CsF to produce difluoromethylpyrimidine L-II-1 (US20150284341). Difluoromethylpyrimidine L-II-1 can be converted to thiomethyl etherpyrimidine LI-1 by treatment with sodium thiomethoxide and zinc chloride in diethyl ether at a temperature below 10°C (WO2012110773). In a similar manner to LI-1, trifluoromethylpyrimidine LI-2 can be prepared from commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine, L-II-2. [ka]

[0212] Scheme 9 is R1 An exemplary preparation of sulfonylpyrimidine L-III (t=2), which may be cycloalkyl, is shown. Treatment of commercially available 5-bromo-2-chloro-4-(methylthio)pyrimidine with a commercially available boronic acid ester / boronic acid / trifluoroborate (see Scheme 7) in the presence of a palladium catalyst (Suzuki coupling) yields thiopyrimidine L-III (t=0). The intermediate thiopyrimidine L-III (t=0) may be converted to sulfonylpyrimidine L-III (t=2) by standard oxidation, for example, with mCPBA. [ka]

[0213] Scheme 10 shows an exemplary preparation of intermediates H(I-XIII) using known methods. G is obtained by treating a commercially available lactam / cyclic carbamate / oxolactam / cyclic urea / diazepanone E with the (Boc) protected bromo intermediate F in the presence of a base, e.g., sodium hydride or potassium tert-butoxide. The Boc protecting group of G can be removed upon exposure to an acid, e.g., HCl or TFA.

[0214] In scheme 10, q can be 0, 1, 2, or 3, r can be 2, 3, or 4, and V is C(R 34 )2, O, or NR 6 It can be done as R 6 is an alkyl group, and n can be 2, 3, or 4, and each R 34 These can independently be H, C1-C6 alkyl, or two R 34 These can combine to form a cycloalkyl group. [ka]

[0215] In another embodiment for preparing H, H-XIV can be prepared from DBU via a one-step process, as illustrated in Scheme 11. DBU can be hydrolyzed with potassium hydroxide in a solution of methanol and water at ambient temperature to obtain H-XIV. [ka]

[0216] Scheme 12 shows exemplary preparations of key intermediates J and K. Key intermediate J can be prepared from H (either a free base or an acid addition salt) by reacting with thiopyrimidine LI, optionally by heating in the presence of an organic base (e.g., triethylamine or DIEA). Similarly, key intermediate K can be prepared from H using either L-II or L-III.

[0217] In scheme 12, q can be 0, 1, 2, or 3, r can be 2, 3, or 4, and V is C(R 34 ) 2、 O, or NR 6 It can be done as R 6 is an alkyl group, and n can be 2, 3, or 4, and each R 34 These can independently be H, C1-C6 alkyl, or two R 34 These can combine to form a cycloalkyl group. [ka]

[0218] Scheme 13 shows an exemplary preparation of the key intermediate M. Typically, treatment of H with commercially available iodopyridine under Buchwald-Hartwig coupling conditions (Cs2CO3, Xantphos, and Pd(OAc)2), carried out in an aprotic solvent (e.g., DME, DMF, DMSO, or NMP) at temperatures ranging from ambient temperature to 140°C, provides the key intermediate M.

[0219] In Scheme 13, R 1 is an alkyl or cycloalkyl group optionally substituted with Br, Cl, one or more fluorine atoms, q can be 0, 1, 2, or 3, r can be 2, 3, or 4, and V is C(R 34 )2, O, or NR 6 It can be done as R 6 is an alkyl group, and n can be 2, 3, or 4, and each R 34 These are independently H, C1-C6 alkyl, or two R 34 These can combine to form a cycloalkyl group. [ka]

[0220] Scheme 14 shows exemplary preparations of compounds of formula I from substituted anilines or aminopyridines (DI). The preparation of formula IA can be achieved from key intermediates K and J. Firstly, the nucleophilic substitution reaction of K with amine D can be carried out in an aprotic solvent, typically at a temperature ranging from ambient temperature to 150°C, and in some embodiments using microwave heating, optionally in the presence of an acid such as 4N HCl in 1,4-dioxane, to obtain formula IA. Compounds DI that are not commercially available can be readily prepared from substituted nitrobenzenes or nitropyridines (see Schemes 1-6). An alternative general synthesis of formula IA is carried out via a two-step process, first converting J(t=0) to a sulfoxide (J(t=1, main product)) by oxidation using various oxidizing agents, such as mCPBA. The sulfoxide reacts with amine DI by nucleophilic substitution, typically in an aprotic solvent in the presence of an acid, such as 4N HCl in 1,4-dioxane or pTSA, optionally at temperatures ranging from ambient temperature to 150°C, and in some embodiments by microwave heating. Formula IA containing nitrogen protecting groups such as a Boc group is deprotected under acidic conditions, and R 4An IA containing free NH (free amine or acid addition salt) can be provided. Formula IA (free base or acid addition salt) can be further treated with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH (reductive amination conditions), thereby R 4 N-substituted formula IA is obtained. For acylation and sulfonylation, the free amine (or salt) can be treated with commercially available acyl chloride or sulfonyl chloride to obtain N-substituted formula IA. [ka]

[0221] Scheme 15 shows an exemplary preparation of the compound of formula IB. The preparation of formula IB can be achieved by a Buchwald-Hartwig coupling reaction with DI and M. The amine DI, which is not commercially available, can be readily prepared from substituted nitrobenzene or nitropyridine (see Schemes 1-6). Formula IB containing a nitrogen protecting group such as a Boc group is deprotected under acidic conditions, and R 4 Formula IB containing the above free NH (free amine or acid addition salt) can be provided. Formula IB (free base or acid addition salt) can be further treated with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH (reductive amination conditions), thereby R 4 N-substituted IB is obtained. In the same manner as in Scheme 14, the free amine (or acid addition salt) can be treated with a commercially available acyl chloride or sulfonyl chloride to obtain N-substituted IB.

[0222] Preparation of intermediates The following compounds were prepared using the synthesis procedures and methods described herein, as well as methods known to those skilled in the art:

[0223] General method A: Aromatic nucleophilic substitution: Intermediate BI-8: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine [ka] A mixture of 2-bromo-4-fluoro-1-nitrobenzene (50 g, 227 mmol) and 1-methylpiperazine (24 g, 250 mmol) in DMF (400 mL) was treated with K2CO3 (63 g, 455 mmol) at room temperature, and the reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with ice water (500 mL), and the precipitated solid was filtered. The solid was further ground with Et2O and n-pentane to obtain 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (58 g, yield 85%) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 7.98 (d,J = 9.4 Hz,1H),7.24 (d,J = 2.1 Hz,1H),7.01 (dd,J = 2.2 and 9.4 Hz,1H),3.42 (m,4H),2.40 (m,4H),2.19 (s,3H); LC-MS (ESI) m / z:299.0 (M+H + ).

[0224] General method B: Deprotection and reductive amination: Intermediate BI-24: 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane [ka] A solution of tert-butyl 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (BI-14, 2.57 g, 6.2 mol) in MeOH (30 mL) was treated with 4N HCl in 1,4-dioxane (16 mL, 62 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was dried under vacuum and concentrated to obtain 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (2.17 g, 100% yield) as a white solid. The material was retained without further purification. A suspension of 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (1.92 g, 5.5 mmol) in DCE (25 mL) was treated with DIEA (2.9 mL, 17 mmol) and formaldehyde (1.2 mL, 17 mmol). The yellow suspension became a clear orange solution. The reaction mixture was stirred at room temperature for 10 minutes, and then acetic acid (0.63 mL, 11 mmol) was added. The orange solution became a yellow suspension and was stirred for 20 minutes. Sodium triacetoxyborohydride (2.33 g, 11 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with aqueous NaHCO3 (50 mL), and the solution was extracted with DCM (3 × 50 mL). The combined organic matter was extracted with anhydrous Na2SO4. The mixture was dried, filtered, and concentrated to obtain a brown solid. The brown solid was purified using silica gel column chromatography (0-15% MeOH / DCM) to obtain 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (1.71 g, 95% yield) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 7.98 (d,J = 9.4 Hz,1H),7.10 (d,J = 2.7 Hz,1H),6.89 (dd,J = 9.5 and 2.7 Hz,1H),3.54 (d,J = 11.6 Hz,2H),3.22 (brs,2H),2.99-3.04 (m,2H),2.22 (s,3H) ,1.92-1.95 (m,2H),1.52-1.56 (m,2H); LC-MS (ESI) m / z:326.0 (M+H + ).

[0225] General method C: Alkylation: Intermediate BI-23: 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine [ka] A mixture of 1-(3-methyl-4-nitrophenyl)piperazine hydrochloride (BI-3, 1.5 g, 0.58 mmol of Boc deprotection product) and K2CO3 (4.0 g, 2.9 mmol) in 1,4-dioxane (20 mL) was treated with 1-fluoro-2-iodoethane (2.0 mL, 2.6 mmol) [Note: This substance is described as being prone to instability - some solids are present in the orange liquid], tightly capped, and heated at 100°C for 24 hours. The mixture was cooled to room temperature, the solid (K2CO3) was removed by filtration, rinsed with DCM, and the filtrate was concentrated to dryness to obtain 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine (1.52 g, 98% yield) as a yellow oil, which solidified into an amber solid upon standing. 1 H NMR (400 MHz,DMSO-d6):δ 7.97 (d,J = 9.6 Hz,1H),6.87-6.89 (m,2H),4.61 (t,J = 4.9 Hz,1H),4.52 (t,J = 4.9 Hz,1H),3.41 (m,4H),2.69 (t,J = LC-MS (ESI) m / z:268.2 (M+H + ).

[0226] The intermediates shown in Table A below were prepared using the general methods A to C described above. Table A. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0227] Intermediate BI-33: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine 2-one [ka] A mixture of tert-butyl(2-aminoethyl)(methyl)carbamate (4.3 g, 24 mmol) and potassium carbonate (3.8 g, 27 mmol) in DMF (50 mL) was treated with 4-fluoro-2-bromo-1-nitrobenzene (5 g, 22 mmol) at room temperature under an N2 atmosphere, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water (200 mL), the solution was extracted with ethyl acetate (2 × 100 mL), the combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to obtain tert-butyl(2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, yield 66%) as a yellow liquid. 1H NMR (400 MHz,DMSO-d6):δ 7.98 (d,J = 9.0 Hz,1H),6.77 (S,1H),6.46 (d,J = 9.0 Hz,1H),3.54 (s,2H),3.31 (t,J = 6.0 Hz,2H),2.90 (s,3H),1.47 (s,9H); LC-MS (ESI) m / z:374.1 (M+H + ).

[0228] A mixture of tert-butyl(2-(3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 15 mmol) and TEA (7.6 g, 75 mmol) in DCM (100 mL) was treated with chloroacetyl chloride (5.1 g, 45 mmol) at 0°C under an N2 atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL), and the solution was extracted with DCM (2 × 100 mL). The combined organic matter was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to obtain tert-butyl(2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetamido)ethyl)(methyl)carbamate (5.6 g, yield 66%) as a yellow liquid. 1 H NMR (400 MHz,DMSO-d6):δ 8.12 (d,J = 8.6 Hz,1H),7.97 (s,1H),6.66 (d,J = 7.4 Hz,1H),4.24 (m,2H),3.82 (s,2H),3.18 (s,2H),2.70 (s,3H),1.41 (s,9H); LC-MS (ESI) m / z:374.1 (M+H + ).

[0229] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.6 g, 12 mmol) in dioxane (100 mL) was treated with 4N HCl in 1,4-dioxane (100 mL) at 0°C under an N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the crude product was purified by crystallization in Et2O (100 mL) to obtain N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (4.79 g, 99% yield) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 8.75 (brs,2H),8.16 (m,2H),7.83 (d,J = 7.8 Hz,1H),4.20 (s,2H),3.98 (t,2H),3.20 (s,2H),2.56 (s,3H),1.41 (s,9H); LC-MS (ESI) m / z:374.1 (M+H + ).

[0230] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.0 g, 12 mmol) in DMF (50 mL) was added to NaH (1.1 g, 25 mmol) in 60% mineral oil at 0°C under an N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL), the solution was extracted with ELISA (2 × 50 mL), the combined organic matter was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV). 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine-2-one (3.1 g, yield 76%) was obtained as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 8.0 (d,J = 9.4 LC-MS (ESI) m / z:314.2 (M+H + ).

[0231] Intermediate BI-34: 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine: [ka] A solution of (5-(4-methylpiperazin-1-yl)-2-nitrophenyl)methanol (1.0 g, 4.0 mmol) in DMF (30 mL) was cooled to 0°C. Sodium hydride (0.80 g, 60% of the mineral content) was added in portions, and the mixture was stirred under the same conditions. Iodomethane (1.7 g, 12 mmol) was added at 0°C, and the mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction product was diluted with siRNA and carefully quenched with ice water. The mixture was extracted with siRNA (3 × 30 mL), the combined organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (hexane / siRNA) to obtain 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine (0.76 g, yield 72%). 1 LC-MS (ESI) m / z:266.2 (M+H + ).

[0232] General method D: Suzuki coupling reaction: Intermediate CV-4: 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole: [ka] A suspension of 4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (0.80 g, 3.0 mmol) and 4-bromo-1-methyl-1H-imidazole (0.49 g, 3.0 mmol) in a mixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated with potassium carbonate (1.26 g, 9.1 mmol), and the suspension was stirred. The reaction mixture was degassed by bubbling argon for 2 minutes and treated with Pd(dppf)Cl2.DCM adduct (0.50 g, 0.61 mmol). The reaction mixture was heated at 100°C for 16 hours. The reaction mixture was diluted with water and extracted with DCM (4 × 25 mL). The organic matter was combined with the oil, dried over anhydrous Na₂SO₄, filtered, and concentrated and dried under vacuum to obtain black oil. The black oil was purified using silica gel (0-15% MeOH / DCM, 15 CV) to obtain 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, yield 47%). 1 LC-MS (ESI) m / z:218.2 (M+H + ).

[0233] The intermediates shown in Table B below were prepared using the general method D described above. Table B [Table 2]

[0234] General method E: Suzuki coupling reaction Intermediate CI-1: 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine [ka] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (BI-8, 20 g, 67 mmol) and cyclopropylboronic acid (8.6 g, 100 mmol) in toluene:H2O (9:1) (200 mL) was treated with K3PO4 (43 g, 200 mmol), and the reaction mixture was purged with nitrogen for 20 minutes. Tricyclohexylphosphine (3.7 g, 13 mmol) and Pd(OAc)2 (2.2 g, 10 mmol) were added to the reaction mixture, and the reaction mixture was then stirred at 100°C for 5 hours. The reaction mixture was diluted with water (100 mL), and the solution was extracted with ELISA (3 × 200 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-80% siRNA / hexane, 15 CV) to obtain 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, yield 69%) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 7.89 (d,J = 9.3 Hz,1H),6.85 (dd,J=2.4 and 9.4Hz1H),6.55 (s,1H),3.36 (m,4H),2.45 (m,1H),2.40 (m,4H),2.20 (s,3H),0.94 (m,2H),0.75 (m,2H); LC-MS (ESI) m / z:261.3 (M+H + ).

[0235] General method F: Suzuki coupling reaction Intermediate CI-12: 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine [ka] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (BI-8, 30 g, 100 mmol) and potassium vinyltrifluoroborate (20 g, 150 mmol) in DMSO (210 mL) was treated with K2CO3 (42 g, 301 mmol) at room temperature, and the reaction mixture was purged with nitrogen for 15 minutes. PdCl2 (dppf) (3.7 g, 5.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with cold water (300 mL), and the solution was extracted with RINKAN (3 × 250 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-80% HCl / hexane, 10 CV) to obtain 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (20 g, yield 81%). 1 H NMR (400 MHz,DMSO-d6):δ 7.96 (d,J = 9.2 Hz,1H),7.21 (m,1H),6.98 (m,2H),5.77 (t,J = 17.2 Hz,1H),5.41 (d,J = 11.2 Hz,1H),3.44 (t,J = 4.8 Hz,4H),2.42 (t,J = 4.8 Hz,4H),2.21 (s,3H); LC-MS (ESI) m / z:247.3 (M+H + ).

[0236] The intermediates shown in Table C below were prepared using either the general method E or general method F of the Suzuki reaction. Table C [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0237] General method G: Reduction Intermediate DI-1: 2-Cyclopropyl-4-(4-methylpiperazine-1-yl)aniline [ka] A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (Cl-1, 12 g, 46 mmol) in MeOH (60 mL) at 0°C was treated with NH4Cl (73 g, 14 mmol), and the reaction mixture was stirred at 0°C for 10 minutes. Zinc powder (30 (g, 459 mmol) was slowly added to the reaction mixture under an ice bath (the internal temperature rose to 20°C). After stirring for 15 minutes, the reaction mixture was warmed to room temperature and vigorously stirred at room temperature for 16 hours. The mixture was filtered through a Celite pad and washed with THF (500 mL). The filtrate was concentrated under reduced pressure to obtain 2-cyclopropyl-4-(4-methylpiperazine-1-yl)aniline (10 g, 95%) as a dark brown viscous solid. 1 H NMR (400 MHz,DMSO-d6):δ 6.52 (m,2H),6.43 (d,J = 2.0 Hz,1H),4.52 (brs,2H),2.88 (m,4H),2.42 (m,4H),2.20 (s,3H),1.65 (m,1H),0.813 (m,2H),0.471 (m,2H); LC-MS (ESI) m / z:213.2 (M+H + ).

[0238] General method H: reduction Intermediate DI-11: 2-ethyl-4-(4-methylpiperazine-1-yl)aniline [ka] A solution of 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (Cl-12, 20 g, 81 mmol) in siRNA (200 mL) was treated with Pd / C (20 g, 10% w / w, 50% water) under a nitrogen atmosphere, and the mixture was then stirred at room temperature for 3 hours under hydrogen balloon pressure. After general processing, 2-ethyl-4-(4-methylpiperazine-1-yl)aniline (16 g, 90% yield) was obtained as a brown, sticky solid. 1 H NMR (400 MHz,DMSO-d6):δ 6.61 (s,1H),6.52 (m,2H),4.25 (brs,2H),2.89 (t,J = 4.4 Hz,4H),2.41 (m,6H),2.19 (s,3H),1.09 (t,J = 7.6 Hz,3H); LC-MS (ESI) m / z:219.3 (M+H + ).

[0239] The intermediates shown in Table D below were prepared using the general methods G or H for preparing DI-1 or DI-11. Table D [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10]

[0240] Intermediate DV-6: 2-ethyl-4-(1-methylpyrrolidine-3-yl)aniline [ka] A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.25 g, 0.85 mmol) and 4-bromo-2-ethylaniline (0.121 g, 0.60 mmol) in a mixture of 1,4-dioxane (5 mL) and water (1 mL) was treated with K2CO3 (0.251 g, 1.8 mmol). The mixture was degassed with Ar for 2 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added. The reaction mixture was heated overnight at 95°C under microwave. The reaction mixture was cooled to room temperature, and the mixture was extracted with EtOAC (2 ×). Combined organic extraction The product was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (0-60% siRNA / hexane, 15 CV) to obtain tert-butyl 3-(4-amino-3-ethylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.12 g, yield 70%), which was carried over without further purification. LC-MS m / z: 289.2 (M+H + ).

[0241] A solution of tert-butyl 3-(4-amino-3-ethylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.12 g, 0.42 mmol) in MeOH (20 mL) was treated with Pd-C (0.040 g, 0.0424 mmol). The reaction mixture was left under balloon overnight. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(4-amino-3-ethylphenyl)pyrrolidine-1-carboxylate (0.12 g, 97% yield) as a colorless viscous oil. 1 H NMR (400 MHz,DMSO-d6):d 6.81 (s,1H),6.80 (m,1H),6.53 (d,J = 8.0 Hz,1H),4.68 (s,2H),3.57 (m,1H),3.41 (m,1H),3.11-3.29 (m,2H),3.04 LC-MS m / z:313.2 (M+H+Na + ).

[0242] A solution of tert-butyl 3-(4-amino-3-ethylphenyl)pyrrolidine-1-carboxylate (0.12 g, 0.40 mmol) in a biphasic mixture of butyl (25 mL) and saturated NaHCO3 (aqueous solution) (25 mL) was treated with benzyl chloroformate (0.086 mL, 0.60 mmol). The mixture was stirred overnight at room temperature. The mixture was partitioned between butyl and saturated NaHCO3, and butyl (2 × 25 mL) was extracted. The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 3-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)pyrrolidine-1-carboxylate (0.18 g, yield 100%), which was carried over without further purification. LC-MS m / z: 447.2 (M + H + Na + ).

[0243] A solution of tert-butyl 3-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)pyrrolidine-1-carboxylate (0.18 g, 0.44 mmol) in DCM (3 mL) was treated with TFA (2 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain the crude TFA salt. The crude product was suspended in DCM and TEA (1 mL) was added. The solvent was removed under reduced pressure and the mixture was dried under vacuum. The resulting mixture was suspended in DCM and AcOH (3 drops). Formaldehyde (5 drops) was added and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and saturated NaHCO3 and stirred for 1 hour. The mixture was extracted with DCM (2 × 25 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain benzyl(2-ethyl-4-(1-methylpyrrolidine-3-yl)phenyl)carbamate (0.14 g, yield 94%), which was carried over without further purification. LC-MS m / z: 339.2 (M + H + ).

[0244] A solution of benzyl(2-ethyl-4-(1-methylpyrrolidine-3-yl)phenyl)carbamate (0.14 g, 0.41 mmol) in siRNA (20 mL) was flushed with Ar. Palladium carbon (0.022 g, 0.02 mmol) was added, and the mixture was hydrogenated overnight under a balloon at room temperature. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain (2-ethyl-4-(1-methylpyrrolidine-3-yl)aniline (0.10 g, yield 119%), which was carried over without further purification. LC-MS m / z: 205.2 (M+H + ).

[0245] Common methods for alkylation of Z-lactams and deprotection of the Boc group: Intermediate H-VII-1 [ka] A solution of 1,4-oxazepan-5-one (10 g, 87 mmol) in dry THF (400 mL) at 0°C was treated portionwise with sodium hydride (3.0 g, 130 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 15 minutes, and then tert-butyl(3-bromopropyl)carbamate (21 g, 87 mmol) was added. The solution was stirred continuously from 0°C to room temperature for 16 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (200 mL), and the solution was extracted with Âr (2 × 150 mL). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered under reduced pressure. The crude product was purified by silica gel column chromatography (40-50% siRNA / hexane, 15 CV) to obtain tert-butyl(3-(5-oxo-1,4-oxazepan-4-yl)propylcarbamate) (12 g, 50% yield) as a yellow liquid. The product was dissolved in DCM (50 mL) and treated with 4N HCl in 1,4-dioxane (4 equivalents). The mixture was stirred at room temperature for 3 hours, then concentrated and dried under high vacuum to obtain 4-(3-aminopropyl)-1,4-oxazepan-5-one HCl salt (100% yield). 1 H NMR (400MHz, DMSO-d6): δ8.09(brs, 3H), 3.62(m, 4H), 3.49(m, 2H), 3.35(t, J=6.8 Hz, 2H), 2.73(m, 2H), 2.62(t, J=4.8Hz, 2H), 1.78(m, 2H), MS(ESI)m / z:173.2(M+H + ).

[0246] Using a general method for preparing H-VII-1, H-VI-1 was prepared from the intermediate H-II-1 shown in Table E below. Table E [Table 5]

[0247] Intermediate H-XIV: 1-(3-aminopropyl)azepan-2-one [ka] A suspension of DBU (22 g, 145 mmol) in MeOH:H2O (1:1) (130 mL) was treated with KOH (12 g, 217 mmol) at 0°C under an N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The solution was extracted with 10% MeOH (3 × 250 mL) in DCM, and combined. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(3-aminopropyl)azepan-2-one (21 g, yield 85%) as a liquid oil. 1 H NMR (400 MHz,CDCl3):δ 3.45 (t,J = 3.5 Hz,2H),3.31 (t,J = 4.4 Hz,2H),2.68 (t,J = 6.5 Hz,2H),2.51 (t,J = 5.8 Hz,2H),1.70 (m,2H),1.65 (m,8H);LC-MS (ESI) m / z:171.4 (M+H + ).

[0248] Intermediate L-III-1: 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine [ka] (A) A suspension of 5-bromo-2-chloro-4-(methylthio)pyrimidine (25.0 g, 105 mmol) and cyclopropylboronic acid (13.7 g, 158 mmol) in toluene:H2O (9:1) (650 mL) was treated with the addition of K3PO4 (66.7 g, 315 mmol). The reaction mixture was purged with nitrogen for 20 minutes, and then tricyclohexylphosphine (5.9 g, 21 mmol) and Pd(OAc)2 (2.35 g, 10.50 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-10% siRNA / hexane) to obtain 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (14.0 g, yield 66%) as a yellow oil. 1 H NMR (400 MHz,DMSO-d6):δ 7.92 (s,1H),2.58 (s,3H),1.67 (m,1H),1.03 (m,2H),0.67 (m,2H); LC-MS (ESI) m / z:201.0 (M+H + ).

[0249] (B) A solution of 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (4.0 g, 20 mmol) in DCM (60 mL) at 0°C was treated with m-CPBA (4.8 g, 28 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated aqueous NaHCO3 (2 × 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine (3.6 g, yield 86%) as a yellow solid. 1 H NMR (400 MHz,DMSO-d6):δ 8.57 (s,1H),2.89 (s,3H),2.16 (m,1H),1.16 (m,2H),0.93 (m,2H); LC-MS (ESI) m / z:217.0 (M+H + ).

[0250] Intermediate LI-2: 4-chloro-2-(methylthio)-5(trifluoromethyl)pyrimidine [ka] A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 g, 0.46 mol) in diethyl ether (2 L) was treated by adding ZnCl2 (1.0 N in ether) (555 mL, 0.56 mol) dropwise at 0°C, and the reaction mixture was stirred for 2 hours. Rium thiomethoxide (49 g, 0.94 mol) was added at 0°C, and the reaction mixture was warmed to room temperature and stirred for 48 hours. The reaction mixture was quenched with 2N HCl under an ice bath, and the solution was then extracted with Et2O (3 × 500 mL). The combined organic extracts were washed with water (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35°C to obtain 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, yield 95%) as a colorless liquid. 1 H NMR (400 MHz,DMSO-d6):δ 9.01 (s 1H),2.62 (s 3H).

[0251] General methods of substitution reactions: Intermediate J-7: 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one [ka] A solution of 4-(3-aminopropyl)1,4-oxazepan-5-one hydrochloride (H-VII-1, 3.0 g, 17.4 mmol) in DMF (60 mL) was treated with DIEA (15.5 mL, 87.2 mmol) at 0°C and stirred for 15 minutes. Then, 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (LI-2, 6.0 g, 26.2 mmol) was added, and the mixture was stirred continuously from 0°C to room temperature for 16 hours. The reaction mixture was quenched with ice water (120 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (40-50% siRNA / hexane, 15 CV) to obtain 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one (3.0 g, yield 47%) as a yellow liquid. 1 H NMR (400 MHz,DMSO-d6):δ 8.25 (s,1H),7.52 (bs,1H),3.64 (m,4H),3.47 (m,2H),3.42 (m,2H),3.32 (m,2H),2.63 (t,J = 4.8 Hz,2H),2.47 (s,3H),1.68 (m,2H); LC-MS (ESI) m / z:365.3 (M+H + ).

[0252] The intermediates listed in Table F below were prepared using the general method for preparing intermediate J-7. Table F. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0253] General method of Pd coupling reaction: Intermediate M-1: 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one [ka] A solution of 1-(3-aminopropyl)piperidine-2-one hydrochloride (H-III-1, 9.0 g, 29.3 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (6.19 g, 32.2 mmol) in toluene (180 mL) was treated with cesium carbonate (23.9 g, 73.2 mmol). The mixture was purged with Ar for 15 minutes. Then, PdCl2(dppf)DCM (2.39 g, 2.93 mmol) was added, and the mixture was further purged with Ar for 5 minutes. The sealed tube was closed, and the mixture was heated normally in a preheated oil bath at 90°C for 16 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). The solution was extracted with siRNA (3 × 100 mL). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-45% siRNA / hexane, 12CV) to obtain 1-(3-((2-chloro-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one (2.6 g, yield 26%) as a brown solid. 1 LC-MS (ESI) m / z:336.1 (M+H + ).

[0254] The intermediates listed in Table G below were prepared using a general method for preparing intermediate M-1. Table G [Table 7]

[0255] General methods for the oxidation of sulfinyl intermediates: Intermediate J-14: 4-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one [ka] A solution of 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one (J-7, 3.0 g, 8.2 mmol) in DCM (60 mL) at 0°C was added, and m-CPBA (2.0 g, 11.5 mmol) was stirred from 0°C to room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution (2 × 90 mL). The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to obtain a mixture of 4-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one and 4-(3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one (3.0 g, 95%, 9:1) as a pale yellow semi-solid. 1 LC-MS (ESI) m / z:381.3 (M+H + ).

[0256] The intermediates listed in Table H below were prepared using the general method for preparing intermediate J-14. Table H [Table 8-1] [Table 8-2]

[0257] Exemplary Compounds: The compounds of formulas IA and IB below were prepared using the method described above. Examples of compounds of formulas IA and IB are shown in Table I. Exemplary methods for preparing the compounds are also presented below.

[0258] General method I: Substitution reaction Example 23: 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one [ka] A solution of 1-(3-((5-bromo-2-chloropyrimidine-4-yl)amino)propyl)piperidine-2-one (K-10, 4.0 g, 11.6 mmol) in 2-butanol (80 mL) at room temperature was treated with 2-ethyl-4-(4-methylpiperazin-1-yl)aniline (DI-11, 2.53 g, 11.6 mmol). The reaction mixture was treated with 4N HCl (3.5 mL, 13.9 mmol) in 1,4-dioxane and stirred at 95°C for 72 hours. The reaction mixture was cooled to room temperature and then made basic with saturated aqueous solution NaHCO3. The solution was extracted with DCM (3 × 50 mL), the combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (4-5% MeOH / DCM, 10 CV). The product was dissolved in DCM (200 mL), and QuadraSil-MP resin (w / w) was added to remove residual palladium. The solution was stirred for 4 hours and filtered. The filtrate was evaporated to obtain 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one (1.70 g, yield 28%) as an off-white solid. 1H NMR (400 MHz,DMSO-d6):δ 8.09 (s,1H),7.81 (s,1H),7.13 (d,J = 8.5 Hz,1H),6.80 (m,1H),6.74 (m,1H),6.71 (m,1H) ,3.21 (m,4H),3.14 (m,2H),3.07 (m,5H),2.43 (m,5H),2.21 (s,5H),1.67 (s ,4H),1.61 (m,2H),1.05 (t,J = 7.4 Hz,3H); LC-MS (ESI) m / z:530.3 (M+H + ).

[0259] General method J: Substitution reaction tert-butyl4-(4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1,4-diazepan-1-carboxyl [ka] A solution of tert-butyl 4-(4-aminophenyl)-1,4-diazepan-1-carboxylate (DI-12, 0.21 g, 0.57 mmol) and 1-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one (J-9, 0.17 g, 0.57 mmol) in DMF (3.0 mL) was sealed and heated at 90°C for 12 hours. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (0-4% MeOH / DCM, 12 CV) to obtain the product tert-butyl 4-(4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1,4-diazepan-1-carboxylate (0.20 g, yield 60%). LC-MS(ESI)m / z:592.4(M+H + ).

[0260] General method K:R 4 Deprotection of the Boc group in the portion Example 9: 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one [ka] A solution of tert-butyl 4-(4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1,4-diazepan-1-carboxylate (0.20 g, 0.34 mmol) in DCM (3 mL) was treated with 4N HCl (1.0 mL) in 1,4-dioxane. The mixture was stirred at room temperature for 2 hours. The solution was concentrated, and the residue was dissolved in water (1.0 mL) and acetonitrile (1 mL), then frozen and lyophilized to obtain 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one hydrochloride (0.12 g, yield 67%). 1 H NMR (400 MHz,DMSO-d6):δ 9.23 (brs,1H),8.27 (s,1H,FA),8.08 (s,1H),7.47 (d,J = 8.5 Hz,2H),7.06 (s,1H),6.67 (d,J = 8.5 Hz,2H),3.51 (t,J = 5.0 Hz,2H),3.47 (t,J = 6.2 Hz,3H),3.34-3.37 (m,3H),3.30 (t,J = 6.9 Hz,3H),3.20 (s,3H),2.98 (t,J = 4.9 Hz,2H),2.80 (t,J = 5.6 Hz,2H),2.21(t,J = 6.0 Hz,2H),1.87-1.90 (m,2H),1.69-1.75 (m,7H); LC-MS (ESI) m / z:492.4 (M+H + ).

[0261] General method L:R 4 Partial reductive alkylation Example 10: 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one [ka] A solution of 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)piperidine-2-one (9, 0.10 g, 0.20 mmol)) in methanol (0.5 mL) was treated with acetaldehyde (0.1 mL, 1.8 mmol) and acetic acid (2 drops). Sodium borocyanohydride (0.026 g, 0.41 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The solution was treated with brine and then extracted with ethyl acetate (3 × 15 mL). The combined organic matter was dried over anhydrous sodium 2 SO4, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (0%~20% CH3CN / H2O (0.1% FA), 15 CV) to obtain 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)piperidine-2-one (56 mg, yield 49%). 1 1H NMR (400 MHz,DMSO-d6):δ 9.21 (brs,1H),8.17 (s,1H,FA),8.08 (s,1H),7.45 (d ,J = 8.3 Hz,2H),7.05 (s,1H),6.63 (d,J = 8.7 Hz,2H),3.47 (t,J = 4.9 Hz,3H),3.36-3.42 (m,5H),3.30 (t,J = 6.9 Hz,3H),3.19 (s,3H),2.72 (t,J = 4.7 MS (ESI) m / z:520.4 (M+H)+ ).

[0262] R 4 Common methods for partial acylation: Example 36: 1-(3-((2-((4-(4-acetylpiperazine-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one [ka] A 2.5 mL solution of 1-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)piperidine-2-one (34, 0.21 g, 0.40 mmol) in 30% MeCN:water was treated with acetic anhydride (1.0 equivalent) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and the solution was diluted with water (15 mL). The solution was extracted with ethyl acetate (3 × 20 mL), and the combined organic matter was washed with saturated NaHCO3 (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-10% DCM / MeOH, 25 CV) to obtain 1-(3-((2-((4-(4-acetylpiperazine-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one (0.13 g, yield 57%) as a clear glassy solid. 1 1H NMR (400 MHz) ,DMSO-d6):δ 8.64 (brs,1H),8.04 (s,1H),7.27 (s,1H),7.05 (brs,1H),6.75 (d,1H),6.46 (s,1H),3.54 (d,4H),3.01-3.24 (m,10 H),2.18-2.19 (m,2H),2.02 (s,3H),1.91-1.96 (m,1H),1.61-1.67 (m,6 H),0.82 (d,2H),0.58 (d,2H); LC-MS (ESI) m / z:560.4 (M+H + ).

[0263] General method: M:Pd coupling reaction Example 97: 1-(3-((2-((5-(4-methylpiperazine-1-yl)pyridine-2-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one [ka] A mixture of commercially available 5-(4-methylpiperazin-1-yl)pyridine-2-amine (0.13 g, 0.66 mmol) and 1-(3-((2-chloro-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one (M-1, 0.20 g, 0.60 mmol) in 1,4-dioxane (3 mL) was treated with cesium carbonate (0.39 g, 1.2 mmol). The solution was sparged with Ar and Pd2(dba)3 (0.055 g, 0.06 mmol) and Xantphos (0.069 g, 0.12 mmol). The mixture was treated with mmol. The mixture was sparged again with Ar, tightly capped, and heated at 90°C for 15 hours. The mixture was cooled to room temperature and diluted with DCM (20 mL) and water (10 mL). The black solid was filtered, and the filtrate was treated with brine. The solution was extracted with additional DCM (3 × 25 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 1-(3-((2-((5-(4-methylpiperazine-1-yl)pyridine-2-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)piperidine-2-one (0.18 g, yield 57%) as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.35 (s,1H),8.01 (s,1H),7.90 (d,J = 3.0 Hz,1H),7.55 (d,J = 9.1 Hz,1H),7.37 (dd,J = 9.1 and 3.1 Hz,1H),7.11 (s,1H),6.19-6.21 (m,1H),3.31-3.35 (m,2H),3.22-3.26 (m,2H),3.13 (q,J = 6.5 Hz,2H),3.05-3.10 (m,4H),2.44-2.49 (m,4H),2.20-2.23 (m,5H),1.66-1.76 (m,6H); LC-MS (ESI) m / z: 492.2 (M+H + ). Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 Table 9-15 Table 9-16 Table 9-17 Table 9-18 Table 9-19 Table 9-20 Table 9-21 Table 9-22 Table 9-23 Table 9-24 Table 9-25 Table 9-26 Table 9-27 Table 9-28 Table 9-29 [Table 9-30] [Table 9-31] [Table 9-32] [Table 9-33] [Table 9-34] [Table 9-35] [Table 9-36] [Table 9-37] [Table 9-38] [Table 9-39] [Table 9-40] [Table 9-41] [Table 9-42] [Table 9-43] [Table 9-44]

[0264] Example 130. Biochemical assay of ULK1.2 (SEQ ID NO: 1) The activity of ULK1 kinase was spectroscopically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 19 nM ULK1 (Eurofins CAT# 14-959), 0.25 mg / mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour timeframe. The reaction rates at each concentration of the compound were converted to percentage inhibition using controls (i.e., reactions without the test compound and reactions with known inhibitors), and IC50 was calculated. 50 The values ​​were calculated by fitting a sigmoid curve for four parameters to the data using Prism (GraphPad software). ULK1 protein sequence (residues 1-314 with N-terminal His tag, SEQ ID NO: 1) MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQ NILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPVPVPSYPSSGSGSSSSSSSTSHLAS

[0265] Example 131. Biochemical assay of ULK1.3 (SEQ ID NO: 2) The activity of ULK1 kinase was spectroscopically determined using a conjugated pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton). The assay was performed using 0.1 nM ULK1 (from Beryllium) in X-100, 0.075 mM peptide substrate (YANWLAASIYLDGKKK), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP. ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour timeframe. The reaction rates at each concentration of the compound were converted to percentage inhibition using controls (i.e., reactions without the test compound and reactions with known inhibitors), and IC50 was calculated. 50 The values ​​were calculated using software routines in Prism (GraphPad software). ULK1 protein sequence (residues 1-283, SEQ ID NO: 2) MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKP QNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS

[0266] Example 132. Biochemical assay of ULK2 (SEQ ID NO: 3) ULK2 kinase activity was spectroscopically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100) containing 9.7 nM ULK2 (Eurofins CAT#14-772), 0.25 mg / mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP. ULK2 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour timeframe. The reaction rates at each concentration of the compound were converted to percentage inhibition using controls (i.e., reactions without the test compound and reactions with known inhibitors), and IC50 was calculated. 50 The values ​​were calculated by fitting a sigmoid curve for four parameters to the data using Prism (GraphPad software). ULK2 protein sequence (residues 1-306 with N-terminal GST and His tags, SEQ ID NO: 3) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFED RLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSI NKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCG SPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0267] In Table 1, "+" indicates an IC with a minimum or maximum impedance of 1 nM and 25 nM. 50 This refers to an IC with a power output greater than 25nM and less than or equal to 100nM. 50 This refers to ICs with a impedance of over 100nM and 500nM or less. 50 This refers to an IC with a minimum impedance of over 500 nM. 50 It refers to.

[0268] Example 133. Cellular inhibition of ULK kinase substrate ATG13 protein pATG13 levels of mutant KRas A549 cells after treatment with a ULK inhibitor in combination with trametinib. Human lung cancer cells (A549 (KRAS variant)) (6,000 cells / well) were added to a 384-well tissue culture plate containing 50 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL of penicillin G, and 100 μg / mL of streptomycin. The cells were grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to each well. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control well. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated. The cells were then washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed at 4°C for 10 minutes with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0269] The cellular levels of phosphoserine 318 ATG13 (pATG13) were measured by ELISA. Wells were coated with total ATG13 antibody (Cell Signaling Cat#13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked at room temperature for 1 hour with assay diluent (Biolegend Cat#421203). The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted with assay diluent, added to each well, and incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. Streptoavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well, then incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. The plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from the blank well was subtracted from the test well. The data were compared to the control well to determine the ATG13 phosphorylation %. IC was calculated using GraphPad Prism. 50 The value was calculated.

[0270] Example 134. Mutant KRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in MiaPaCa-2 cells MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were added to a 384-well tissue culture plate containing 50 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin, and 2.5% horse serum. The cells were grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to each well. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control well. The wells were mixed by gently shaking the plate, and then incubated overnight at 37°C. The following day, the culture medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed at 4°C for 10 minutes with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0271] The cellular levels of phosphoserine 318 ATG13 (pATG13) were measured by ELISA. Wells were coated with total ATG13 antibody (Cell Signaling Cat#13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then rinsed at room temperature with assay diluent (Biolegend Cat#421203) for 1 hour. Inter-blocking was performed. Plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted with assay diluent and added to each well, and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted with assay diluent and added to each well, and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from the blank well was subtracted from the test well. The data was compared with the control well to determine the ATG13 phosphorylation %. IC was analyzed using GraphPad Prism. 50 The value was calculated.

[0272] Example 135. Mutant KRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in HCT-116 cells HCT-116 human colon cancer cells (10,000 cells / well) were added to a 384-well tissue culture plate containing 50 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL of penicillin G, and 100 μg / mL of streptomycin. The cells were grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to each well. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control well. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed at 4°C for 10 minutes with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0273] The cellular levels of phosphoserine 318 ATG13 (pATG13) were measured by ELISA. Wells were coated with total ATG13 antibody (Cell Signaling Cat#13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked at room temperature for 1 hour with assay diluent (Biolegend Cat#421203). The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted with assay diluent, added to each well, and incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. Streptoavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well, then incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. The plate was then pre-treated to measure absorbance at 450 nm and 540 nm (background). The analysis was performed on a GraphPad Prism. The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from the blank well was subtracted from the test well. The data was compared to the control well to determine the ATG13 phosphorylation percentage. IC was analyzed using GraphPad Prism. 50 The value was calculated.

[0274] Example 136. Mutant BRAF treated with a ULK inhibitor in combination with trametinib. pATG13 levels in A375 cells Human malignant melanoma cancer cells (20,000 cells / well) were added to a 96-well tissue culture plate containing 100 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL of penicillin G, and 100 μg / mL of streptomycin. The cells were grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 100 μL of medium containing trametinib or DMSO as a control was added to each well. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.5 μL per well) was added. DMSO (0.5 μL) was added to the control well. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed at 4°C for 10 minutes with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0275] The cellular levels of phosphoserine 318 ATG13 (pATG13) were measured by ELISA. Wells were coated with total ATG13 antibody (Cell Signaling Cat#13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked at room temperature for 1 hour with assay diluent (Biolegend Cat#421203). The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted with assay diluent, added to each well, and incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. Streptoavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well, then incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. The plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from the blank well was subtracted from the test well. The data were compared to the control well to determine the ATG13 phosphorylation %. IC was calculated using GraphPad Prism. 50 The value was calculated.

[0276] Example 137. Mutant HRas after treatment with a ULK inhibitor in combination with trametinib. T24 cell pATG13 levels T24 human bladder cancer cells (25,000 cells / well) were pre-treated in 100 μL of wells supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL of penicillin G, and 100 μg / mL of streptomycin. The cells were added to a 96-well tissue culture plate containing warmed DMEM medium and grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 100 μL of medium containing trametinib or DMSO as a control was added to each well. The final concentration of trametinib in the wells was 250 nM. A dose-response of the test compound (0.5 μL per well) was added. DMSO (0.5 μL) was added to the control well. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) with shaking at 4°C for 10 minutes.

[0277] The cellular levels of phosphoserine 318 ATG13 (pATG13) were measured by ELISA. Wells were coated with total ATG13 antibody (Cell Signaling Cat#13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked at room temperature for 1 hour with assay diluent (Biolegend Cat#421203). The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted with assay diluent, added to each well, and incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. Streptoavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well, then incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. The plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from the blank well was subtracted from the test well. The data were compared to the control well to determine %ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 The value was calculated. [Table 11-1] [Table 11-2] [Table 11-3]

[0278] In Table 2, "+" indicates an IC with a impedance greater than 10 nM and less than or equal to 100 nM. 50 This refers to ICs with a impedance greater than 100nM and less than or equal to 300nM. 50 This refers to ICs with a impedance of over 300nM and 600nM or less. 50 This refers to an IC with a minimum impedance of over 600 nM. 50 It refers to.

[0279] Example 138. Biochemical assay of LRRK2 (SEQ ID NO: 4) The activity of LRRK2 kinase was spectroscopically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 26.4 nM LRRK2 (Thermo Fisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100). LRRK2 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorption at 340 nm was continuously monitored for 6 hours at 30°C using a multimode microplate reader (BioTek). The reaction rate was calculated using a time frame of 2-3 hours. The reaction rate at each concentration of the compound was converted to percentage inhibition using a control (i.e., a reaction without the test compound and a reaction with a known inhibitor), and IC was calculated. 50 The values ​​were calculated using software routines in Prism (GraphPad software). LRRK2 protein sequence (residues 970-2528; SEQ ID NO: 4) MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIA WPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGTMHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELK [Table 12-1] [Table 12-2]

[0280] In Table 3, "+" indicates an IC with a power of more than 1 nM and less than or equal to 100 nM. 50 This refers to ICs with a impedance greater than 100nM and less than or equal to 300nM. 50 This refers to ICs with a impedance of over 300nM and 600nM or less. 50 This refers to an IC with a minimum impedance of over 600 nM. 50 It refers to.

[0281] Example 139. In vitro and in vivo evaluation of ULK inhibitors in pancreatic ductal adenocarcinoma (PDAC). ULK inhibitors were evaluated by PDAC flux assay, and Trp53 lox / + LSL-Kras G12D Rosa-rtTA LSL p48Cre + IC of compounds in a panel of multiple PDAC cell lines, including cells derived from primary tumors of ) 50 This is determined using clonal 2D assays and 3D organoid assays, in or out of the presence of trametinib.

[0282] Inhibition of autophagy flux using a flux reporter in in vivo PDAC tumors will be evaluated using synogeneic orthotopic models after single and multiple doses.

[0283] The therapeutic efficacy of ULK inhibitors in the PDAC model is evaluated by (i) subcutaneously assessing the tumor dynamics of PDAC; (ii) orthotopically assessing the tumor dynamics of PDAC (KPC-transplanted C57 black mice) in the pancreas of a syngeneic model; (iii) evaluating tumor growth dynamics in the syngeneic model with ULK inhibitors and MEK inhibitors; (iv) evaluating the compounds in the PDAC orthotopic model; (v) evaluating histological changes in the tumor microenvironment; (vi) evaluating changes in immune cell infiltration in the tumor upon inhibition with ULK inhibitors; and (vii) evaluating the efficacy of ULK inhibitors in combination with immune checkpoint inhibition.

[0284] Equal portions While specific embodiments have been discussed, the above specification is illustrative and not limiting. Many variations of the embodiments will become apparent to those skilled in the art through the examination of this specification. The full scope of what is disclosed should be determined by referring to the claims, the full scope of the equivalents, and the specification, as well as such variations.

[0285] Unless otherwise indicated, all numbers representing quantities of components, reaction conditions, etc., used herein and in the claims should be understood in all cases to be modified by the term “approximately.” Therefore, unless otherwise indicated, numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained.

Claims

1. Compounds of formula I-A: 【Chemistry 1】 Alternatively, a method for preparing a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein in the above formula X is either CH or N; Y is C(R ３ ) or N; However, both X and Y are not N; R １ is selected from the group consisting of halogen, cyano, C １ -C ５ alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ５ alkyl and C ３ -C ５ cycloalkyl may be optionally substituted by one, two, or three independent occurrences of fluorine; R ２ H, halogen, cyano, C １ -C ５ Alkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Alkenil, C ２ -C ５ Alkinyl, C １ -C ５ Alkoxy, and C １ -C ５ Alkoxy-C ２ -C ５ Selected from the group consisting of alkyl groups, each C １ -C ５ Alkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Alkenil, C ２ -C ５ Alkinyl and C １ -C ５ The alkoxy may optionally be substituted with one, two, or three independently generated fluorine or cyanonucleotides; R ３ H, halogen, C １ -C ６ Alkyl and C １ -C ６ Selected from the group consisting of alkoxys, each C １ -C ６ Alkyl and C １ -C ６ The alkoxy may optionally be substituted with one or more independently generated fluorine molecules; R ４ B, D, NR ６ R ９ , NR ６ - (C(R １０ ) ２ ) ｐ -NR ９ R ９ , C(O)-NR ６ R ９ Selected from the group consisting of C(O)-B, C(O)-D, and CN; B is selected from N-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional cyclic nitrogen or oxygen, and B is R ７ It may be optionally substituted on one or more available carbons by R ９ It may optionally be substituted on available nitrogen; D is selected from C-bonded heterocyclyls and heteroaryls having at least one nitrogen and optionally additional cyclic nitrogen or oxygen, and D is R ７ It may be optionally substituted on one or more available carbons by R ９ It may optionally be substituted on available nitrogen; R ７ Each occurrence is independent of H and C. １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, cyano, and (C(R) １０ ) ２ ) ｈ -NR ９ R ９ Selected from the group consisting of each C １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl group may optionally be substituted with one or more independently generated fluorines, or with two R groups. ７ However, they bond together with the atoms they are bonded to to form an oxo; R ６ and R ９ each occurrence of which is independently selected from the group consisting of H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C １ -C ５ alkoxy-C ２ -C ５ alkyl, C(=O)R ５ , SO ２ R ５ and C-bonded heterocyclyl having at least one nitrogen and optionally additional ring nitrogen or oxygen, and heteroaryl, each C １ -C ６ alkyl and C ３ -C ６ cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R ５ Each occurrence of which is independently selected from the group consisting of H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, and heterocyclyl, and each C １ -C ６ alkyl and C ３ -C ６ cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R １０ Each occurrence is independent of H and C. １ -C ３ Alkyl and C ３ -C ５ Selected from the group consisting of cycloalkyl groups, each C １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl group may optionally be substituted with one or more independently generated fluorines, or with two R groups. １０ However, they bond together with the carbon that they are bonded to. ３ -C ５ Forms a cycloalkyl group; h is 1, 2, or 3; m is 0, 1, 2, or 3; n is 2, 3, or 4; p is either 2 or 3; Z is, 【Chemistry 2】 And; During the ceremony, V is oxygen, C (R ３４ ) ２ , and NR ６ Selected from the group consisting of; R ３４ Each occurrence of H and R is independent. ３６ Selected from, R ３６ Each occurrence is independent of C １ -C ６ Alkyl and C ３ -C ６ Selected from cycloalkyl groups, or two R groups ３６ However, they bond together with the carbon that they are bonded to. ３ -C ６ Forms a cycloalkyl group; q is 0, 1, 2, or 3; r is 2, 3, or 4; However, if q is 0, then r is not 2, The aforementioned method is: Compounds of formula K or formula J (t=1): 【Transformation 3】 The compound of formula D-I: 【Chemistry 4】 A method that includes causing a reaction.

2. The method according to claim 1, comprising reacting a compound of formula K or formula J (t=1) with a compound of formula D-I in a polar solvent at a temperature ranging from ambient temperature to 150°C.

3. The method according to claim 1 or 2, comprising microwave heating.

4. The method according to any one of claims 1 to 3, comprising the presence of an acid.

5. The method according to claim 4, wherein the acid for the reaction between the compound of formula K and the compound of formula D-I is 4N HCl in 1,4-dioxane.

6. The method according to claim 4, wherein the acid for the reaction between the compound of formula J (t=1) and the compound of formula D-I is 4N HCl in 1,4-dioxane or p-toluenesulfonate.

7. The method according to any one of claims 1 to 5, further comprising, if formula I-A further contains a protecting group, forming a compound of formula I-A by deprotecting the protecting group under acidic conditions.

8. The method according to claim 7, further comprising reacting a compound of formula I-A with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone, or with an acyl chloride or sulfonyl chloride, in the presence of a catalytic amount of acetic acid in a polar solvent, to form an N-substituted compound of formula I-A.

9. A method according to any one of claims 1 to 8, comprising a compound of formula H: 【Transformation 5】 {wherein n and Z are as defined in equation I-A}, Compounds of formula L-II or L-III: 【Transformation 6】 {In the formula, R in formula L-II} １ is Cl, Br, or I, and R in formula L-III １ It is cyclopropyl. A method further comprising forming a compound of formula K by reacting with [another compound].

10. A method according to any one of claims 1 to 8, comprising a compound of formula J (t=0): 【Transformation 7】 By reacting it with an oxidizing agent, a compound of formula J (t=1) is obtained: 【Transformation 8】 This includes forming a compound, where the oxidizing agent may be m-chloroperbenzoic acid (mCPBA), and further Compound of formula H: 【Chemistry 9】 {wherein n and Z are as defined in equation I-A}, Compounds of formula L-I: 【Chemistry 10】 {In the formula, R in formula L - I} １ CHF ２ CF ３ A method further comprising reacting with {which is CN} to form formula J(t=0).

11. The method according to claim 9 or 10, Z is 【Chemistry 11】 And; in the formula, q is 0, 1, 2, or 3; r is 2, 3, or 4; V is C(R ３４ ) ２ , O, or NR ６ And R ６ is alkyl; Each R ３４ H or C １ -C ６ It is alkyl, or has two R's ３４ They can come together to form a cycloalkyl group; n is a method where n is 2, 3, or 4.

12. Z is, 【Chemistry 11a】 And; In the formula, q is 0, 1, 2, or 3; r is 2, 3, or 4; V is C(R34)2, O, or NR6, where R6 is alkyl; Each R 34 can independently be H or C1-C6 alkyl, or two R 34s can combine to form a cycloalkyl group; n is 2, 3, or 4; The method according to claim 10, wherein the reaction of the compound of formula H with the compound of formula L-I is carried out in the presence of a base.

13. The method according to claim 12, wherein the base is triethylamine or DIEA.

14. A method according to any one of claims 11 to 13, Compound of formula E: 【Chemistry 12】 The compound of formula F: 【Chemistry 13】 By reacting with it, the compound of formula G is produced: 【Chemistry 14】 {During the ceremony, Z is, 【Chemistry 15】 And; q is 0, 1, 2, or 3; r is 2, 3, or 4; V is C(R ３４ ) ２ , O, or NR ６ And R ６ is alkyl; Each R ３４ H or C １ -C ６ It is alkyl, or has two R's ３４ They can come together to form a cycloalkyl group; A method further comprising causing n to form { n is 2, 3, or 4}.

15. The method according to claim 14, further comprising forming a compound of formula H by deprotecting a compound of formula G.

16. The method according to claim 14, wherein the reaction between the compound of formula E and the compound of formula F takes place in the presence of a base.

17. Z: 【Chemistry 16】 Selected from; in the formula, V is oxygen, C (R ３４ ) ２、 and NR ６ Selected from the group consisting of; R ３４ Each occurrence of H and R is independent. ３６ Selected from, R ３６ Each occurrence is independent of C １ -C ６ Alkyl and C ３ -C ６ Selected from cycloalkyl groups, or two R groups ３６ However, they bond together with the carbon that they are bonded to. ３ -C ６ Forms a cycloalkyl group; q is 0, 1, 2, or 3; r is either 2 or 3; However, if q is 0, then r is not 2. The method according to any one of claims 1 to 10.

18. Z: 【Chemistry 17】 A method according to any one of claims 1 to 16, selected from the group consisting of the following.

19. Z: [Chemistry 18] A method according to any one of claims 1 to 16, selected from the group consisting of the following.

20. R ４ but: 【Chemistry 19】 The method according to any one of claims 1 to 19, wherein a selection is made from the group consisting of the following, and in the formula u is 1 or 2.

21. R ４ but: 【Chemistry 20】 A method according to any one of claims 1 to 19, selected from the group consisting of the following.

22. R ４ but: 【Chemistry 21】 A method according to any one of claims 1 to 19, selected from the group consisting of the following.

23. R ４ but: 【Chemistry 22】 A method according to any one of claims 1 to 19, selected from the group consisting of the following.

24. R １ However, halogen, C １ -C ５ Alkyl and C ３ -C ５ Selected from the group consisting of cycloalkyl groups, C １ -C ５ The method according to any one of claims 1 to 23, wherein the alkyl group may be optionally substituted with one, two, or three generated fluorines.

25. R ２ However, C １－２ Alkyl and C ３－４ The method according to any one of claims 1 to 24, selected from the group consisting of cycloalkyl groups.

26. The method according to any one of claims 1 to 25, wherein n is 3.

27. The method according to claim 1, wherein the compound of formula I-A is: 【Chemistry 23】 or represented by a pharmaceutically acceptable salt thereof, in the formula R １ CF ３ CF ２ Selected from the group consisting of H, bromo, chloro, and cyclopropyl; R ２ C １ -C ２ Alkyl, C ３ -C ４ Selected from the group consisting of cycloalkyls and halogens; R ９ C １ -C ３ Alkyl, H, and C ３ -C ５ A method selected from the group consisting of cycloalkyl groups.

28. The method according to claim 1, wherein the compound of formula I-A is: 【Chemistry 24】 or represented by a pharmaceutically acceptable salt thereof, in the formula R １ , bromo, chloro, CF ３ CF ２ Selected from the group consisting of H and cyclopropyl; R ２ C １ -C ２ Alkyl, C ３ -C ４ Selected from the group consisting of cycloalkyls and halogens; R ９ C １ -C ３ Alkyl, H, and C ３ -C ５ A method selected from the group consisting of cycloalkyl groups.

29. R １ However, CF ３ And; R ２ However, C １ -C ２ Alkyl, C ３ -C ４ Selected from cycloalkyl, bromo, and chloro; R ９ However, C １ -C ３ The method according to claim 27 or 28, selected from alkyl and H.

30. R １ However, it is Bromo; R ２ However, C １ -C ２ Alkyl, C ３ -C ４ Selected from cycloalkyl, bromo, and chloro; R ９ However, C １ -C ３ The method according to claim 27 or 28, selected from alkyl and H.

31. The compound of formula I-A is: 1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidine-4-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, (R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((2-((4-(4-cyclopropylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-ethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-cyclopropyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)-1-methylpiperazine-2-one, 1-(3-((5-bromo-2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(1-methylpiperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-(2-fluoroethyl)piperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(piperidine-4-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-acetylpiperazine-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, (S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidine-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-isopropylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-cyclobutylpiperazine-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-methyl-4-(piperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, rac-(R)-3-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxadinan-2-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azepan-2-one, 4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-ethylpiperazine-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, rac-4-(3-((2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, rac-(R)-4-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((4-ethyl-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((2-((4-ethyl-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 4-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 4-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((4-ethyl-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 3-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-(3-((2-((2-ethyl-4-(1-methylpiperidine-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, 4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1]nonane-9-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(1-methylpyrrolidine-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethynyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((ethynyl-d)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((ethyl-d5)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzonitrile, 2-methyl-2-(5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)propanenitrile, 2-(5-(4-methylpiperazine-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)acetonitrile, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((difluoromethyl)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-bromo-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, (R)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, (S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyltetrahydropyrimidine-2(1H)-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (R)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(piperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(piperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxadinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidine-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidine-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)p Ropyr (amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxadinan-2one, 4-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, 4-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2one, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxazepan-2one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxadinan-2-one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 8-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonan-9-one, 4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-3,3-dimethylazetidine-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azetidine-2-one, 4-(3-((2-((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-ethyl-4-(2-(pyrroridine-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-cyclopropyl-4-((dimethylaminomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2-one, 3-Methoxy-N-(1-methylpiperidine-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzamide, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)piperidine-2-one, 1-(3-((2-((2-ethyl-4-(2-(pyrroridine-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-((dimethylaminomethyl)piperidine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(3,3-dimethylpiperazine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,5,5-tetramethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 1-(3-((2-((2-chloro-4-(3,4-dimethylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)azepan-2-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxadinan-2-one, 4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, 4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5one, 4-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-(2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,3-oxadinan-2-one, 3-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 3-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,3-oxadinan-2one, 4-(3-((2-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-3one, 4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-3one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-((difluoromethoxy)-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxadinan-2-one, 4-(3-((2-((4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)piperidine-2-one, 4-(3-((2-((4-(3-((dimethylamino)methyl)azetidine-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)aminopropyl)-1,4-oxazepan-5-one, The method according to claim 1, further comprising a selection from the group consisting of pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

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