Phenylaminopyrimidine amide autophagy inhibitors and methods 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-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 62 / 846,251, filed May 10, 2019, U.S. Application No. 62 / 846,258, filed May 10, 2019, U.S. Application No. 62 / 911,728, filed October 7, 2019, and U.S. Application No. 62 / 711,730, filed October 7, 2019, the contents of each of which are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on May 5, 2020, is named DCP-079WO_SL.txt and is 27,196 bytes in size. [Background technology]

[0003] Autophagy (literally meaning "eating oneself") is a process that allows cells to regenerate organelles, proteins, stored lipids, glucagon, and other materials for the purpose of generating nutrients under stress. These cellular contents are regenerated by phagocytosis into vesicles called autophagosomes. The autophagosomes then fuse with lysosomes, which degrade the autophagosome contents for recycling nutrients to the cell. Tumor cells are prone to activating autophagy because they have high metabolic demands, experience cellular stress, and are often in hypoxic environments with limited blood flow and nutrient supply. In addition, chemotherapy and targeted therapies have been shown to induce autophagy as a therapeutic resistance mechanism, and the combination of autophagy inhibition (by genetic loss of function mutations in autophagy genes or by pharmacological means) with chemotherapy regimens has been shown to suppress tumor growth and induce apoptosis of tumor cells more extensively than monotherapy chemotherapy.

[0004] Mutant Ras proteins drive approximately 30% of all human cancers, including 95% of pancreatic 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 may be 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 inactivating proteases that are sequestered in the lysosomal compartment and increase the pH of these lysosomes, thereby degrading and regenerating 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 agents that selectively block autophagy and do not exhibit the toxicity of these antimalarial drugs. ULK1 kinase is an initiator protein of autophagy and is a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stresses, including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity through inhibition of mTORC1, and energy depletion activates AMP-activated protein (AMP-AP), which activates AMP-activated protein (AMP-AP). ULK kinase activity is activated through activation by the protein kinase AMPK. Importantly, kinase-dead mutants of ULK kinases block the initiation of canonical autophagy, suggesting that small molecule inhibitors of ULK kinase activity can block autophagy.

[0006] Further mechanistic studies showed that genetic deletion of ULK1 inhibits autophagy in cancer cells and alleviates FOX3A turnover and upregulation of the proapoptotic protein PUMA. In addition to the classical activation of canonical 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 canonical protumoral activities of ULK.

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

[0008] Mutant Ras cancers are dependent on autophagy. In pancreatic cancer, mutant Ras signals primarily through the MAPKAP pathway. Mutant Ras activates RAF kinase, which then activates MEK kinase, and finally ERK kinase: mutant Ras → RAF → MEK → ERK. Despite mutant Ras signaling through the MAPKAP pathway, inhibitors of this pathway have provided no or little clinical benefit in clinical trials when used as single agents. 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, there was synergistic activity leading to regression of numerous mutant Ras or mutant BRAF cancers. Similarly, when ERK inhibitors were combined with the autophagy inhibitors hydroxychloroquine or chloroquine, there was synergistic activity leading to inhibition of mutant Ras pancreatic cancers. It has been demonstrated that genetic depletion of RAF kinases (CRAF and BRAF) led to synergistic antitumor activity in mutant Ras cancer cell lines when autophagy was also genetically depleted. Combined, recent publications highlight that dual inhibition of MAPKAP and autophagy pathways in mutant Ras cancers is a promising therapeutic regimen for patients with mutant Ras cancers. Other targeted therapies and chemotherapeutic agents have also been demonstrated to activate tumor autophagy as a resistance mechanism, and therefore there is a rationale for combining such targeted therapies or chemotherapeutic agents with inhibitors of autophagy.

[0009] Mutations in the gene encoding the LRRK2 kinase are the cause of Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) as well as sporadic Parkinson's disease patients. The most common mutation in LRRK2 in Parkinson's disease is LRRK2 G2019S. These mutations in LRRK2 are gain-of-function mutations that cause overactivation of LRRK2 signaling. Ongoing autophagy is a process used by brain neurons to maintain health and homeostasis. Autophagy allows cells to remove cellular senescence and other proteins from the body. Autophagy is the process by which cellular cellular functions such as the cellular endothelium, the cellular endothelium, and the cellular endothelium are transformed into cellular endothelium. Autophagy is a process that identifies, localizes, and destroys organelles and structural elements that are involved in the functioning of the endothelium, particularly for proteins known to aggregate in neurons, and it eliminates such toxic protein aggregates to maintain neuronal health. LRRK2 activity suppresses autophagy, and the LRRK2 G2019S gain-of-function mutant further suppresses autophagy and is associated with an aggressive form of Parkinson's disease.

[0010] Increased LRRK2 kinase activity has also been linked to immune-inflammatory diseases, including colitis and 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 NFkB pathway and increased TNF-alpha production in dendritic cells from Crohn's disease patients.

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

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

[0013] Described herein are compounds that are inhibitors of autophagy, pharmaceutical compositions, and their use as medicaments in the treatment of disorders such as cancer, the process for their preparation, and pharmaceutical compositions that contain them as active ingredients.These pharmaceutical compositions may contain the compounds as the only active agent or in combination with other active agents 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, compounds provided herein have the following formula (I): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein W is CH or N, X is CH or N, and Y is C(R 3 ) or N, R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each of which is optionally substituted by one, two, or three independent occurrences of fluorine; R 2 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, each of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 Alkynyl, and C1-C5 alkoxy are optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; R 3 and R 33 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, each of which is optionally substituted by one or more independent occurrences of fluorine; 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 9 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 may be optionally substituted on available nitrogen by R 5 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; 7 Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 9 R 9 wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form an oxo, R 6 and R 9 each occurrence is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 and D, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, each C1-C3 alkyl and C3-C5 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 10are joined together with the carbons to which they are attached to form a C3-C5 cycloalkyl, Z is selected from the group consisting of a 4-membered lactam ring bonded through a nitrogen atom, or a 6-10-membered lactam ring bonded through a nitrogen atom, and a lactam ring atom is selected from the group consisting of oxygen or NR 6 an available carbon atom on the 4-membered lactam ring or the 6- to 10-membered lactam may optionally be R 36 is optionally replaced by R 36 each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 36 are joined together with the carbons 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, and p is 2 or 3, with the proviso that X and Y are not both N. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The features and other details of the present disclosure will now be described in more detail.Specific terms employed in the specification, examples and appended claims are summarized here.These definitions should be read in light of the remaining parts of this disclosure as understood by those skilled in the art.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 a saturated straight chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C36, C37, C38, C49, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C67, C68, C69, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C81, C92, C93, C94, C95, C96, C97, C98, C99, C101, C112, C123, C132, C143, C151, C152, C163, C174, C185, C196, C197, C198, C199, C199 These include straight chain or branched hydrocarbons of 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms, referred to as -C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 alkyl. Exemplary 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, hexyl, and the like.

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

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

[0019] As used herein, the term "alkoxyalkyl" refers to a straight or branched alkyl group attached to an oxygen, which is attached to a second straight or branched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups referred to herein as C1-C6 alkoxy-C1-C6 alkyl, where each alkyl group independently contains 1 to 6 carbon atoms. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

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

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

[0022] As used herein, the term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3 to 6 or 4 to 6 carbons, referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary 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 attached to an oxygen (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, Examples of cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3 to 6 carbon atoms, referred to herein as C3-C6 cycloalkoxy groups. 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, such as 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. When possible, the aforementioned heteroaryl ring may be linked to the adjacent radical through a 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, and the like.

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

[0027] As used herein, the term "lactam" refers to cyclic amides of aminocarboxylic acids having a 1-azacycloalkan-2-one structure, or analogs having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. "Alpha-lactam" refers to lactams consisting of a three-membered ring. "Beta-lactam" refers to lactams consisting of a four-membered ring. "Gamma-lactam" refers to lactams consisting of a five-membered ring. "Delta-lactam" refers to lactams consisting of a six-membered ring. "Epsilon-lactam" refers to lactams consisting of a seven-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, eg, 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] An "individual", "patient" or "subject" is used interchangeably herein and includes 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 also to other mammals, such as animals requiring veterinary treatment, for example, pets (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

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

[0033] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0034] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvent, dispersion medium, coating, isotonic and absorption retarding agent, etc., that are compatible with pharmaceutical administration. 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 complementary, additional, or enhanced therapeutic functions.

[0035] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0036] As used herein, the term "pharmaceutical acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition that are acidic in nature can form base salts with various pharmacologically 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 that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compound can exist as an acid addition salt, zwitterion, or base salt.

[0037] The compounds of the present disclosure may contain one or more chiral centers and therefore exist as stereoisomers. As used herein, the term "stereoisomers" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of the substituents around the stereogenic carbon atom, although those of skill 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 in the nomenclature as "(±)", although those of skill in the art will recognize that the structure may implicitly indicate a chiral center.

[0038] As used herein, a "therapeutically effective amount" includes an amount of a subject compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

[0039] As used herein, "treating" includes any effect of attenuating, reducing, modulating, or eliminating, e.g., resulting in the improvement of a condition, disease, disorder, or the like.

[0040] The present disclosure also encompasses isotopically labeled compounds that are identical to those enumerated herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that 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, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and36 Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0041] 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 by preparation of racemic mixtures 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 with 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. Racemic mixtures may also be resolved into their 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 unequal 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 enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0042] compound As used herein, a compound represented by formula I: [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. wherein 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 halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each of which is optionally substituted by one, two, or three independent occurrences of fluorine; R 2 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, wherein each of the formulas C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by one, two, or three independent occurrences of fluorine or cyano; 3 and R 33 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, each of which is optionally substituted by one or more independent occurrences of fluorine; 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 9 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 may be optionally substituted on available nitrogen by R 5each occurrence is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; R 7 Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 9 R 9 wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form an oxo, R 6 and R 9 Each occurrence of is independently selected from H, C1-C6 alkyl, C 3- C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 and D, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, each C1-C3 alkyl and C3-C5 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 10 are joined together with the carbons to which they are attached to form a C3-C5 cycloalkyl, Z is selected from the group consisting of a 4-membered lactam ring bonded through a nitrogen atom, or a 6- to 10-membered lactam ring bonded through a nitrogen atom, and the lactam ring atoms, when the lactam ring is a 6- to 10-membered ring, are optionally selected from the group consisting of oxygen or NR 6 and an available carbon atom on the 4-membered lactam ring or the 6- to 10-membered lactam is R 36 is optionally replaced by R 36each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 36 are joined together with the carbons 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, and p is 2 or 3, with the proviso that X and Y are not both 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: [ka] where V is oxygen, CH2, and NR 6 R 34 Each occurrence of is independently H and R 36 Selected from R 36 each occurrence of is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, or two R 36 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, q is 0, 1, 2, or 3, and r is 2 or 4, with the proviso that when q is 0, r is not 2.

[0045] In some embodiments, Z is selected from: [ka] In the formula, V is oxygen, C(R 34 )2, and NR 6 R 34 Each occurrence of is independently H and R 36Selected from R 36 each occurrence of is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, or two R 36 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, q is 0, 1, 2, or 3, and r is 2 or 3, with the proviso that when q is 0, r is not 2.

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

[0047] In some embodiments, Z is selected from: [ka] where V is oxygen, CH2, and NR 6 wherein q is 0, 1, 2, or 3, and r is 2 or 3, with the proviso that when q is 0, then r is not 2.

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

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

[0050] In some embodiments, R 4 is selected from the group consisting of: [ka] In the formula, u is 1 or 2.

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

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

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

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

[0055] In some embodiments, R 4 is selected from the group consisting of: [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 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl is optionally substituted with 1, 2, or 3 occurrences of fluorine. 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. Some In embodiments, R 1 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, each C1-C5 alkyl being optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 2 is C 1-2 Alkyl and C 3-4 In some embodiments, R 2 is selected from the group consisting of chloro and bromo.

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

[0060] In some embodiments, n is 3.

[0061] In some embodiments, the compound is represented by formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein n is 2, 3, or 4; 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each of which is optionally substituted by one, two, or three independent occurrences of fluorine; R 2is selected from the group consisting of halogen, C1-C2 alkyl and C3-C4 cycloalkyl, and R4 is selected from the group consisting of: [ka] R 6 and R 9 each occurrence is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 and D, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted with one or more independent occurrences of fluorine; R 5 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; 7 Each occurrence of is independently H, C1-C6 alkyl, and C3 -C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 7 are joined together with the atoms to which they are attached to form oxo, D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 and Z is selected from the group consisting of: [ka] R 34 Each occurrence of is independently H and R 36 Selected from R 36each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C5 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 36 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl.

[0062] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl is optionally substituted with 1, 2, or 3 occurrences of fluorine, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 is cyclopropyl.

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

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

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

[0066] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, each of which is optionally substituted by one or more independent occurrences of fluorine.

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

[0068] In some embodiments, R 34 Each occurrence of R is independently selected from the group consisting of H and C1-C5 alkyl, where C1-C5 alkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl.

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

[0070] In some embodiments, Z is selected from the group consisting of: [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: [ka] In the formula, R 1each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 9 each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl; R 34 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 of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl; R 34 is independently selected from the group consisting of H and C1-C2 alkyl, and n is 3. 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H, n is 3, be.

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

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

[0076] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

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

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

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

[0082] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 Each occurrence of 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 of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 6 each occurrence of is selected from C1-C3 alkyl and C3-C4 cycloalkyl; R 9 Each occurrence of is selected from H and C1-C3 alkyl, and n is 3. In some embodiments, R1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

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

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

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

[0088] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3.

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

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

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

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

[0094] In some embodiments, the compound is represented by a formula selected from: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

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

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

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

[0100] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3.

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

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

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

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

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

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

[0107] In some embodiments, the compound is represented by the formula: [ka] In the formula, R 1 is selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 1 is CF3, R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 1 is bromo, R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 1 is CF2H, R 2 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 formula: [ka] In the formula, R 1 is selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen. 1 is CF3, R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 1 is bromo, R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro. 1 is CF2H, R 2 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 formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein n is 2, 3, or 4; 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each of which is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; R 4 is selected from the group consisting of: [ka] R6 and R 9 each occurrence is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 and D, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted with one or more independent occurrences of fluorine; R 5 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; 7 each occurrence is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 7 are joined together with the atoms to which they are attached to form oxo, D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 and Z is selected from the group consisting of: [ka] R 34 Each occurrence of is independently H and R 36 Selected from R 36 each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C5 alkyl and C3-C6 cycloalkyl being optionally substituted by one or more independent occurrences of fluorine, or two R 36 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl.

[0110] In some embodiments, R1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl is optionally substituted with 1, 2, or 3 occurrences of fluorine, and C3-C5 cycloalkyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 is cyclopropyl.

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

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

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

[0114] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, each of which is optionally substituted by one or more independent occurrences of fluorine.

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

[0116] In some embodiments, R 34 is selected from the group consisting of H and C1-C5 alkyl, where C1-C5 alkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine. In some embodiments, two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl.

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

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

[0119] In some embodiments, n is 3.

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

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

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

[0124] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

[0126] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 Each occurrence of is independently C1-C2 alkyl, C3 R is selected from the group consisting of -C4 cycloalkyl, and halogen; 9 each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl; R 34 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 of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl; R 34is independently selected from the group consisting of H and C1-C2 alkyl, and n is 3. 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

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

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

[0130] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 Each occurrence of is independently C1-C2 alkyl, C3- C4 cycloalkyl, and halogen; R 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

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

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

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

[0136] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3.

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

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

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

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

[0142] In some embodiments, the compound is represented by a formula selected from: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6 each occurrence of is independently selected from C1-C3 alkyl, and C3-C4 cycloalkyl; R 9 each occurrence is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

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

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

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

[0148] In some embodiments, the compound is represented by a formula selected from the group consisting of: [ka] In the formula, R 1 each occurrence of is independently selected from the group consisting of bromo, chloro, CF, CFH, and cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; 6each occurrence is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3.

[0149] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 6 Each occurrence of is selected from C-C alkyl and C-C cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; 6 is independently selected from C-C alkyl and C-C cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF2H and R 2 Each occurrence of is independently C1-C2 alkyl, C3-C4 cycloalkyl R is selected from alkyl, bromo, and chloro; 6 each occurrence is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl, and n is 3. In one embodiment, described herein is a compound selected from the group consisting of 1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((2-cyclopropyl)phenyl)amino ... 1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidine-2-one, Peridine-2-one, (R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((2-((4-(4-cyclopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((2-isopropyl-4-(4-methyl)pyrimidin-2-yl)amino)propyl) 1-(3-((2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one,4-(3-cyclopropyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-one, 1-(3-((5-bromo-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl )amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, -((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propy, (S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidine-2-one, (S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-isopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-isopropyl propyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-cyclobutylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-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)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-bromo-2- ((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl, )pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, rac-(R)-3-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[ 1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, fluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4 -(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl. 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, )propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one Sazepan-3-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl )-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl )amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-ethyl) 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2 -((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazin 1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((4-(4-cyclopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-5,5-Dimethylpyrrolidin-2-one, 1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-(( 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((5-(4-methylpiperazin, (R)-4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-(( 2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-ethyl -6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4-(4-methylpiperazin-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)pyrimidin-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)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile, (R)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile (S)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile, (R)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)a 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4 -(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-(3-((2-((2-ethyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1]nonan-9-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (S)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one 4-(3-((2-((2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethynyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethynyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, fluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(ethynyl-d)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(ethyl-d5)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one. 5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile; 2-methyl-2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanol; 2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)acetonitrile, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino) azetidin-1-yl) phenyl) amino)-5-(trifluoromethyl) pyrimidin-4-yl) amino) propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino) methyl) azetidin-1-yl) phenyl) amino)-5-(trifluoromethyl) pyrimidin-4-yl) amino) propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((2-(( 2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-2-one, Pan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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 ]octan-3-yl)phenyl)amino)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-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 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, (S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3- ((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl -4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-, 4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diaze Pan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl- 4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octadecane) 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-oxazinan-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-oxazinan-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-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (R)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl )amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile. 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazin-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-methylpiperazin-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-methylpiperazin-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-methylpiperazin-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-methylpiperazin-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)pyrimidin-4-yl)amino)propyl)piperidin-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)pyrimidin-4-yl)amino)propyl)piperidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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) pyrimidin-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)pyrimidin-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)pyrimidin-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]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin 8-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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-oxa-8-azaspiro[2.6]nonan-9-one; -(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 4-(3-((2-((4-(1,4-diazabicyclo[3.2.1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl) 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-4-yl). 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, fluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3 -Dimethylazetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2 -((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-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)pyrimidin-4-yl)amino)propyl)pyrrolidin-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)pyrimidin-4-yl)amino)propyl)pyrrolidin-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)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl. 1-(3-((5-chloro-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)pyrrolidin-2-one, )amino)-5-chloropyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidine- 4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-bromopyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2- ((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl) )amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-((dimethylamino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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-methylpiperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide, 4-(3-((2-((4-(4-(diethylamino)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, (S)-4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((, 2-ethyl-4-(2-(pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-((dimethylamino)methyl)piperidin-1-yl )-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(3,3-dimethylpiperazin-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-tetramethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan -5-one, 4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 1-(3-((2-((2-chloro-4-(3,4-Dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 3-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azepan-2-one 4-(3-((2-((4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, )phenyl)amino)-5-(trifluoromethyl)pyridin-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)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3 -oxazepan-2-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-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)pyridin-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)pyridin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)a 4-(3-((2-((2-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one ,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2 -((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-fluoro-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-((1,1-dioxidethiomorpholino)methyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((4-(3-(diethylamino)propyl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl 4-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((2 -(2-hydroxypropan-2-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(2-hydroxypropan-2-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1-hydroxyethyl)- 4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3- (3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, -yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, one, 3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2- ((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-( 1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-( 3-((2-((4-(3-((dimethylamino)methyl)azetidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, and pharma- ceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

[0150] Treatment method The compounds described herein can act as an inhibitor of autophagy, which is useful for treating disorders in patients who need it.Disorders can be, for example, tumors, for example solid tumors.Disorders can also be cancer.

[0151] Exemplary disorders also include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancers that are metastatic to bone, Cancers treated by the methods described herein may be metastatic cancers.

[0152] In some embodiments, the compounds described herein are useful for treating cancer caused by RAS mutations. In some embodiments, the cancer is caused by KRAS mutations. 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.

[0153] In some embodiments, the determination of cellular inhibition of autophagy by the compounds described herein is determined by monitoring autophagic flux, for example, by monitoring the inhibition of autophagy-mediated clearance of 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, the 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, the in vivo inhibition of ULK kinase by the compounds described herein is determined in host tissues, including immune cells. In some embodiments, the in vivo inhibition of autophagic flux by the compounds described herein can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is determined in pancreatic cancer-bearing animals. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is determined in lung cancer-bearing animals. In some embodiments, the in vivo inhibition of ULK kinase is determined in colorectal cancer-bearing animals. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of autophagic flux in tumor cells or non-tumor host tissues by monitoring inhibition of autophagosome formation, or by accumulation of autophagic proteins such as p62 or LC-III. 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, inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in xenograft studies utilizing human RAS mutant cell lines in immunodeficient mice, such as SCID or nude mice. In some embodiments, inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in xenograft studies utilizing human RAS mutant patient-derived tumor xenografts (PDX) in immunodeficient mice, such as SCID or nude mice. In some embodiments, the xenograft studies include evaluation of the compounds described herein in pancreatic cancer models. In some embodiments, inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in syngeneic mouse genetically engineered models (GEM) of mutant RAS cancer. In some embodiments, inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in the KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / + , Pdx-1-Cre) or a variant of the KPC model, a mouse GEM syngeneic orthotopic pancreatic cancer 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, inhibition of autophagy and anti-tumor activity by the compounds described herein are evaluated in an immunocompetent mouse cancer model to evaluate the immunomodulatory component to the mechanism of action of ULK inhibitors. In some embodiments, the immunocompetent mouse model is the KPC model (LSL-Kras G12D / + , LSL-Trp53R172H / + , Pdx-1-Cre) or a variant of the 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 enhanced activity of antigen presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced anti-tumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced activity of effector T cells, including cytotoxic T cells.

[0160] In one embodiment, provided herein is a method of treating a disorder described herein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, and administering to a patient in need thereof a therapeutically effective amount of a compound described herein, and administering to a patient in need thereof during or after the course of administration (e.g., at a discrete time point, e.g., the final concentration of the intended compound). and detecting the engagement of the compound with ULK kinase after the first week, two weeks, or the following month after administration, where 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, contemplated methods include 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 prior to administration of the compound, and comparing the level of phospho-ATG13 in the sample obtained before administration with the level of phospho-ATG13 in the sample obtained during or after the course of administration. In some embodiments, the phospho-ATG13 is p-S318ATG13.

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

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

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

[0164] The compounds provided herein can be administered to patients (animals and humans) in need of such treatment in doses that will provide optimal pharmaceutical efficacy. It will be understood that the dosage required for use in any particular application 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 age and condition of the patient, any concomitant medications or special diets the patient is subsequently following, and other factors that one skilled in the art would recognize, and the appropriate dosage will ultimately be left to the discretion of the attending physician. To treat the above-mentioned clinical conditions and diseases, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmacologic acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.

[0165] Treatment can continue for as long or as short as desired. The composition may be administered, for example, on a regimen of 1 to 4 times a day or more. A suitable treatment period 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, e.g., compounds of formula I as defined herein, can be administered in combination with one or more additional therapeutic agents to treat disorders described herein, such as cancer. For example, the present disclosure provides pharmaceutical compositions comprising compounds described herein, e.g., compounds of formula I as defined herein, one or more additional therapeutic agents, and a pharma- ceutically acceptable excipient. In some embodiments, a compound of formula I as defined herein and one additional therapeutic agent are administered. In some embodiments, a compound of formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound 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, a compound of formula I as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, e.g., a pharmaceutical composition comprising a compound of formula I as one therapeutic agent and one or more additional therapeutic agents, such as a MAPKAP pathway inhibitor or a chemotherapeutic agent. For example, the compound of formula I defined herein and the additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed in combination therapy. Two or more agents in combination therapy can be administered simultaneously, but this is not required. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, two or more agents can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not required, that two or more agents used in combination therapy are present in the patient's body at the same time.

[0167] Combination therapy can also include more than one administration of one or more of the agents used in the combination with the component agents in a different order, for example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, for example, in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0168] In some embodiments, one or more of the compounds provided herein may be administered in combination with The one or more additional therapeutic agents may be MAPKAP pathway inhibitors, including, for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.

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

[0170] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiation therapy, antitubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, antiestrogens, antiandrogens, steroids, anti-EGFR drugs, 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, antiangiogenic agents, proteasome inhibitors, PARP inhibitors, cell cycle regulating kinase inhibitors, thalidomide, lenalidomide, antibody-drug conjugates (ADC), immunotherapeutic agents including immunomodulatory agents, targeted therapeutic agents, cancer vaccines, and CAR-T cell therapy.

[0171] In one embodiment, the additional therapeutic agent is selected from the group consisting of, but not limited to, an antitubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents or DNA topoisomerase inhibitors (including, for example, anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin; camptothecins such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacitadine (5-azacitadine), The chemotherapy agents may include cyclosporine, gemcitabine, and methotrexate.

[0172] In some embodiments, the additional therapeutic agent is a kinase inhibitor, including but not limited to 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, loxo 292, larotrectinib, and quizartinib; anti-estrogens, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; anti-androgens, including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate; steroids, including but not limited to prednisone and dexamethasone; PARP inhibitors, including but not limited to neraparib, olaparib, talazoparib, and rucaparib; topoisomers, including but not limited to irinotecan, camptothecin, exatecan, and topotecan; topoisomerase I inhibitors, anthracyclines, etoposide, etoposide phosphate, 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, pomalidomide; trastuzumab, adotrastuzumab, pertuzumab, setuzumab, anti-PD-1 including pembrolizumab, nivolumab, pidilizumab, and cemiplimab; anti-PD-L1 including atezolizumab, avelumab, durvalumab, and BMS-936559; anti-angiogenic agents including bevacizumab and aflibercept; and antibody-drug-conjugates (ADCs) including DM1, DM4, MMAE, MMAF, or camptothecin payloads, brentuximab vedotin, and trastuzumab emtansine; radiation therapy; and therapeutic vaccines including, but not limited to, sipuleucel-T.

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

[0174] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0175] In some embodiments, the additional therapeutic agent is 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, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucantone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atlasenta Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl ]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6,Azgly 10] acetate salt (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 Oi4-(C2H4O2) x(wherein x=1 to 2.4)], goserelin acetate, leuprorelin acetate, triptorelin 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, lonafarnib, BMS-214662, tipifarnib; amifostine, 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, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevac, hydroxyurea, idarubicin, ifosfamide, ibuprofen, Matinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoid acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, 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 diftitox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and erbitux, cremophor-free paclitaxel, epithilone BB), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestran , acolbifene, lasofoxifene, idoxifene, 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, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage 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, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, doramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, ss pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0176] Pharmaceutical Compositions and Kits Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with a pharma- ceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with one or more pharma- ceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable administration form in any particular case depends on the extent and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral or subcutaneous administration.

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

[0178] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid composition containing the compounds provided herein, or their non-toxic pharmaceutical equivalents. Solid preformulation compositions can be formed that contain homogenous mixtures of the physiologically acceptable salts. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredients are evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0179] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as glycerol; (5) glyceryl stearate, (6) glyceryl stearate, (7) glyceryl stearate, (8) sorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as such high molecular weight polyethylene glycols.

[0180] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as, for example, enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0181] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or their mixtures, and powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the subject composition, said liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as 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] Suspensions may contain, in addition to the subject compositions, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

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

[0184] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any required 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, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0186] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0187] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposing the agent to shear, which may result in the degradation of the compounds contained in the subject compositions. Usually, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, 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 the subject compositions in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, and may contain antioxidants, buffers, bacteriostats, solutes that render the solution isotonic with the blood of the intended recipient, or suspending or thickening agents.

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

[0190] In another aspect, an enteric pharmaceutical formulation is provided that includes the disclosed compound and an enteric material, and a pharma- ceutically acceptable carrier or excipient thereof. An enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is predominantly soluble in intestinal fluids at a particular pH. The intestine is the part of the digestive tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5.

[0191] Thus, the enteric material does not dissolve until a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers, natural resins such as zein, shellac, and copal collophorium, and several commercially available enteric dispersions (e.g., Eudragit Examples of suitable enteric materials include Eudragit 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 can be easily determined in vitro. The foregoing is a list of possible materials, but one skilled in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that meet the objectives described herein.

[0192] Advantageously, kits are provided herein for use by a purchaser in need of, for example, a cancer treatment. Such kits include a suitable dosage form, such as those described above, and instructions that explain how to use such dosage form to mediate, reduce, or prevent inflammation. The instructions direct the purchaser or medical practitioner to administer the dosage form according to an administration mode known to those skilled in the art. Such kits can be advantageously packaged and sold in single or multiple kit units. One example of such a kit 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.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil on the face of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through said openings.

[0193] A memory aid may be provided on the kit, for example in the form of numbers next to the tablets or capsules. It may be desirable to provide a memory aid, the number of which corresponds to the day in the regimen on which the tablet or capsule so designated should be taken. Another example of such a memory aid is a calendar, for example printed on a card, with, for example, "Week 1, Monday, Tuesday , ...etc... Week 2, Monday, Tuesday, ..." etc. Other types of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or multiple tablets or capsules. Also, a daily dose of a first compound can consist of one tablet or capsule and a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this. EXAMPLES

[0194] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.In the description of the synthetic methods described below, all reaction conditions proposed, including the selection of solvents, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, can be selected to be the standard conditions for the reaction, unless otherwise specified.Those skilled in the art of organic synthesis understand that the functionality present on various parts of the molecule must be compatible with the proposed reagents and reactions.Substituents that are not compatible with the reaction conditions will be clear to those skilled in the art, and therefore alternative methods are shown.The starting materials of the examples are commercially available or easily 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]undec-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. where "DMEM" is Dulbecco's modified Eagle's medium, "DMSO" is dimethylsulfoxide, "DPPA" is diphenylphosphoryl azide, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, "ESI" is electrospray ionization, "Et2O" is diethyl ether, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hour(s), "HBTU" is (2-(1H-benzotriazol-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" is ethanol. 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 minute(s), 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 on carbon, and "Pd2(dba)3" is tris(dibenzyl acetone)dipalladium. um(0), "Pd(OAc)2" is palladium(II) acetate, "Pd(PPh3)4" is tetrakis(triphenylphosphine)palladium(0), "prep-HPLC" is preparative high performance liquid chromatography, "PyBOP" is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, "rt" is room temperature also known as "ambient temperature" and is understood to comprise the range of normal laboratory temperatures ranging 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 Exemplary compounds described herein are accessible via the general synthetic methods illustrated in the following schemes, intermediate preparations, and accompanying examples. [ka]

[0197] Scheme 1 shows an exemplary preparation of amines DIi, DI-ii, and DI-iii. The amine R, which can be aliphatic or heterocyclic, is reacted with amine R in the presence of a base (e.g., CsCO or KCO). 4 Treatment of AI with -H gives compound BI. R can be catalyzed with commercially available boronic esters / boronic acids / trifluoroborates in the presence of palladium catalysts (Suzuki coupling) or Sonogashira coupling reactions. 2a Further treatment of BI where R is Br gives compound CI. Intermediate CI can be converted to compound R by mild reducing conditions, such as zinc or iron metal with ammonium chloride.2b 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 a mild It may be reduced to DI-ii by reducing conditions, such as zinc or iron metal with ammonium chloride.

[0198] In Scheme 1, examples of X include N and CH, and examples of Y include N, CH, and CF, but both X and Y are not N and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include N-linked alkyl and N-linked heterocyclyl, bearing appropriate optional substituents as exemplified by the table of intermediates below. [ka]

[0199] Scheme 2 shows an exemplary preparation of amines D-II-i, D-II-ii, and D-II-iii. A-II (commercially available 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) can be reacted with A-II to give amine R. 4 Reaction of R with -H gives compound B-II. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, 2a Further treatment of B-II, where R is Br, with commercially available boronic esters / boronic acids / trifluoroborates gives compound C-II. Intermediate C-II can be converted to R by mild reduction conditions, e.g., zinc or iron metal with ammonium chloride. 2b The intermediate C-II can be completely reduced to D-II-iii by palladium catalyzed hydrogenation. 2aIntermediate B-II, where is Cl, Br, alkyl, CN, or alkoxy, may be reduced to D-II-ii by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0200] In Scheme 2, examples of X include N and CH, and examples of Y include N, CH, and CF, but both X and Y are not N and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples include N-linked alkyl and N-linked heterocyclyl with appropriate optional substituents as exemplified by the table of intermediates below. [ka]

[0201] Scheme 3 shows an exemplary preparation of amines D-III-i, D-III-ii, and D-III-iii. Reduction of A-III-i with a reducing agent such as DIBAL gives aldehyde A-III-ii. Another method to prepare A-III-ii is to reduce A-III-i to the corresponding alcohol, followed by mild oxidation conditions such as using MnO2. The reduction of 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) affords the aldehyde A-III-ii. 4 Reaction of A-III-I with -H gives compound B-III. Another method to prepare B-III is reduction of A-III-I to the alcohol followed by conversion of the alcohol to the sulfonate A-III-iii. Reaction of A-III-iii with amine R in the presence of a base such as triethylamine, Hunig's base, or cesium carbonate gives compound B-III. 4 Reaction with -H gives B-III. Reaction with commercially available boronic esters / boronic acids / trifluoroborates in the presence of palladium catalysts (Suzuki coupling) or Sonogashira coupling reactions gives B-III. 2aFurther treatment of B-III where R is Br gives compound C-III. Intermediate C-III can be converted to R by mild reducing conditions, such as zinc or iron metal with ammonium chloride. 2b may be selectively converted to the amine D-III-iii, which is alkenyl, alkynyl, or cycloalkyl. Intermediate C-III can be completely reduced to D-III-ii by palladium-catalyzed hydrogenation. 2a Intermediate B-III, where is Cl, Br, alkyl, CN, or alkoxy, can be reduced to D-III-i by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0202] In Scheme 3, examples of X include N and CH, examples of Y include N, CH, and CF, but where both X and Y are not N, examples of R include methyl and ethyl, and R 2 Examples of alkyl and cycloalkyl, R 4 Examples of are illustrated in the table of intermediates below, as well as by the examples of LG, which include mesylates and tosylates, and include N-linked alkyls and N-linked heterocyclyls with appropriate optional substituents. [ka]

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

[0204] In Scheme 4, examples of X include N and CH, examples of Y include N, CH, and CF, but where both X and Y are not N, examples of R include methyl and ethyl, and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples include -C(O)-alkyl and -C(O)-heterocyclyl, where the alkyl and heterocyclyl moieties are N-linked to any suitable substituent as illustrated in the table below. [ka]

[0205] Scheme 5 shows an exemplary preparation of amine DV. BV reacts with a boronic ester / acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to give compound CV. Many boronic esters / acids / trifluoroborates are commercially available, and some can be easily prepared from the corresponding carboxylic acid (see Scheme 7). Intermediate CV can be converted to amine DV by standard reduction conditions, such as palladium catalyzed hydrogenation, or by mild reduction conditions involving zinc metal and ammonium chloride.

[0206] In Scheme 5, examples of X include N and CH, examples of Y include N, CH, and CF, and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include C-linked heterocyclyl and heteroaryl with any suitable substituents as illustrated in the table of intermediates below. [ka]

[0207] Scheme 6 shows an exemplary preparation of D-VI from C-VI-i, in which R 4 contains a nitrogen protecting group, e.g., a Boc group. C-VI-i can be deprotected under acidic conditions to provide the 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) affords C-VI. Intermediate C-VI can be converted to the aniline D-VI by standard reduction conditions, e.g., by palladium catalyzed hydrogenation, or by mild reduction conditions involving zinc metal and ammonium chloride.

[0208] In Scheme 6, examples of X include N and CH, and examples of Y include N, CH, and CF, except that both X and Y are not N and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include heterocyclyls with suitable optional substituents as exemplified by the table of intermediates below. [ka]

[0209] Scheme 7 shows an exemplary preparation of commercially unavailable boronic acids / boronic esters T. These compounds can be easily prepared from substituted carboxylic acids. The starting carboxylic acid can be activated by 2-hydroxyisoindoline-1,3-dione in the presence of a coupling reagent (e.g., DCI or Et3N / HATU) to give Q. Intermediate Q can be converted to boronic ester T by nickel-catalyzed decarboxylative borylation reaction with methyllithium and [B2pin2Me]Li complex premixed with B2pin2 (Science, 356, 1045 (2017), JACS, 138, 2174 (2016)).

[0210] In Scheme 7, examples of m include 0, 1, and 2; R 4 Examples of include alkyl, cycloalkyl, and heterocyclyl, bearing appropriate optional substituents as exemplified by the table of intermediates below. [ka]

[0211] Scheme 8 shows an exemplary preparation of LI-1 and LI-2. Commercially available 2,4-dichloro-5-iodopyrimidine is reacted 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 thiomethyletherpyrimidine 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 shows the R1 An exemplary preparation of sulfonylpyrimidine L-III (t=2) is shown, where t can be cycloalkyl. Commercially available 5-bromo-2-chloro-4-(methylthio)pyrimidine is treated with commercially available boronic esters / boronic acids / trifluoroborates (see Scheme 7) in the presence of a palladium catalyst (Suzuki coupling) to give thiopyrimidine L-III (t=0). The intermediate thiopyrimidine L-III (t=0) can be converted to sulfonylpyrimidine L-III (t=2) by standard oxidation, for example by mCPBA. [ka]

[0213] Scheme 10 illustrates an exemplary preparation of intermediates H (I-XIII) using known methods. Treatment of commercially available lactam / cyclic carbamate / oxolactam / cyclic urea / diazepanone E with (Boc)-protected bromo intermediate F in the presence of a base, such as sodium hydride or potassium tert-butoxide, affords G. The Boc protecting group of G can be removed upon exposure to an acid, such as 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 R 6 is alkyl, n can be 2, 3, or 4, and each R 34 can be independently H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl. [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 give H-XIV. [ka]

[0216] Scheme 12 shows an exemplary preparation of key intermediates J and K. Key intermediate J can be prepared from H (either the free base or acid addition salt) by reaction with thiopyrimidine LI in the presence of an organic base (e.g., triethylamine or DIEA) and optionally by heating. In a similar manner, 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 R 6 is alkyl, n can be 2, 3, or 4, and each R 34 can be independently H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl group. [ka]

[0218] Scheme 13 shows an exemplary preparation of key intermediate M. Treatment of H with commercially available iodopyridines under Buchwald-Hartwig coupling conditions (CsCO, Xantphos, and Pd(OAc)), typically performed in an aprotic solvent (e.g., DME, DMF, DMSO, or NMP) at temperatures ranging from ambient to 140° C., provides key intermediate M.

[0219] In Scheme 13, R 1 can be Br, Cl, alkyl optionally substituted with one or more fluorine atoms, or cycloalkyl; 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 R 6 is alkyl, n can be 2, 3, or 4, and each R 34 are independently H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl. [ka]

[0220] Scheme 14 shows an exemplary preparation of compounds of formula I from substituted anilines or aminopyridines (DI). Preparation of formula IA can be achieved from key intermediates K and J. First, nucleophilic substitution reaction of K with amine D can be carried out in an aprotic solvent, typically at temperatures ranging from ambient to 150° C., in some embodiments with microwave heating, optionally in the presence of an acid, such as 4N HCl in 1,4-dioxane, to give formula IA. Compound DI, which is not commercially available, can be easily 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 by first converting J (t=0) to a sulfoxide (J (t=1, major product) by oxidation using a variety of oxidizing agents such as, for example, mCPBA. The sulfoxide is reacted with an amine DI via a nucleophilic substitution reaction, typically performed in an aprotic solvent at temperatures ranging from ambient to 150° C., in some embodiments with microwave heating, optionally in the presence of an acid such as, for example, 4N HCl in 1,4-dioxane or pTSA. Formula IA, which contains a nitrogen protecting group such as a Boc group, is deprotected under acidic conditions to give R 4Further treatment of formula IA (free base or acid addition 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) can provide compounds of formula R 4 To give the N-substituted formula IA. For acylation and sulfonylation, the free amine (or salt) can be treated with commercially available acyl chlorides or sulfonyl chlorides to give the N-substituted formula IA. [ka]

[0221] Scheme 15 shows an exemplary preparation of a compound of formula IB. The preparation of formula IB can be accomplished by a Buchwald-Hartwig coupling reaction with DI and M. The commercially unavailable amine DI can be readily prepared from substituted nitrobenzenes or nitropyridines (see Schemes 1-6). Formula IB, which contains a nitrogen protecting group such as a Boc group, is deprotected under acidic conditions to give R. 4 Formula IB containing the free NH (free amine or acid addition salt) above can be provided. Further treatment of formula IB (free base or acid addition 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) can provide R 4 N-substituted formula IB can be obtained. In a similar manner to Scheme 14, the free amine (or acid addition salt) can be treated with commercially available acyl chlorides or sulfonyl chlorides to obtain N-substituted formula IB.

[0222] Preparation of intermediates Using the synthetic procedures and methods described herein, as well as methods known to those skilled in the art, the following compounds were made:

[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 h. The reaction mixture was diluted with ice water (500 mL) and the precipitated solid was filtered. The solid was further triturated with Et2O and n-pentane to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (58 g, 85% yield) 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) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under vacuum to give 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 carried forward 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 min and then acetic acid (0.63 mL, 11 mmol) was added. The orange solution became a yellow suspension and was stirred for 20 min. Sodium triacetoxyborohydride (2.33 g, 11 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous NaHCO3 (50 mL) and the solution was extracted with DCM (3 x 50 mL). The combined organics were washed with anhydrous Na2SO4 The mixture was dried at 40° C., filtered, and concentrated to give a brown solid, which was purified using silica gel column chromatography (0-15% MeOH / DCM) to give 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 (Boc deprotected product of BI-3 1.5 g, 0.58 mmol) 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: material described as unstable - some solids present in orange liquid], tightly capped and heated to 100 °C for 24 h. The mixture was cooled to room temperature, the solid (K2CO3) was removed via filtration, rinsed with DCM and the filtrate was concentrated to dryness to give 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine (1.52 g, 98% yield) as a yellow oil that solidified to an amber solid on 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] Using general methods AC above, the intermediates in Table A below were prepared. 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-methylpiperazin-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 N2 atmosphere, and the mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (200 mL), the solution was extracted with EtOAc (2 x 100 mL), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give tert-butyl (2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 66% yield) 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 N2 atmosphere and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and the solution was extracted with DCM (2 x 100 mL). The combined organics were evaporated under reduced pressure and the crude was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give tert-butyl (2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetamido)ethyl)(methyl)carbamate (5.6 g, 66% yield) 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 N2 atmosphere and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure and the crude was purified by crystallization in Et2O (100 mL) to give 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 60% NaH in mineral oil (1.1 g, 25 mmol) at 0° C. under N2 atmosphere and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and the solution was extracted with EtOAc (2×50 mL), the combined organics were evaporated under reduced pressure and the crude was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give 1-(3-Bromo-4-nitrophenyl)-4-methylpiperazin-2-one (3.1 g, 76% yield) 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% in mineral) 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 h. The reaction was diluted with EtOAc and carefully quenched with ice water. The mixture was extracted with EtOAc (3×30 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (hexane / EtOAc) to give 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine (0.76 g, 72% yield). 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 allowed to stir. The reaction mixture was degassed by bubbling argon for 2 min and treated with Pd(dppf)Cl2.DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100 °C for 16 h. The reaction was diluted with water and extracted with DCM (4 x 25 mL). The organics were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum to give a black oil. The black oil was purified using silica gel (0-15% MeOH / DCM, 15 CV) to give 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, 47% yield). 1 LC-MS (ESI) m / z:218.2 (M+H + ).

[0233] Using general method D above, the intermediates in Table B below were prepared. 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 min. 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 h. The reaction mixture was diluted with water (100 mL) and the solution was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-80% EtOAc / Hexanes, 15 CV) to give 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, 69% yield) 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 min. 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 h. The reaction mixture was diluted with cold water (300 mL) and the solution was extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-80% EtOAc / Hexanes, 10 CV) to give 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (20 g, 81% yield). 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 following intermediates in Table C were prepared using General Method E or General Method F of the Suzuki reaction. [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-methylpiperazin-1-yl)aniline [ka] A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (CI-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 min. Zinc dust (30 g, 459 mmol) was slowly added to the reaction mixture under ice-water bath (internal temperature rose to 20° C.). After stirring for 15 min, the reaction mixture was warmed to room temperature and stirred vigorously at room temperature for 16 h. The mixture was filtered through a pad of Celite and washed with THF (500 mL). The filtrate was concentrated under reduced pressure to give 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline (10 g, 95%) as a dark brown sticky 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-methylpiperazin-1-yl)aniline [ka] A solution of 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (CI-12, 20 g, 81 mmol) in EtOAc (200 mL) was treated with Pd / C (20 g, 10% w / w, 50% water) under nitrogen atmosphere, and the mixture was then stirred at room temperature under hydrogen balloon pressure for 3 h. After general workup, 2-ethyl-4-(4-methylpiperazin-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] Using general procedures G or H for preparing DI-1 or DI-11, the intermediates in Table D below were prepared. 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-methylpyrrolidin-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), 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 min and then bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added. The reaction mixture was heated at 95° C. overnight in a microwave. The reaction mixture was cooled to room temperature and the mixture was extracted with EtOAC (2×). The combined organic extractions The material was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (0-60% EtOAc / Hexanes, 15 CV) to give tert-butyl 3-(4-amino-3-ethylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.12 g, 70% yield), which was carried forward 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 placed under a balloon overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(4-amino-3-ethylphenyl)pyrrolidine-1-carboxylate (0.12 g, 97% yield) as a colorless sticky 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 EtOAc (25 mL) and saturated NaHCO3 (aq) (25 mL) was treated with benzyl chloroformate (0.086 mL, 0.60 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and saturated NaHCO3 and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)pyrrolidine-1-carboxylate (0.18 g, 100% yield), which was carried forward 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 h. The solvent was removed to give the crude TFA salt. The crude was suspended in DCM and TEA (1 mL) was added. The solvent was removed under reduced pressure and 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 h. 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 h. The mixture was extracted with DCM (2 x 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give benzyl (2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)carbamate (0.14 g, 94% yield), which was carried forward without further purification. LC-MS m / z: 339.2 (M+H + ).

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

[0245] General method 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 portion wise with sodium hydride (3.0 g, 130 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min, then tert-butyl (3-bromopropyl)carbamate (21 g, 87 mmol) was added. The solution was kept stirring from 0° C. to room temperature for 16 h. The reaction mixture was quenched with a saturated solution of NH4Cl (200 mL), then the solution was extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered under reduced pressure. The crude was purified by silica gel column chromatography (40-50% EtOAc / Hexanes, 15 CV) to give 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 equiv.). The mixture was stirred at room temperature for 3 h, then concentrated and dried under high vacuum to give 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] H-VI-1 was prepared from intermediate H-II-1 in Table E below using the general method for the preparation of H-VII-1. 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 N2 atmosphere and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure and the residue was diluted with water (200 mL). The solution was extracted with 10% MeOH in DCM (3 x 250 mL) and the combined The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(3-aminopropyl)azepan-2-one (21 g, 85% yield) 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 min, 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 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-10% EtOAc / hexanes) to give 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (14.0 g, 66% yield) 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 h. 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 give 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine (3.6 g, 86% yield) 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 dropwise with ZnCl2 (1.0 N in ether) (555 mL, 0.56 mol) at 0 °C, and the reaction mixture was stirred for 2 h. Lithium thiomethoxide (49 g, 0.94 mol) was added at 0° C., and the reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was quenched with 2N HCl under ice-water bath, and then the solution was 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 give 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, 95% yield) as a colorless liquid. 1 H NMR (400 MHz,DMSO-d6):δ 9.01 (s 1H),2.62 (s 3H).

[0251] General method for substitution reactions: Intermediate J-7: 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-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 min. Then 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (LI-2, 6.0 g, 26.2 mmol) was added and stirring was continued from 0° C. to room temperature for 16 h. 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 Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (40-50% EtOAc / Hexanes, 15 CV) to give 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one (3.0 g, 47% yield) 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] Using the general method for the preparation of intermediate J-7, the following intermediates in Table F were prepared. Table F. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0253] General method for Pd coupling reactions: Intermediate M-1: 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one [ka] A solution of 1-(3-aminopropyl)piperidin-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 min. PdCl2(dppf)DCM (2.39 g, 2.93 mmol) was then added and the mixture was purged with Ar for another 5 min. The seal tube was closed and heated normally at 90 °C in a preheated oil bath for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). The solution was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-45% EtOAc / Hexanes, 12 CV) to give 1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one (2.6 g, 26% yield) as a brown solid. 1 LC-MS (ESI) m / z:336.1 (M+H + ).

[0254] Using the general method for the preparation of intermediate M-1, the intermediates in Table G below were prepared. Table G [Table 7]

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

[0256] Using the general method for the preparation of intermediate J-14, the following intermediates in Table H were prepared. [Table 8-1] [Table 8-2]

[0257] Exemplary Compounds: Using the methods described above, the following compounds of formula IA and formula IB were prepared. Examples of compounds of formula IA and formula IB are shown in Table I. Exemplary methods for the preparation of the compounds are also provided below.

[0258] General Method I: Substitution Reactions Example 23: 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one [ka] A solution of 1-(3-((5-bromo-2-chloropyrimidin-4-yl)amino)propyl)piperidin-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 in 1,4-dioxane (3.5 mL, 13.9 mmol) and stirred at 95 °C for 72 h. The reaction mixture was cooled to room temperature and then basified with saturated aqueous NaHCO3. The solution was extracted with DCM (3 x 50 mL) and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude 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 h and filtered. The filtrate was evaporated to give 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one (1.70 g, 28% yield) 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 Reactions tert-Butyl 4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxyl [ka] A solution of tert-butyl 4-(4-aminophenyl)-1,4-diazepane-1-carboxylate (DI-12, 0.21 g, 0.57 mmol) and 1-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (J-9, 0.17 g, 0.57 mmol) in DMF (3.0 mL) was sealed and heated at 90° C. for 12 h. The mixture was concentrated and the crude was purified by silica gel column chromatography (0-4% MeOH / DCM, 12 CV) to give the product tert-butyl 4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxylate (0.20 g, 60% yield). LC-MS(ESI)m / z:592.4(M+H + ).

[0260] General method K:R 4 Deprotection of the Boc group of the moiety Example 9: 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one [ka] A solution of tert-butyl 4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxylate (0.20 g, 0.34 mmol) in DCM (3 mL) was treated with 4 N HCl in 1,4-dioxane (1.0 mL). 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), frozen and lyophilized to give 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one hydrochloride (0.12 g, 67% yield). 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 Reductive alkylation of the moiety Example 10: 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one [ka] A solution of 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-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 cyanoborohydride (0.026 g, 0.41 mmol) was added and the mixture was stirred at room temperature for 6 h. The solution was treated with brine and then extracted with EtOAc (3×15 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by reverse phase column chromatography (0% to 20% CHCN / HO (0.1% FA), 15 CV) to give 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (56 mg, 49% yield). 1 H 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 General method for acylation of moieties: Example 36: 1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one [ka] A solution of 1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (34, 0.21 g, 0.40 mmol) in 2.5 mL of 30% MeCN:water was treated with acetic anhydride (1.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 30 min and the solution was diluted with water (15 mL). The solution was extracted with EtOAc (3×20 mL) and the combined organics were washed with saturated NaHCO3 (15 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-10% DCM / MeOH, 25 CV) to give 1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (0.13 g, 57% yield) as a clear glassy solid. 1 H 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-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one [ka] A mixture of commercially available 5-(4-methylpiperazin-1-yl)pyridin-2-amine (0.13 g, 0.66 mmol) and 1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-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 diluted with Pd2(dba)3 (0.055 g, 0.06 mmol) and Xantphos (0.069 g, 0.12 mmol). The mixture was treated with 1-(3-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one (0.18 g, 57% yield) 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

[0264] Example 130. Biochemical Assays of ULK1.2 (SEQ ID NO:1) ULK1 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (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). Inhibition of ULK1 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 h at 30 °C on a multimode microplate reader (BioTek). Reaction rates were calculated using a time frame of 2-3 h. Reaction rates at each concentration of compound were converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 Values ​​were calculated by fitting a four parameter sigmoidal curve 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 Assays of ULK1.3 (SEQ ID NO:2) The activity of ULK1 kinase was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in 384-well plates (final volume 100 μL) 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-10). Assays were performed using 0.1 nM ULK1 (from Beryllium) in 100 mM KCl, 0.075 mM peptide substrate (YANWLAASIYLDGKKK), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in 100 mM KCl. Inhibition of ULK1 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously on a multimode microplate reader (BioTek) for 6 h at 30 °C. Reaction rates were calculated using a 2-3 h time frame. Reaction rates at each concentration of compound were converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and IC 50 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 determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 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 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). Inhibition of ULK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 h at 30 °C on a multimode microplate reader (BioTek). Reaction rates were calculated using a time frame of 2-3 h. Reaction rates at each concentration of compound were converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 Values ​​were calculated by fitting a four parameter sigmoidal curve to the data using Prism (GraphPad software). ULK2 protein sequence (residues 1-306 with N-terminal GST and His tag, 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 IC > 1 nM and ≤ 25 nM 50 "++" indicates IC > 25 nM and ≤ 100 nM 50 "+++" indicates IC greater than 100nM and less than 500nM 50 "++++" indicates IC greater than 500nM 50 Refers to...

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

[0269] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. Plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). Wells were then blocked with Assay Diluent (Biolegend Cat#421203) for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in Assay Diluent and added to each well and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive 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). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background corrected absorbance at 450 nm from blank wells was then subtracted from the test wells. Data was compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were 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 (10000 cells / well) were added to 384-well tissue culture treated plates in 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, and grown overnight at 37° C., 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. 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 wells. The wells were mixed by gently shaking the plate, then incubated overnight at 37° C. The next 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 inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4° C. with shaking.

[0271] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. Plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). Wells were then washed with Assay Diluent (Biolegend Cat#421203) at room temperature for 1 hour. 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 in 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 in 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). Signals were calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background corrected absorbance at 450 nm from blank wells was then subtracted from the test wells. Data were compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0272] Example 135. Mutated KRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in HCT-116 cells HCT-116 human colon cancer cells (10000 cells / well) were added to 384-well tissue culture treated plates in 50 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin and grown overnight at 37° C., 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. 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 wells. The wells were mixed by gently shaking the plate and then incubated overnight at 37° C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate buffered saline (Gibco). Cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4°C for 10 min with shaking.

[0273] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. Plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). Wells were then blocked with Assay Diluent (Biolegend Cat#421203) for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in Assay Diluent and added to each well and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. High sensitivity TMB substrate (Biolegend Cat#421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was stopped with 2N sulfuric acid. The plate was then plated for measuring absorbance at 450 nm and 540 nm (background). The assay was analyzed on a graph reader. Signal was first calculated by subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background corrected absorbance at 450 nm from blank wells was then subtracted from the test wells. Data was compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0274] Example 136. Mutated BRAF after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in A375 cells A375 human malignant melanoma cancer cells (20000 cells / well) were added to 96-well tissue culture treated plates in 100 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin 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 the wells. 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 wells. The wells were mixed by gently shaking the plate 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 with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4°C for 10 min with shaking.

[0275] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. Plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). Wells were then blocked with Assay Diluent (Biolegend Cat#421203) for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in Assay Diluent and added to each well and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive 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). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background corrected absorbance at 450 nm from blank wells was then subtracted from the test wells. Data was compared to control wells to determine % ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

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

[0277] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. Plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). Wells were then blocked with Assay Diluent (Biolegend Cat#421203) for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in Assay Diluent and added to each well and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive 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). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background corrected absorbance at 450 nm from blank wells was then subtracted from the test wells. Data was compared to control wells to determine %ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated. [Table 11-1] [Table 11-2] [Table 11-3]

[0278] In Table 2, "+" indicates IC > 10 nM and < 100 nM 50 "++" indicates IC > 100nM and < 300nM 50 "+++" indicates IC greater than 300nM and less than 600nM 50 "++++" indicates IC > 600nM 50 Refers to...

[0279] Example 138. Biochemical Assay of LRRK2 (SEQ ID NO: 4) LRRK2 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (see, e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 26.4 nM LRRK2 (Thermo Fisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ), 1.5 units of pyruvate kinase, 2.1 units of 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). Inhibition of LRRK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored on a multimode microplate reader (BioTek) for 6 h at 30°C. Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 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 IC > 1 nM and < 100 nM 50 "++" indicates IC > 100nM and < 300nM 50 "+++" indicates IC greater than 300nM and less than 600nM 50 "++++" indicates IC > 600nM 50 Refers to...

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

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

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

[0284] Equivalent Although 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 upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, the full scope of equivalents, and the specification, and such variations.

[0285] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

1. A compound represented by: 【Chemistry 1】 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, Wherein W is CH or N; X is CH or N; Y is C(R ３ ) or N, R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl, each C １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine; R ２ is H, halogen, cyano, C １ -C ５ Alkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Alkenyl, C ２ -C ５ Alkynyl, C １ -C ５ Alkoxy, and C １ -C ５ Alkoxy-C ２ -C ５ alkyl, each C １ -C ５ Alkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Alkenyl, C ２ -C ５ Alkynyl, and C １ -C ５ The alkoxy may be optionally substituted by one, two or three independent occurrences of fluorine or cyano; R ３ and R ３３ Each occurrence of is independently H, halogen, C １ -C ６ Alkyl, and C １ -C ６ alkoxy, each C １ -C ６ Alkyl and C １ -C ６ The alkoxy may be optionally substituted by one or more independent occurrences of fluorine; R ４ B, D, NR ６ R ９ , N.R. ６ -(C(R １０ ) ２ ) ｐ -NR ９ R ９ , C(O)-NR ６ R ９ , C(O)-B, C(O)-D, and CN; B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen; B is selected from R ７ and R ９ may be optionally substituted on available nitrogen by D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen; D is selected from R ７ and R ９ may be optionally substituted on available nitrogen by R ５ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and heterocyclyl; each C １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, cyano, and (C(R １０ ) ２ ) ｈ -NR ９ R ９ Each C is selected from the group consisting of １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R ７ combine with the atom to which they are attached to form oxo, R ６ and R ９ Each occurrence of is independently 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 , S.O. ２ R ５ and D, １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R １０ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl, each C １ -C ３ Alkyl and C ３ -C ５ Cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R １０ However, they are bonded together with the carbon to which they are attached to form C ３ -C ５ Forming a cycloalkyl, Z is selected from the group consisting of a 4-membered lactam ring bonded through a nitrogen atom, or a 6- to 10-membered lactam ring bonded through a nitrogen atom, and the lactam ring atoms are optionally selected from oxygen or NR ６ and an available carbon atom on the 4-membered lactam ring or the 6- to 10-membered lactam is R ３６ and optionally replaced by R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, each C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R ３６ However, they are bonded together with the carbon to which they are attached to form C ３ -C ６ Forming a 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; The compound, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, with the proviso that both X and Y are not N.

2. The compound of claim 1 , wherein W is N.

3. 3. The compound of claim 1 or 2, wherein X is CH and Y is N.

4. X is CH and Y is C(R ３ 3. The compound according to claim 1 or 2, wherein

5. Z, 【Chemistry 2】 is selected from the group consisting of V is oxygen, C(R ３４ ) ２ , and N.R. ６ is selected from the group consisting of R ３４ Each occurrence of is independently H and R ３６ is selected from R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, or two R ３６ However, they are bonded together with the carbon to which they are attached to form C ３ -C ６ Forming cycloalkyl death, q is 0, 1, 2, or 3; r is 2 or 4; The compound according to any one of claims 1 to 4, with the proviso that when q is 0, then r is not 2.

6. Z, 【Chemistry 3】 is selected from the group consisting of V is oxygen, C(R ３４ ) ２ , and N.R. ６ is selected from the group consisting of R ３４ Each occurrence of is independently H and R ３６ is selected from R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, or two R ３６ However, they are bonded together with the carbon to which they are attached to form C ３ -C ６ Forming a cycloalkyl, q is 0, 1, 2, or 3; r is 2 or 3; The compound according to any one of claims 1 to 5, with the proviso that when q is 0, then r is not 2.

7. Z is the group consisting of: 【Chemistry 4】 The compound according to any one of claims 1 to 6, selected from:

8. Z is the following 【Chemistry 5】 is selected from the group consisting of V is oxygen, C(R ３４ ) ２、 and N.R. ６ is selected from the group consisting of q is 0, 1, 2, or 3; r is 2 or 3; The compound according to any one of claims 1 to 7, with the proviso that when q is 0, then r is not 2.

9. The compound of any one of claims 1 to 8, wherein Z is selected from the group consisting of: 【Chemistry 6】

10. R ４ The compound according to any one of claims 1 to 9, wherein is B.

11. R ４ is selected from the group consisting of: 【Chemistry 7】 10. The compound according to any one of claims 1 to 9, selected from:

12. R ４ is selected from the group consisting of: 【Chemistry 8】 The compound according to any one of claims 1 to 11, selected from:

13. R ４ But, 【Chemistry 9】 The compound according to any one of claims 1 to 12, selected from the group consisting of:

14. R ４ is selected from the group consisting of: 【Chemistry 10】 The compound according to any one of claims 1 to 13, selected from:

15. R ４ The compound according to any one of claims 1 to 9, wherein is D.

16. R ４ is selected from the group consisting of: 【Chemistry 11】 The compound according to any one of claims 1 to 9, selected from:

17. The compound according to any one of claims 1 to 16, wherein m is 0.

18. The compound according to any one of claims 1 to 16, wherein m is 1.

19. The compound according to any one of claims 1 to 16, wherein m is 2.

20. The compound according to any one of claims 1 to 16, wherein m is 3.

21. R １ But halogen, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １－ C ５ A compound according to any one of claims 1 to 20, wherein the alkyl is optionally substituted by one, two or three occurrences of fluorine.

22. R １ But, CF ３ The compound according to any one of claims 1 to 21,

23. R １ But, CF ２ The compound according to any one of claims 1 to 21, wherein R is H.

24. R １ The compound according to any one of claims 1 to 21, wherein is halogen.

25. R １ The compound of claim 24, wherein is bromo.

26. R １ The compound according to any one of claims 1 to 21, wherein is cyclopropyl.

27. R ２ But, H, C ３ -C ５ Cycloalkyl, C １ -C ５ Alkyl, halogen, CN, C ２ -C ５ Alkenyl, and C ２ -C ５ alkynyl, １ -C ５ 27. The compound of any one of claims 1 to 26, wherein the alkyl is optionally substituted by one, two or three independent occurrences of fluorine.

28. R ２ But, C １－２ Alkyl and C ３－４ 27. The compound of any one of claims 1 to 26, selected from the group consisting of cycloalkyl.

29. R ２ The compound according to any one of claims 1 to 26, wherein is selected from the group consisting of chloro and bromo.

30. R ２ But, C １ -C ５ Alkyl, H, and C ３ -C ４ 27. The compound of any one of claims 1 to 26, selected from the group consisting of cycloalkyl.

31. The compound according to any one of claims 1 to 30, wherein n is 3.

32. A compound represented by: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, In the formula, n is 2, 3, or 4; R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl, each C １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine; R ２ is halogen, C １ -C ２ Alkyl, and C ３ -C ４ cycloalkyl; R ４ is the group consisting of: 【Chemistry 13】 is selected from R ６ and R ９ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C(=O)R ５ , S.O. ２ R ５ and D, １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R ５ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and heterocyclyl; each C １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl, each C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R ７ combine with the atom to which they are attached to form oxo, D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen; D is selected from R ７ and R ９ may be optionally substituted on available nitrogen by Z is the group consisting of: 【Chemistry 14】 is selected from R ３４ Each occurrence of is independently H and R ３６ is selected from R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, each C １ -C ５ Alkyl and C ３ -C ６ Cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R ３６ However, they are bonded together with the carbon to which they are attached to form C ３ -C ６ A compound, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

33. R １ But halogen, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl may contain one, two or three occurrences of fluorine and C ３ -C ５ 33. The compound of claim 32, optionally substituted with cycloalkyl. 。

34. R １ But, CF ３ 34. The compound of claim 32 or claim 33,

35. R １ But, CF ２ 34. The compound of claim 32 or claim 33, wherein:

36. R １ 34. The compound of claim 32 or claim 33, wherein is halogen.

37. R １ The compound of claim 32, claim 33, or claim 36, wherein is bromo.

38. R １ is cyclopropyl.

39. R ２ But, H, C ３ -C ４ Cycloalkyl, C １ -C ５ The compound of any one of claims 32 to 38, wherein the alkyl group is selected from the group consisting of alkyl, and halogen.

40. R ２ But, C １ -C ２ Alkyl, C ３ -C ４ The compound of any one of claims 32 to 39, wherein the compound is selected from the group consisting of cycloalkyl, bromo, and chloro.

41. R ４ is selected from the group consisting of: 【Chemistry 15】 The compound according to any one of claims 32 to 40, selected from:

42. R ４ is selected from the group consisting of: 【Chemistry 16】 The compound according to any one of claims 32 to 41, selected from:

43. R ６ and R ９ Each occurrence of is independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; １ -C ６ Alkyl and C ３ -C ６ The compound of any one of claims 32-42, wherein each cycloalkyl is optionally substituted with one or more independent occurrences of fluorine.

44. R ７ The compound of any one of claims 32 to 45, wherein each occurrence of is H.

45. R ３４ Each occurrence of is independently H and C １ -C ５ alkyl, C １ -C ５ 47. The compound of any one of claims 32 to 46, wherein the alkyl is optionally substituted by one, two or three independent occurrences of fluorine.

46. Two R's ３４ However, they are bonded together with the carbon to which they are attached to form C ３ -C ６ A compound according to any one of claims 32 to 44 which forms a cycloalkyl.

47. Z is the following 【Chemistry 17】 The compound according to any one of claims 32 to 46, selected from the group consisting of:

48. Z is the following 【Chemistry 18】 The compound according to any one of claims 32 to 47, selected from the group consisting of:

49. The compound according to any one of claims 32 to 48, wherein n is 3.

50. A compound represented by: 【Chemistry 19】 During the ceremony, R １ CF ３ , C.F. ２ H, bromo, chloro, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ９ is C １ -C ３ Alkyl, H, and C ３ -C ５ A compound selected from the group consisting of cycloalkyl.

51. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 51. The compound of claim 50, wherein said alkyl is selected from alkyl and H.

52. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 52. The compound of claim 51, wherein said alkyl is selected from alkyl and H.

53. A compound represented by: 【Chemistry 20】 During the ceremony, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ９ is C １ -C ３ Alkyl, H, or C ３ -C ５ A compound selected from the group consisting of cycloalkyl.

54. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 54. The compound of claim 53, wherein said alkyl is selected from alkyl and H.

55. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 54. The compound of claim 53, wherein said alkyl is selected from alkyl and H.

56. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 54. The compound of claim 53, wherein said alkyl is selected from alkyl and H.

57. A compound represented by: 【Chemistry 21】 During the ceremony, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ９ is C １－ C ３ Alkyl, H, or C ３ -C ５ A compound which is a cycloalkyl.

58. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 58. The compound of claim 57, wherein said alkyl is selected from H and alkyl.

59. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 58. The compound of claim 57, wherein said alkyl is selected from H and alkyl.

60. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 58. The compound of claim 57, wherein said alkyl is selected from H and alkyl.

61. A compound represented by: 【Chemical 22】 During the ceremony, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ９ is C １ -C ３ Alkyl, H, and C ３ -C ５ A compound selected from the group consisting of cycloalkyl.

62. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 62. The compound of claim 61, wherein said alkyl is selected from H and alkyl.

63. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 62. The compound of claim 61, wherein said alkyl is selected from H and alkyl.

64. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 62. The compound of claim 61, wherein said alkyl is selected from H and alkyl.

65. A compound represented by: 【Chemistry 23】 During the ceremony, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ９ is C １ -C ３ Alkyl, H, or C ３ -C ５ A compound which is a cycloalkyl.

66. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 66. The compound of claim 65, wherein said alkyl is selected from H and alkyl.

67. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 66. The compound of claim 65, wherein said alkyl is selected from H and alkyl.

68. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 66. The compound of claim 65, wherein said alkyl is selected from H and alkyl.

69. A compound represented by: 【Chemistry 24】 In the formula, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ A compound selected from the group consisting of cycloalkyl, and halogen.

70. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ 70. The compound of claim 69, wherein the alkyl group is selected from the group consisting of cycloalkyl, bromo, and chloro.

71. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ 70. The compound of claim 69, wherein the alkyl group is selected from the group consisting of cycloalkyl, bromo, and chloro.

72. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, bromo, and chloro; R ９ But, C １ -C ３ 70. The compound of claim 69, wherein said alkyl is selected from alkyl and H.

73. A compound represented by: 【Chemistry 25】 During the ceremony, R １ is bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ is C １ -C ２ Alkyl, C ３ -C ４ A compound selected from the group consisting of cycloalkyl, and halogen.

74. R １ But, CF ３ and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ 73. The compound of claim 72, wherein the alkyl group is selected from the group consisting of cycloalkyl, bromo, and chloro.

75. R １ is bromo, R ２ But, C １ -C ２ Alkyl, C ３ -C ４ 73. The compound of claim 72, wherein the alkyl group is selected from the group consisting of cycloalkyl, bromo, and chloro.

76. R １ But, CF ２ H and R ２ But, C １ -C ２ Alkyl, C ３ -C ４ 73. The compound of claim 72, wherein the alkyl group is selected from the group consisting of cycloalkyl, bromo, and chloro.

77. Compounds from the following group: 1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, b-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-(4-(4-cyclopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, (R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((2-((4-(4-cyclopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl) 1-(3-((2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-cyclopropyl-4-((4-((3-(2- oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-one, 1-(3-((5-bromo-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino )propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino) 1-(3-((2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, (S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile, 1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-isopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(4-cyclobutylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-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)pyrimidin-4-yl)amino)propyl)piperidine-2-one 1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin 1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2-one, 1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclohexyl)pyrimidin-4-yl)amino)propyl) 3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl )-1,3-oxazinan-2-one, 3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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- rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-(3-((2-((2-ethyl-4-morpholin-4-yl)amino)propyl)azepan-2-one, 4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidin 4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, , 4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one , 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, -((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidine 4-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4- (3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((2-cyano cyclopropyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, rac-(R)-4-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(4-methyl) ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyridin- 4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((4-(4-cyclopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-5,5-dimethylpyrrolidin-2-one, 1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-5,5-dimethylpyrrolidin-2-one, 1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-methyl-6-(4- methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)- 4-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4 1-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, -(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4-(4-methylpiperazin-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)pyrimidin-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)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetate (R)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile, (S)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)acetonitrile, (R)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methyl 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3, -(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-(3-((2-((2-ethyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1]nonan-9 ... (S)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidine 4-(3-((2-((2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethynyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(ethynyl-d)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(ethyl-d5)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)- 2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan 2-methyl-2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile, 2-methyl-2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile, 2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5 -(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)acetonitrile, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one , 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, (trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl- 4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicin 3-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, (R)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinane-, 2-one, (S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan- 2-one, 3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, no)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinane-3 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-oxazinan-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-oxazinan-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-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-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-oxazinan-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-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, (S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl-4-(4-methylpiperazin-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-methylpiperazin-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-methylpiperazin-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-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((2-cyclopropyl 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-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)pyrimidin-4-yl)amino)propyl)piperidin-2-one, ,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-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)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((2-((2-cyclopropyl-4-((1 R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-((1R,5 S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2 -dimethyl-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-Oxazepan-5-one, 8-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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-(tri, 4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl) 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-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)pyrimidin-4-yl)amino)propyl)azetidin-2-one, pyrimidin-4-yl)amino)propyl)azetidin-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)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-Dimethylazetidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5 -diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-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)pyrimidin-4-yl)amino)propyl)pyrrolidin-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)pyrimidin-4-yl)amino)propyl)pyrrolidin-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)pyrimidin-4-yl)amino)propyl)-3,3-di ethylpyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-( (2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-chloropyrimidine- 4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-bromopyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-ethyl-4, -(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl-4-((dimethylamino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-cyclopropyl 3-methoxy-N-(1-methylpiperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide, 4-(3-((2-((4-(4-(diethylamino)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, (S)-4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(mo 1-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine 4-(3-((2-((4-(4-(dimethylamino)methyl)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan- 5-one, 4-(3-((2-((4-(3,3-dimethylpiperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,5,5-tetramethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 1-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl) phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 3-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)amino)-5-(trifluoromethyl), pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(5-methyl 1,4-oxazepan-5-one, 3-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, (trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-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)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyridin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((2-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin- 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one Nan-2-one, 3-(3-((2-((2-fluoro-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((2-cyclopropyl-4-((1,1-dioxidothiomorpholino)methyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((2-cyclopropyl-4-((4-methylpiperazin-1-yl)sulfo 3-(3-((2-((4-(3-(diethylamino)propyl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(morpholinosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidine-2-, oxazepan-5-one, 4-(3-((2-((2-(1-hydroxyethyl)pyrimidin-4-yl)amino)propyl)-1,4- ... 4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-di azabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-o Xazinan-2-one, 3-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one nan-2-one, 3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-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)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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 3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-o oxazepan-3-one, 4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-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)pyrimidin-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]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1, 4-Oxazepan-5-one, 4-(3-((2-((2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinane- 2-one, 3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-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)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((4-(3-((dimethylamino)methyl, 4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, and pharma- ceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

78. 78. A pharmaceutical composition comprising a compound according to any one of claims 1 to 77 and a pharma- ceutically acceptable excipient.

79. 80. A pharmaceutical composition comprising a compound according to any one of claims 1 to 77, one or more additional therapeutic agents, and a pharma- ceutically acceptable excipient.

80. 80. The pharmaceutical composition of claim 79, wherein the composition comprises one additional therapeutic agent.

81. 81. The pharmaceutical composition of claim 79 or claim 80, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

82. 82. The pharmaceutical composition of claim 81, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

83. 83. The pharmaceutical composition of claim 82, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.

84. 83. The pharmaceutical composition of claim 82, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharma- ceutically acceptable salts thereof.

85. 83. The pharmaceutical composition of claim 82, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharma- ceutically acceptable salts thereof.

86. 83. The pharmaceutical composition of claim 82, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharma- ceutically acceptable salts thereof.

87. 81. The pharmaceutical composition of claim 79 or claim 80, wherein the additional therapeutic agent is a chemotherapeutic agent.

88. 88. The pharmaceutical composition of claim 87, wherein the chemotherapeutic agent is selected from the group consisting of antitubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine, and methotrexate.

89. 82. A method of treating a tumor in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 77.

90. 82. A method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 77.

91. 91. The method of claim 90, wherein the cancer is selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer metastasizing to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.

92. 92. The method of claim 90 or claim 91, wherein the cancer is metastatic.

93. 82. A method of treating a disorder selected from the group consisting of melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer metastasizing to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-77.

94. 94. The method of any one of claims 89-93, further comprising administering to the patient one or more additional therapeutic agents.

95. 95. The method of claim 94, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

96. 96. The method of claim 95, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

97. 96. The method of claim 95, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.

98. 96. The method of claim 95, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof.

99. 96. The method of claim 95, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharma- ceutically acceptable salts thereof.

100. 96. The method of claim 95, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharma- ceutically acceptable salts thereof.

101. 95. The method of claim 94, wherein the additional therapeutic agent is a chemotherapeutic agent.

102. 102. The method of claim 101, wherein the chemotherapeutic agent is selected from the group consisting of antitubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate.

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