Heteroarylaminopyrimidine 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: The invention provides a compound represented by the formula in the figure, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof. In the formula, A, R1, R2, R4, Z and L each represent a specific group, and n represents 2, 3, or 4.SELECTED DRAWING: None

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a division of USSN 62 / 846, filed May 10, 2019. ,260, filed May 10, 2019, USSN 62 / 846,264, filed October 7, 2019, USSN 62 / 911,733, filed October 7, 2019, and USSN 62 / 911,736, filed October 7, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing [0001.1] This application contains a Sequence Listing which has been submitted electronically in ASCII format, the entirety of which is hereby incorporated by reference. This ASCII copy, created on May 5, 2020, is named DCP-080WO_SL.txt and is 27,200 bytes in size. [Background technology]

[0003]

[0002] Autophagy (literally meaning "self-eating") is a process that allows cells to synthesize nutrients under stress. Autophagy is a process that allows cells to regenerate organelles, proteins, stored lipids, glucagon, and other substances for the purpose of cell growth. These cellular contents are recycled by engulfment into vesicles called autophagosomes. The autophagosomes then fuse with lysosomes, which degrade the contents of the autophagosomes for the recycling of nutrients to the cell. Tumor cells tend to activate autophagy because they have high metabolic demands, experience cellular stress, and often live in a hypoxic environment with limited blood flow and nutrient supply. Furthermore, chemotherapy and targeted therapies have been shown to induce autophagy as a mechanism of therapeutic resistance, and the combination of autophagy inhibition (either through genetic loss of function mutations in autophagy genes or pharmacological means) with chemotherapy regimens has been shown to suppress tumor growth and induce widespread tumor cell apoptosis more effectively than monotherapy chemotherapy.

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

[0005]

[0004] Currently, the most widely used autophagy inhibitor is the well-known antimalarial drug These antimalarial drugs are chloroquine and hydroxychloroquine. These antimalarial drugs are thought to block autophagy by sequestering it in the lysosomal compartment and increasing the pH of these lysosomes, thereby inactivating proteases that degrade and regenerate nutrients. These antimalarial drugs have multiple mechanisms of action beyond lysosomal inhibition and are known to induce retinopathy in patients. Therefore, there is a need for more targeted agents that selectively block autophagy without the toxicity of these antimalarial drugs. ULK1 kinase is an autophagy initiator protein and 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 activity. ULK kinase activity is activated through activation by the activating 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 have shown that genetic deletion of ULK1 inhibits autophagy in cancer cells. Inhibition of ULK1 kinase has been shown to alleviate FOX3A turnover and upregulation of the pro-apoptotic 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 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. ULK1 kinase activation has also been shown to inactivate the STING pathway in immune cells through inhibitory phosphorylation of STING, mediating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Thus, autophagy is not only activated in tumor cells (cancer cell-autonomous), but also in other cells within the tumor microenvironment or host tissue (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 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 via the MAPKAP pathway, inhibitors of this pathway have provided little or no clinical benefit in clinical trials when used as single agents. It has recently been reported that inhibition of the MAPKAP pathway induces autophagy as a compensatory survival mechanism. When MEK inhibitors were combined with the autophagy inhibitor hydroxychloroquine, there was synergistic activity, resulting in the 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 the inhibition of mutant Ras pancreatic cancers. Genetic depletion of RAF kinases (CRAF and BRAF) has been demonstrated to result in synergistic antitumor activity in mutant Ras cancer cell lines when autophagy was also genetically depleted. Combined, recent publications highlight that dual inhibition of the 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, thus providing a rationale for combining such targeted therapies or chemotherapeutic agents with inhibitors of autophagy.

[0009] Mutations in the gene encoding LRRK2 kinase are a cause of Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) and sporadic Parkinson's disease patients. The most common 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 keeps brain neurons healthy. Autophagy is a process used by cells to maintain homeostasis and function. Autophagy is the process by which cells identify, localize, and destroy aging organelles and structural elements within the cell. In the case of proteins known to aggregate in neurons, autophagy 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 implicated in colitis and Crohn's disease and in inflammatory conditions. LRRK2 has also been implicated in immune-mediated inflammatory diseases, including enteropathy. 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, including activation of the NFkB pathway and increased TNF-alpha production in dendritic cells from Crohn's disease patients.

[0011]

[0010] Inhibitors of LRRK2 are sought for the treatment of neurodegenerative diseases, including Parkinson's disease, and also for the treatment of gastrointestinal diseases, including Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0012]

[0011] MAPKAP pathway inhibitors, chemotherapeutic agents, and / or New targeted therapies that can be used in combination with other targeted therapeutic agents are needed. Summary of the Invention

[0013]

[0012] The present specification provides compounds, pharmaceutical compositions, and methods for treating autophagy. Their use as medicaments in the treatment of disorders such as cancer, processes for their preparation, and pharmaceutical compositions containing them as active ingredients are described. Such pharmaceutical compositions may contain the compounds as the sole active agent or in combination with other active agents in the presence of a pharmaceutically acceptable excipient. In one embodiment, the described compounds are inhibitors of ULK kinase activity, including ULK1 and ULK2 activity.

[0014] For example, the compounds provided herein can be those of Formula I, as described [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is a 5-membered heteroaryl having at least one ring nitrogen, W is CH or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each C1-C5 alkyl and C3-C5 cycloalkyl being optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is H, halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy and C1-C5 alkoxy-C1-C5 alkyl, wherein each C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 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 an available nitrogen by R 5 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and heterocyclyl, wherein each C-C alkyl and C-C cycloalkyl is optionally substituted by one or more independent occurrences of fluorine; 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 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 oxo, and 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 C-C alkyl and C-C cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; 10each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is 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 4-10 membered lactam rings, the lactam ring is bonded through a nitrogen atom, and the lactam ring atoms are optionally selected from oxygen or NR when the lactam ring is a 6-10 membered ring. 6 and an available carbon atom on the 4-membered lactam ring or the 6- to 10-membered lactam may be one or more independent occurrences of R 36 and optionally substituted by R 36 each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl 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, and L is -(C(R 10 )2) m -, 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 when m is 0, R 4 is C-bonded to ring A and m is 1, then R 4 is C-bonded to L, and then when m is 2 or 3, R 4 is N- or C-bonded to L. DETAILED DESCRIPTION OF THE INVENTION

[0015]

[0014] 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 remainder 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. refers to an element. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons of 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 alkyl, respectively. 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]

[0016] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched 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]

[0017] As used herein, the term "alkoxy" refers to a straight-chain 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]

[0018] As used herein, the term "alkoxyalkyl" refers to a straight-chain or branched alkyl group attached to an oxygen atom, which is attached to a second straight-chain 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 and C1-C6 alkoxy-C2-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]

[0019] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain 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]

[0021] 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]

[0022] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to oxygen (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3 to 6 carbon atoms, referred to herein as C3-6 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]

[0024] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 5- or 6-membered ring system containing one or more heteroatoms, e.g., 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heteroaryl ring may be linked to an adjacent radical through a carbon or nitrogen atom. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, or pyrimidine.

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

[0027] As used herein, the term "lactam" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkan-2-one structure, or an analog having unsaturation or a heteroatom replacing one or more carbon atoms of the ring. "Alpha-lactam" refers to a lactam consisting of a three-membered ring. "Beta-lactam" refers to a lactam consisting of a four-membered ring. "Gamma-lactam" refers to a lactam consisting of a five-membered ring. "Delta-lactam" refers to a lactam consisting of a six-membered ring. "Epsilon-lactam" refers to a lactam consisting of a seven-membered ring.

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

[0029]

[0028] "Combination therapy" is a treatment that involves 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]

[0029] In this specification, the terms "disease," "disorder," and "condition" are used interchangeably.

[0031]

[0030] "Individual," "patient," or "subject" are used interchangeably herein and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered to mammals such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0032]

[0031] "MAPKAP pathway inhibitor" is an inhibitor of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510 or MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, or LY3009120), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, or cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, or LY3214996). The terms "MAPKAP pathway inhibitor" and "MAPKAP kinase inhibitor" are used interchangeably herein.

[0033] "Pharmaceutically 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]

[0033] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvent, dispersion medium, coating, isotonic and absorption delaying 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]

[0034] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0036]

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to the salt of an acidic or basic group that may be present in the compound used in the composition. The compounds contained in the present composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that 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. The 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. The compounds contained in the present composition that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The 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 compounds can exist as acid addition salts, zwitterions, or base salts.

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

[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 therapeutically effective amounts to treat disorders.

[0039]

[0038] As used herein, "treating" includes any effect of attenuating, reducing, modulating, or eliminating, for example, resulting in the improvement of a condition, disease, disorder, or the like.

[0040]

[0039] 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 can 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, and 36 Cl, etc. 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 stereogenic centers, or by the 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 a 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 a mixture of optical enantiomers on 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, 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, compounds represented by formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is a 5-membered heteroaryl having at least one ring nitrogen, W is CH or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each C1-C5 alkyl and C3-C5 cycloalkyl being optionally substituted by 1, 2, or 3 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-C1-C5 alkyl, wherein each C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 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 an available nitrogen by R 5is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and heterocyclyl, wherein each C-C alkyl and C-C cycloalkyl is optionally substituted by one or more independent occurrences of fluorine; 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 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 oxo, and 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 C-C alkyl and C-C cycloalkyl being optionally substituted by one or more independent occurrences of fluorine; 10 each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbons to which they are attached to form a C3-C5 cycloalkyl, Z is selected from the group consisting of 4-10 membered lactam rings, the lactam ring is 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 substituted by R 36each occurrence is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl, each C1-C6 alkyl and C3-C6 cycloalkyl 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, and L is -(C(R 10 )2) m -, m is 0, 1, 2, or 3, n is 2, 3, or 4, p is 2 or 3, and h is 1, 2, or 3, with the proviso that when m is 0, R 4 is C-bonded to ring A and m is 1, then R 4 is C-bonded to L, and then when m is 2 or 3, R 4 is N- or C-bonded to L.

[0043] In some embodiments, 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 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

[0044] In some embodiments, Z is selected from the group consisting of a 4-10 membered lactam ring attached through a nitrogen atom, and any available carbon atom on the 4-10 membered lactam ring is bonded to R 36 and the lactam ring atoms are optionally substituted by oxygen or NR when the lactam ring is a 6- to 10-membered ring. 6 may be.

[0045] In some embodiments, W is N. In some embodiments, A is selected from the group consisting of pyrazolyl, triazolyl, thiazolyl, and oxazolyl.

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

[0047] In some embodiments, [ka] is selected from the group consisting of: [ka]

[0048] In some embodiments, [ka] is as follows: [ka]

[0049] In some embodiments, Z is selected from: [ka] where V is oxygen, C(R 34 )2, and NR 6 and 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-C6 alkyl and C3-C6 cycloalkyl optionally substituted by one or more independent occurrences of fluorine, or two R 36are 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.

[0050] In some embodiments, Z is selected from: [ka] where V is oxygen, C(R 34 )2, and NR 6 and 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-C6 alkyl and C3-C6 cycloalkyl 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; q is 0, 1, 2, or 3; and r is 2 or 3.

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

[0052] In some embodiments, Z is selected from: [ka] where V is oxygen, CH, and NR 6 wherein q is 0, 1, 2, or 3; and r is 2 or 3.

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

[0057] In some embodiments, R 4 is B.

[0058] In some embodiments, R 4 is selected from the group consisting of: [ka] In the formula, u is 1 or 2.

[0059] In some embodiments, R 4 is selected from the group consisting of: [ka]

[0060] In some embodiments, R 4 is selected from the group consisting of: [ka]

[0061] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0062] In some embodiments, L is a direct bond to the A ring, ie, m is 0.

[0063] In some embodiments, L is selected from the group consisting of -CH2-, -CH2CH2-, and -CH2CH2CH2-. In some embodiments, L is -CH2-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -CH2CH2CH2-.

[0064] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, and is selected from the group consisting of C1-C5 alkyl or C 3- The C5 cycloalkyl may be optionally substituted with 1, 2, or 3 independent occurrences of fluorine. In some embodiments, R 1 is CF. In some embodiments, R 1 is halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is CF2H.

[0065] In some embodiments, R 2 is selected from the group consisting of C1-C5 alkyl, H, and C3-C4 cycloalkyl, and is selected from the group consisting of C1-C5 alkyl or C 3- The C4 cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0066] In some embodiments, R 2is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl. In some embodiments, R 2 is halogen. In some embodiments, R 2 is selected from the group consisting of chloro and bromo. 2 is bromo. In some embodiments, R 2 is chloro.

[0067] In some embodiments, n is 3.

[0068] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein A-1 is selected from the group consisting of: [ka] R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each C1-C5 alkyl and C3-C5 cycloalkyl being optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of halogen, C1-C2 alkyl, and C3-C4 cycloalkyl, each C1-C2 alkyl and C3-C4 cycloalkyl optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 4 is selected from the group consisting of: [ka] R 7 each occurrence is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7combine with the carbon to which they are attached to form oxo, and R 6 and R 9 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein each C-C alkyl and C-C cycloalkyl is optionally substituted by one or more independent occurrences of fluorine; 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-C6 alkyl and C3-C6 cycloalkyl optionally substituted by one or more independent occurrences of fluorine, or two R 36 combine with the carbon to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m - and R 10 each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted by one or more independent occurrences of fluorine, or two R 10 are joined to the carbons to which they are attached to form a C3-C5 cycloalkyl, m is 0, 1, 2, or 3, and n is 2, 3, or 4, with the proviso that when m is 0, R 4 is C-bonded to the pyrazole ring and m is 1, R 4 is C-bonded to L, and then when m is 2 or 3, R 4 is N- or C-bonded to L.

[0069] In some embodiments, A-1 is: [ka]

[0070] In some embodiments, n is 3.

[0071] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0072] In some embodiments, L is a direct bond.

[0073] In some embodiments, L is selected from the group consisting of -CH2-, -CH2CH2-, and -CH2CH2CH2-. In some embodiments, L is -CH2-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -CH2CH2CH2-.

[0074] In some embodiments, Z is selected from the group consisting of: [ka]

[0075] In some embodiments, Z is selected from the group consisting of: [ka]

[0076] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl may be optionally substituted with 1, 2, or 3 occurrences of fluorine. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1is halogen. In some embodiments, R 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0077] 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, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is 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 is selected from the group consisting of cycloalkyl. 2 is selected from the group consisting of chloro and bromo.

[0078] 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.

[0079] In some embodiments, R 4 is as follows: [ka]

[0080] 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 C-C alkyl, C-C cycloalkyl, and halogen; 9 Each occurrence of is independent R is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl; 34 is independently selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0081] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 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, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF3 and R 2each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0083] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0084] In some embodiments, the compound is represented by formula IIA.1, as defined above. In some embodiments, the compound is of formula IIA.3, as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IIA.3, formula IIA.4, formula IIA.5, formula IIA.6, and formula IIA.7, as defined above.

[0085] 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 C-C alkyl, C-C cycloalkyl, and halogen; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0086] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is selected from C-C alkyl and C-C cycloalkyl; R 9 Each occurrence of is selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0087] 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 C-C alkyl, C-C cycloalkyl, and halogen; 9 Each occurrence of is independent R is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0088] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0089] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0090] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0091] 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 C-C alkyl, C-C cycloalkyl, and halogen; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0092] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is selected from C-C alkyl and C-C cycloalkyl; R 9 Each occurrence of is selected from H and C1-C3 alkyl. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0093] 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 C-C alkyl, C-C cycloalkyl, and halogen; 9each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0094] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0095] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of 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 C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0096] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0097] In some embodiments, the compound is represented by formula IIA.19, as defined above. In some embodiments, the compound is represented by formula IIA.21, as defined above.

[0098] 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 C-C alkyl, C-C cycloalkyl, and halogen; 6 each occurrence is independently selected from C-C alkyl and C-C 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.

[0099] In some embodiments, R 1Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0100] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein A-1 is selected from the group consisting of: [ka] R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, each C1-C5 alkyl and C3-C5 cycloalkyl being optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2is selected from C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; R 4 is selected from the group consisting of: [ka] R 7 each occurrence is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the carbon to which they are attached to form oxo, and R 6 and R 9 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein each C-C alkyl and C-C cycloalkyl is optionally substituted by one or more independent occurrences of fluorine; 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-C6 alkyl and C3-C6 cycloalkyl optionally substituted by one or more independent occurrences of fluorine, or two R 36 combine with the carbon to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m - and R 10 each occurrence of is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted by one or more independent occurrences of fluorine, or two R 10are joined to the carbons to which they are attached to form a C3-C5 cycloalkyl, m is 0, 1, 2, or 3, and n is 2, 3, or 4, with the proviso that when m is 0, R 4 is C-bonded to the pyrazole ring and m is 1, R 4 is C-bonded to L, and then when m is 2 or 3, R 4 is N- or C-bonded to L.

[0101] [000100] In some embodiments, A-1 is: [ka]

[0102] [000101] In some embodiments, n is 3.

[0103] [000102] In some embodiments, m is 0. In some embodiments, m is , 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0104] [000103] In some embodiments, L is a direct bond.

[0105] [000104] In some embodiments, L is selected from -CH2-, -CH2CH2-, and - In some embodiments, L is selected from the group consisting of -CH2CH2CH2-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -CH2CH2CH2-.

[0106] [000105] In some embodiments, Z is selected from the group consisting of: [ka]

[0107] [000106] In some embodiments, Z is selected from the group consisting of: [ka]

[0108] [000107] In some embodiments, R 1 is halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, C1-C5 alkyl or C 3- C5 cycloalkyl is optionally substituted with 1, 2, or 3 occurrences of fluorine. In some embodiments, R 1 is CF. 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.

[0109] [000108] In some embodiments, R 2 is H, C3-C5 cycloalkyl, C1- In some embodiments, R is selected from the group consisting of C alkyl, halogen, CN, C-C alkenyl, and C-C alkynyl, wherein each C-C alkyl or C-C cycloalkyl is 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 chloro and bromo.

[0110] [000109] In some embodiments, R 2 is C1-C5 alkyl, H, and C3- In some embodiments, R is selected from the group consisting of C4 cycloalkyl. 2 is selected from C1-C2 alkyl and C3-C4 cycloalkyl. In some embodiments, R 2 is selected from chloro and bromo.

[0111] [000110] In some embodiments, R 4 is as follows: [ka]

[0112] [000111] In one embodiment, the compound is represented by a formula selected from the group consisting of: R, [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 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0113] [000112] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , 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, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0114] [000113] In some embodiments, R 1 Each occurrence of is CF3 and R 2 Each occurrence of , independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of 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 C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0115] [000114] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 Each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34is H and n is 3.

[0116] [000115] In some embodiments, the compound is according to a formula selected from the group consisting of: It is expressed as [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 C-C alkyl, C-C cycloalkyl, and halogen; 6 each occurrence of is independently selected from C-C alkyl, and C-C cycloalkyl; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0117] [000116] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 6 each occurrence of is selected from C-C alkyl and C-C cycloalkyl; R 9 Each occurrence of is selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF2H and R 2each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0118] [000117] In some embodiments, the compound is according to a formula selected from the group consisting of: It is expressed as [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 C-C alkyl, C-C cycloalkyl, and halogen; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0119] [000118] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , 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, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0120] [000119] In some embodiments, R 1 Each occurrence of is CF3 and R 2 Each occurrence of , independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of 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 C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0121] [000120] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 Each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0122] [000121] In some embodiments, the compound is according to a formula selected from the group consisting of: It is expressed as [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 R is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, bromo, and chloro, and halogen; each occurrence of R is independently selected from C-C alkyl and C-C cycloalkyl; each occurrence of R is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; and n is 3.

[0123] [000122] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 6 each occurrence of is selected from C-C alkyl and C-C cycloalkyl; R 9 Each occurrence of is selected from H and C1-C3 alkyl. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6each occurrence of is independently selected from the group consisting of C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0124] [000123] In some embodiments, the compound is according to a formula selected from the group consisting of: It is expressed as [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 C-C alkyl, C-C cycloalkyl, and halogen; 9 Each occurrence of is independent R is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0125] [000124] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , 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, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0126] [000125] In some embodiments, R 1 Each occurrence of is CF3 and R 2 Each occurrence of , independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of 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 C-C alkyl and C-C cycloalkyl; R 9 each occurrence is independently selected from H and C-C alkyl, and each R 34 is H and n is 3.

[0127] [000126] In some embodiments, R 1 Each occurrence of is CHF2 and R 2 Each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H and C1-C3 alkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CHF2 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 each occurrence of is selected from H and C1-C3 alkyl, and each R 34 is H and n is 3.

[0128] [000127] 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 C-C alkyl, C-C cycloalkyl, and halogen; 6 each occurrence is independently selected from C-C alkyl and C-C 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.

[0129] [000128] In some embodiments, R 1 Each occurrence of is bromo and R 2 Each occurrence of , independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromo, and chloro; R 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C 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 C-C alkyl, C-C cycloalkyl, bromo, and chloro; 6 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0130] [000129] In some embodiments, the compound is 1-(3-((5-cyclopropyl- 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) Piperidin-2-one, 1-(3-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoro 1-(3-((2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((1- (piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropyl-d7-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetyl 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-(cyclopropylmethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-(cyclopropylmethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one 1-(3-((2-((3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one 1-(3-((2-((3-methyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,rac-(R)-1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidine- 2-one, 1-(3-((5-chloro-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-d3-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4- 1-(3-((2-((3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4 1-(3-((2-((1-(3-(dimethylamino)propyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((1-(1-isopropylpyrrolidin-3-yl ... azetidin-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl 1-(3-((2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl-1-(1-ethylpiperidine- 4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-iodo-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidine-2- 1-(3-((5-bromo-2-((3-methyl-d3-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-methyl-d3-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-bromo-2-((3-ethyl-1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl-1-(1-methylpiperidin-4-yl), 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-(methyl-d3)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-(methyl-d3)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-(2-fluoroethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidine- 3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3 -((5-bromo-2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one, 2-methyl-2-(3-methyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 3-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(3-((5-cyclopropyl-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-5,5-dimethylpyrrolidin-2-one, 3-(3-((2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3- Oxazinan-2-one, 3-(3-((5-bromo-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-chloro-2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 4- (3-((5-cyclopropyl-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 4-(3-((5-cyclopropyl-2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one Pan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl )amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ami 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)azepan-2-one -5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-cyclobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-cyclopentylpiperidin-4-yl) -3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-(sec-butyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, (S)-1- (3-((2-((1-(1-isopropylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-methyl-d3-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)pyrrolidin-2-one -5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)- 1,4-Oxazepan-3-one, (R)-4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino), propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1, 4-oxazepan-3-one, (R)-4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((1-(2-(dimethylamino)ethyl) -3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(2-(diethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 2-methyl-2-(3-methyl-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5 -(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 3-(3-((2-((4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one , 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((5-chloro-2-, ((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl) )pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl) -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 4-(3-((5-bromo-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 4-(3-((2-((1-(2-(diethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amido) 1-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylimidazolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylimidazolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-5,5-Dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-5-methylpyrrolidin-2-one, 1-methyl-3-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)imidazolidine -2-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)imidazolidin-2-one, 1-(3-((5-bromo-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidine-, 2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylpyrrolidin-2-one, ra c-(R)-1-(4-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)butan-2-yl)pyrrolidin-2-one, rac-(R)-1-(4-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)butan-2-yl)pyrrolidin-2-one, (R)-1-(3-((5-chloro-2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (R)-1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (R)-1-(3-((5-bromo-2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (S)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,(S)-1-(3-((2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 2-methyl-2-(3-methyl-4-((4-((3-(3-oxo-1,4- oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile, 1-(3-((2-((4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl, )amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-( (2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)- 2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1, 3-Oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3 ... yl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, -methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one -yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazo 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-( 4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(4 -methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 1-methyl-4-(3-(( 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-methyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[4.2.1.2]phenyl)-2-methyl-1H-pyrazol-4-yl)amino)propyl)-1,4-diazepan-2-one, chloro[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-methyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, 3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one 1-methyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo [3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl. 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-methyl-1-(3-((2-( (3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazolin-3-yl)-1H-pyrazolin-4-yl)amino)propyl)morpholin-3-one, 3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one 6,6-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-1,4-oxazepan-5-one 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 6,6-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl) 6,6-dimethyl-4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)a amino)propyl)azetidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-( difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, )propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((, 5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl -1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-(( 3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(di. fluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidine-4-yl)- 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl) -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl) -2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pi 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, Bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-. pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-bromo-2-((3-methyl-1 -(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino) propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-Oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8- Azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3- Methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-, Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-chloro-2-((3-methyl- 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1, 3-oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3- ((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidine -3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-Oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazepan-3-one, Sadinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4 ... 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazolin ... 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)amino)pyrimidine-5-carbonitrile 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1- (1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine-5-carbonitrile 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, -((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine rimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxopiperidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepa 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, ...1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)- 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3. -methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(2,2-dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile 4-((3-(2,2-dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(2,2- Dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile 4-((3-(3,3-dimethyl-2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl-2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl-2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidine- 4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((1-(1-. methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3 -(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl- 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2. 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, Sazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl- 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2- ((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one,. 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)- 3,3-Dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1 ]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl ) pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) pyrrolidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5- (Difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol ... pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8- Azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-. 2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol- 4-(3-((2-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 4-(3-((2-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(2-(dimethylamino)ethyl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one 3-(3-((2-((5-ethyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-((4-methylpiperazin-1-yl)methyl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-ethyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-((4-methylpiperazin-1-yl)methyl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, N-(1-methylpiperidin-4-yl)-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)thiazole-2-carboxamide, 4-(3-((2-((2-(3-(dimethylamino)propyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(2-(dimethylamino)ethyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4 -oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazine-1-carbonyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-(dimethylglycyl)piperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1,1-dioxidethiomorpholino)thiazol-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1,1-dioxidethiomorpholino)thiazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((2-morpholinooxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)propyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-morpholinooxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)propyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4 4-(3-((2-((2-((dimethylamino)methyl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-((dimethylamino)methyl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-((2-(dimethylamino)ethyl)(methyl)amino)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 2-(dimethylamino)-N-methyl-N-(5-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)oxazol-2-yl)acetamide, 1-(3-((2-((1-(1-(dimethylglycyl)pyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, ... 3,3-dimethylazetidin-2-one, 3,3-dimethyl-1-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 4-(3-((2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 4-(3-((2-((1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((2-((3-fluoro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methoxy-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3- Oxazinan-2-one, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4-(3-((2-((3-ethynyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 8-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)- 4-Oxa-8-azaspiro[2.6]nonan-9-one, 8-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonan-9-one, 9-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-9-azaspiro[3.6]decan-10-one, 9-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6-oxa-9-azaspiro[3.6]decan-10-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-( trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)- 1,3-Oxazepan-2-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3- ((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one (S)-4-(3-((2-((3-methyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (S)-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-diazepan-2-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one )amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-((dimethylamino)methyl)azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-Oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-, ((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, )pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2 -((3-methoxy-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-((3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl) 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile, 6-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-Oxazepan-4-yl)propyl)amino)nicotinonitrile, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(1-methyl Piperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4-(3-((2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-(1-methylpiperidine-4 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyraz ...4-oxazepan-3-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azetidin-2-one, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trimethylsilyl) 4-(3-((2-((2-(4-(dimethylglycyl)piperazin-1-yl)-5-methylthiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1,1-dioxidethiomorpholino)-5-methylthiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4 -(3-((5-(difluoromethyl)-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H- or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0131] Treatment method [000130] The compounds described herein are useful in treating disorders in patients in need thereof. The disorder may be, for example, a tumor, such as a solid tumor. The disorder may also be cancer.

[0132] [000131] Exemplary disorders also include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, and gastrointestinal stromal tumors. Cancers that can be treated by the methods described herein include glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer that metastasizes to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.The cancer that can be treated by the methods described herein can be metastatic cancer.

[0133] [000132] In some embodiments, the compounds described herein inhibit RAS mutations In some embodiments, the cancer is useful for treating cancers 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.

[0134] [000133] In some embodiments, autophagy by the compounds described herein Determining cellular inhibition of mCherry / GFP-LC3 is determined by monitoring autophagic flux, e.g., by monitoring inhibition of autophagy-mediated clearance of an mCherry / GFP-LC3 fusion protein. In some embodiments, the compounds described herein The determination of cellular inhibition of autophagy by a compound described herein is determined by monitoring the accumulation of autophagy proteins such as p62 or LC-3. In some embodiments, the determination of cellular inhibition of autophagy by a compound 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 a compound described herein is determined by monitoring the decrease in cellular autophagosomes, for example, by measuring fluorescent puncta using the autophagosome marker Cyto-ID.

[0135] [000134] In some embodiments, ULK kinase inhibitors are administered by the compounds described herein. Cellular inhibition of ULK kinases 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 kinases by the compounds described herein is determined in host tissues, including immune cells.

[0136] [000135] In some embodiments, autophagy by the compounds described herein In vivo inhibition of ULK kinase by compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in host tissues, including immune cells. In some embodiments, in vivo inhibition of autophagic flux by compounds described herein can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in pancreatic cancer-bearing animals. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in lung cancer-bearing animals. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in colorectal cancer-bearing animals. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibiting autophagic flux in tumor cells or non-tumor host tissues by monitoring the inhibition of autophagosome formation or the accumulation of autophagy proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is determined in host tissues containing immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition.

[0137] [000136] In some embodiments, autophagy by the compounds described herein Inhibition of autophagy and anti-tumor activity by compounds described herein is assessed in xenograft studies utilizing human RAS mutant cell lines in immunodeficient mice, such as, for example, SCID or nude mice. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is assessed in xenograft studies utilizing human RAS mutant patient-derived tumor xenografts (PDX) in immunodeficient mice, such as, for example, SCID or nude mice. In some embodiments, xenograft studies include evaluation of compounds described herein in pancreatic cancer models. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is assessed in syngeneic genetically engineered mouse models (GEM) of mutant RAS cancer. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is assessed in the KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / + , Pdx-1-Cre) or a variant of the KPC model, known as the GEM syngeneic orthotopic pancreatic cancer model.

[0138] [000137] In some embodiments, the compounds described herein may be combined with a MEK inhibitor. 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.

[0139] [000138] In some embodiments, autophagy by the compounds described herein Inhibition of tumor growth and anti-tumor activity is assessed in an immunocompetent mouse cancer model to assess the immunomodulatory component to the mechanism of action of the ULK inhibitor. In some embodiments, the immunocompetent mouse model is the KPC model (LSL-Kras G12D / +, LSL-Trp53 R172H / + The mouse GEM syngeneic orthotopic pancreatic cancer model is known as a variant of the KPC model (Pdx-1-Cre, Pdx-1-Cre, or KPC model). In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a MEK inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a RAF inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with an ERK inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a RAS G12C direct inhibitor.

[0140] [000139] In some embodiments, the immunomodulatory component of ULK inhibition is associated with enhanced innate immunity. 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.

[0141] [000140] In some embodiments, provided herein are A method for treating a disorder characterized by ULK kinase activity includes administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the intended compound), wherein the detection includes contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of phospho-ATG13 in the sample. In some embodiments, the contemplated method includes optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay before administration of the compound and comparing the level of phospho-ATG13 in the sample obtained before administration with the level of phospho-ATG13 in a sample obtained during or after the administration course. In some embodiments, the phospho-ATG13 is p-S318ATG13.

[0142] [000141] In some embodiments, provided herein are and detecting, during or after the course of administration (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the intended compound), engagement of the compound with a ULK kinase, wherein the detection is based, for example, on the level of phospho-ATG14 in the sample, on detecting inhibition of ULK kinase activity. -ATG14 antibody ELISA assay. In some embodiments, contemplated methods include optionally contacting a sample (including, but not limited to, tumor, blood, saliva, or tissue) obtained from a patient prior to administration of a compound with a phospho-ATG14 antibody ELISA assay, and comparing the level of phospho-ATG14 in the sample obtained prior to administration with the level of phospho-ATG14 in samples obtained during or after the course of administration. In some embodiments, the phospho-ATG14 is p-ATG14 Ser29.

[0143] [000142] In some embodiments, provided herein are A method of treating a disorder characterized by ULK kinase activity, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting engagement of the compound with ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the contemplated 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, contemplated methods comprise 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 a sample obtained during or after the administration course.

[0144] [000143] In some embodiments, provided herein are A method of treating a disorder characterized by ULK kinase activity, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting engagement of the compound with ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or 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, contemplated methods comprise 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 a sample obtained during or after the administration course.

[0145] [000144] The compounds provided herein can be administered to patients (animals and The compounds can be administered to animals (and humans) in dosages 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 particular 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 of ordinary skill in the art would recognize, and that the appropriate dosage will ultimately be at 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 pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0146] [000145] Treatment can continue for as long or as short a period as desired. The compound may be administered, for example, one to four times daily or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinitely. The treatment period can be terminated when the desired results are achieved.

[0147] Combination therapy [000146] A compound described herein, for example, a compound 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 a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically 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, a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more drugs in combination therapy can be administered at the same time, but this is not required. For example, the administration of the first drug (or combination of drugs) can precede the administration of the second drug (or combination of drugs) by a few minutes, a few hours, a few days, or a few weeks. Thus, two or more drugs can be administered within a few 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, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or more weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessary, that two or more drugs used in combination therapy be present in the patient's body at the same time.

[0148] [000147] Combination therapy is one or more drugs used in combination with the component drugs in different sequences. For example, when drug X and drug Y are used in combination, they can be administered one or more times sequentially in any combination, e.g., in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0149] [000148] In some embodiments, administration in combination with compounds provided herein The one or more additional therapeutic agents that may be administered may be a MAPKAP pathway inhibitor, such as a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, or a Ras inhibitor.

[0150] [000149] Exemplary MEK inhibitors include, but are not limited to, trametinib , selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts. Exemplary ERK inhibitors include but are not limited to ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and their pharmaceutically acceptable salts. Exemplary RAF inhibitors include but are not limited to LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and their pharmaceutically acceptable salts. Exemplary Ras inhibitors include but are not limited to AMG-510, MRTX849, and their pharmaceutically acceptable salts.

[0151] [000150] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents may include radiation therapy, anti-tumor therapy, anti-cancer drugs, anti-inflammatory ... These include immunotherapeutics including rabines, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalators, 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, anti-angiogenesis agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug conjugates (ADCs), immunomodulators, targeted therapies, cancer vaccines, and CAR-T cell therapies.

[0152] [000151] In some embodiments, the additional therapeutic agent may be, but is not limited to, an anti- Tubulin agents (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 intercalators or DNA topoisomerase inhibitors (e.g., 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-azacytadine (5-azacytadine), The chemotherapeutic agents may include cyclosporine, gemcitabine, and methotrexate.

[0153] [000152] In some other embodiments, the additional therapeutic agent is erlotinib, gefitinib, kinase inhibitors, including but not limited to, rifacilin, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, loxo292, larotrectinib, and quizartinib; Antiestrogens, including but not limited to moxifen, fulvestrant, anastrozole, letrozole, and exemestane; antiandrogens, 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; irinotecan, camptothecin, exemestane topoisomerase I inhibitors, including but not limited to satecan, and topotecan; topoisomerase II inhibitors, including but not limited to 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; bortezomib and carfilzomib; proteasome inhibitors including but not limited to tetracycline, lenalidomide, and pomalidomide; biologic agents including but not limited to trastuzumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, and tremelimumab; 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 DM1, DM4, MMAE, and MMAF.or therapeutic vaccines, including but not limited to antibody-drug conjugates (ADCs) with a payload of camptothecin, brentuximab vedotin and trastuzumab emtansine, radiation therapy, and sipuleucel-T.

[0154] [000153] In some embodiments, the additional therapeutic agent is pembrolizumab, nivolumab, or anti-PD-1 or anti-PDL-1 therapeutics including mab, atezolizumab, durvalumab, BMS-936559, or avelumab; anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453; anti-LAG3 therapeutics including but not limited to leratolimab, LAG525, or TSR-033; CD40 agonist therapeutics including but not limited to anti-4-1BB (anti-CD37, anti-TNFRSF9), SGN-40, CP-870, 893, or RO7009789; anti-CD47 therapeutics including but not limited to Hu5F9-G4; anti-CD20 therapeutics; anti-C D38 therapeutic agents include, but are not limited to, STING agonists, including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazole, anthracyclines, including but not limited to doxorubicin or mitoxantrone, hypomethylating agents, including but not limited to azacitidine or decitabine; or other immunomodulatory therapeutic agents, including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone.

[0155] [000154] In some embodiments, the additional therapeutic agent is goserelin and leuprolide. and wherein the compound is selected from luteinizing hormone-releasing hormone (LHRH) analogs including:

[0156] [000155] 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, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, 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 estrogens, bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 O4-(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-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin, 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 B B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, 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 colony-stimulating factor, histrelin, PEGylated Interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene , tositumomab, arsenic trioxide, cortisone, editronate ), mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, spegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0157] Pharmaceutical Compositions and Kits [000156] Another aspect of the present disclosure is a method for treating a pulmonary arthritis with a steroid drug, comprising administering to a subject a subject in need thereof a therapeutically effective amount of ...

[0010] Pharmaceutical compositions comprising the compounds disclosed herein are provided. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with one or more pharmaceutically 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 appropriate administration form in any particular case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral or subcutaneous administration.

[0158] [000157] Exemplary pharmaceutical compositions are in the form of pharmaceutical preparations, e.g., those containing the compounds described herein as an active ingredient. One or more of the compounds described herein may be used in solid, semi-solid, or liquid form, mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. The active ingredient may be formulated with a conventional non-toxic pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0159] [000158] To prepare solid compositions such as tablets, the main active ingredient is added to a pharmaceutical carrier, e.g. For example, conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, can be mixed to form solid preformulation compositions containing homogeneous mixtures of the compounds provided herein, or their non-toxic pharmaceutically acceptable salts. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0160] [000159] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) In the method, the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as hydroxybenzoates; (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0161] [000160] A tablet is 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 dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0162] [000161] Compositions for inhalation or insufflation may be prepared from pharmaceutically acceptable, aqueous or organic The liquid dosage forms for oral administration include solutions and suspensions in solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the 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.

[0163] [000162] The suspension may contain, in addition to the subject composition, for example, an ethoxylated isostearyl alcohol. The emulsion may also contain suspending agents such as sorbitol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0164] [000163] Formulations for rectal or vaginal administration may be presented as suppositories, This 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, suppository waxes or salicylates, which are solid at room temperature but become liquid at body temperature and thus melt in the body cavity and release the active agent(s).

[0165] [000164] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, and the like. These include creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0166] [000165] Ointments, pastes, creams, and gels may be used in addition to the subject compositions to treat animals and and excipients such as vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0167] [000166] Powders and sprays may contain, in addition to the subject composition, lactose, talc, silica, Sprays may also contain excipients such as aluminum hydroxide, calcium silicate 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.

[0168] [000167] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This can be achieved by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Ultrasonic nebulizers can be used to minimize exposure of the drug to shear, which can result in degradation of the compound contained in the subject composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on 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, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0169] [000168] Pharmaceutical compositions of the present disclosure suitable for parenteral administration may comprise one or more pharmaceutically acceptable The subject compositions include 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 before 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.

[0170] [000169] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions provided herein Examples of suitable carriers include water, ethanol, polyols (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. The 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.

[0171] [000170] In another aspect, the disclosed compounds and enteric materials, and their pharmaceutical compositions, Enteric pharmaceutical formulations are provided that include a commercially acceptable carrier or excipient. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluids at a specific pH. The small intestine is the portion 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 approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5.

[0172] [000171] Thus, the enteric material may be, for example, about 5.0, about 5.2, about 5.4, about 5 0.6, 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 methacrylic acid 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 copolymer, natural resins such as zein, shellac and copal colofolium collophorium), and several commercially available enteric dispersions (e.g., 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 readily determined in vitro. While the foregoing is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that will meet the objectives described herein.

[0173] [000172] Advantageously, the present disclosure provides a method for the treatment of cancer, for example, by a purchaser in need of treatment.

[0003] Kits for use in the manufacture of pharmaceuticals are provided. Such kits include an appropriate dosage form, such as those described above, and instructions describing how to use such dosage form to mediate, reduce, or prevent inflammation. The instructions instruct the purchaser or medical professional 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 a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a 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 to the plastic foil on the side 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 tablets or capsules can be removed from the blister pack by manually applying pressure to the depressions, thereby forming openings in the sheet at the locations of the depressions, and the tablets or capsules can then be removed through said openings.

[0174] [000173] 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 (a "daily dose"), the numbers of which correspond to the days in the regimen on which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, e.g., "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. [Example]

[0175] [000174] The compounds described herein may be prepared in accordance with the teachings contained herein and the art. These compounds can be prepared in a number of ways based on synthetic procedures known in the art, as described below. In describing synthetic methods, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected to be standard conditions for the reaction unless otherwise specified. Those skilled in the art of organic synthesis understand that the functionality present on various portions of the molecule must be compatible with the proposed reagents and reactions. Reaction Conditions Substituents that are incompatible with the formula (I) will be apparent to one skilled in the art, and alternative methods are indicated accordingly. Starting materials in the examples are either commercially available or readily prepared by standard methods from known materials.

[0176] [000175] 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, "dppf" is 1,1'-bis(diphenylphosphino)ferrocene, and "DMEM" is Dulbecco's Modified Eagle's medium, "DMSO" is dimethyl sulfoxide, "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, "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 hydroxybenzotriazole. 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, "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, "Pd2(dba)3" is tris(dibenzylideneacetone)dipalladium(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," understood to comprise the range of normal laboratory temperatures in the range of 15-25°C, and "satd." is saturated, "T3P" 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.

[0177] general chemistry [000176] Exemplary compounds described herein are shown in the following schemes, intermediate preparations, and and by the general synthetic methods set forth in the accompanying examples. [ka]

[0178] [000177] Exemplary methods for the preparation of pyrazoles are described in WO 2006 / 071940 and WO 2008 / 1311227, the contents of which are incorporated herein by reference in their entireties. 4 -L-substituted pyrazole amine DI is R 4 The R-substituted pyrazoles BI are accessible by condensation of hydrazine 4-1 (readily available to those skilled in the art) with 1,1,3,3-tetramethoxypropane AI to afford the R-substituted pyrazoles BI. Conditions for this transformation include heating in ethanolic HCl. Those skilled in the art will recognize that in some embodiments, the R-substituted pyrazoles BI may be obtained by condensation of hydrazine 4-1 (readily available to those skilled in the art) with 1,1,3,3-tetramethoxypropane AI to afford the R-substituted pyrazoles BI. 4It will be further appreciated that -L-substituted pyrazoles BI can be prepared by direct alkylation of pyrazoles. In some embodiments, pyrazoles BI are regioselectively nitrated to provide nitro-pyrazoles CI using standard conditions familiar to those skilled in the art. Finally, hydrogenation of nitro-pyrazoles CI using a hydrogenation catalyst such as palladium or nickel provides pyrazole amines DI.

[0179] [000178] In Scheme 1, R 4 Examples of suitable intermediates are illustrated by the table of intermediates below. Heterocyclyl with optional substituents, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m wherein m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0180] [000179] Single R2-substituted general pyrazole-amines DI-1 and D- I-2 (i.e., one R 2Additional examples of keto-esters AI-1 (where R is not hydrogen) are prepared as described in Scheme 2. Reaction of keto-ester AI-1 with either N,N-dimethylformamide dimethyl acetal or triethyl orthoformate / acetic anhydride affords AI-2 (where LG is a suitable leaving group required for the subsequent cyclization / pyrazole formation reaction). Reaction of AI-2 with hydrazine 4-1 (readily available to those skilled in the art) in the presence of acid primarily affords either BI-1 or its regioisomer BI-2. The regiochemistry of the cyclization is controlled under conditions (such as temperature and solvent) well known to those skilled in the art. BI-1 (R 2 Conditions for the synthesis of BI-1 (wherein CI-1 is not hydrogen) include LG in OEt in a protic solvent (such as ethanol) at low temperature (-10°C to RT) in the presence of an acid. Conditions for the synthesis of BI-2 include LG in NMe2 in a protic solvent (such as ethanol) at reflux in the presence of an acid. The ester of either BI-1 or BI-2 is then converted to the corresponding acid CI-1 or CI-2 using standard conditions known to those skilled in the art. Either CI-1 or CI-2 is converted to the corresponding amine DI-1 or DI-2 by Curtius rearrangement.

[0181] [000180] In Scheme 2, examples of LG include OMe, OEt, and N(CH3)2. Mi, R 2 Examples of R include alkyl and cycloalkyl, which may optionally be fluorinated; 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m wherein m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0182] [000181] Similar to Scheme 2, Scheme 3 shows the general preparation of amine DI-3. Pyrazole ester BI-3 is prepared by reaction of intermediate AI-3 with hydrazine 4-1 (readily available to one skilled in the art). In some embodiments, R 2 Part and R 3 The part is R 3 R 2 The esters BI-3 are independently varied to be the same as or different from the corresponding acids CI-3 using standard conditions known to those skilled in the art. The acids CI-3 are converted to the corresponding amines DI-3 under standard Curtius rearrangement conditions known to those skilled in the art.

[0183] [000182] In Scheme 3, R 2 and R 3 Examples of are independently alkyl and cyclo. alkyl, and the alkyl and cycloalkyl may optionally be fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m wherein m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0184] [000183] In some embodiments, commercially unavailable hydrazine 4-1 can be prepared according to the scheme 4 is readily prepared by two methods, as shown in Figure 4. One method involves diazotization of amine 4-2 followed by reduction using conditions familiar to those skilled in the art, for example, by treatment with Sn(II)Cl in the presence of a proton source. Alternatively, hydrazine 4-1 is available from the corresponding N-tert-butoxycarbonylhydrazine 4-3 by acid-catalyzed removal of the tert-butoxycarbonyl group. Those skilled in the art will recognize that in some embodiments, conversion of carbamate 4-3 to hydrazine 4-1 is also achieved in situ within the reaction sequence. Thus, carbamate 4-3 substitutes for hydrazine 4-1 in all schemes where hydrazine 4-1 is typically used in the presence of acid. N-tert-butoxycarbonylhydrazine 4-3 can be prepared by reductive amination using commercially available aldehyde or ketone 4-4 and tert-butylhydrazine carboxylate.

[0185] [000184] In Scheme 4, R 4 Examples of suitable intermediates are illustrated by the table of intermediates below. Heterocyclyl with optional substituents, and NR 6 R 9 wherein R 6 and R 9 Each of may independently be an alkyl group, and examples of L include -(C(R 10 )2) m wherein R 10 An example of is H, where m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to nitrogen, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0186] [000185] In some embodiments, the general pyrazole-amine DI-4 or D -I-5 can be prepared by two methods shown in Scheme 5. In this scheme, R 4 Examples of -L-bonds 5-1 or 5-2 are shown. One method involves alkylation of commercially available 5-1 with BI-4 (readily available to those skilled in the art) to afford nitropyrazoles CI-4 and / or CI-5 in the presence of a base (e.g., potassium carbonate, cesium carbonate, or sodium hydride) and a polar aprotic solvent (dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc.) at temperatures between ambient and 150 °C. An alternative preparation of DI-4 or DI-5 involves the Mitsunobu reaction of commercially available 5-2 with BI-4 to afford nitropyrazoles CI-4 and CI-5. It will be understood by those skilled in the art that, if produced as a mixture, CI-4 and CI-5 can be separated by SFC purification, crystallization, or chromatography. Finally, reduction of nitropyrazoles CI-4 and CI-5 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mildly reducing conditions such as zinc or iron and ammonium chloride, affords pyrazole-amines DI-4 and DI-5.

[0187] [000186] In Scheme 5, examples of LG include Cl and Br, and R 2 Examples of alkyl, cycloalkyl, alkoxy, halogen, and CN, wherein alkyl, cycloalkyl, or alkoxy may be optionally fluorinated; R 4 Examples of C(O)NR include heterocyclyl, C(O)NR, with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 , and N.R. 6 R 9 wherein R 6 and R 9 Each of may independently be H or an alkyl group, and examples of L include -(CH)m wherein m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0188] [000187] In some embodiments, the general pyrazole-amines DI-6 and D -I-7 is prepared as shown in Scheme 6. In this scheme, R 4 An example of the -L-bond 6-1 is shown. Alkylation of BI-4 (easily available to those skilled in the art) with 6-1 leads to a mixture of nitro-pyrazoles BI-5 and BI-6. These two regioisomers BI-5 and BI-6 can be separated by SFC purification, crystallization, or chromatography. Each isomer BI-5 or BI-6 can be activated using MsCl or TsCl to give BI-7 or BI-8 (where R is M or T), respectively. The amine R of OM or OT can be 4 Replacement with -H affords CI-6 or CI-7, respectively. Finally, reduction of nitro-pyrazoles CI-6 or CI-7 in the presence of a hydrogenation catalyst such as palladium, nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride affords pyrazole-amines DI-6 or DI-7.

[0189] [000188] In Scheme 6, examples of LG include Cl and Br, and examples of R include mesile. R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m wherein m is 2 or 3; and R 4 is N-bonded. [ka]

[0190] [000189] Scheme 7 shows the synthesis of general amines DI-8 and DI-9. Thus, the condensation of glyoxal with commercially available aldehydes in the presence of ammonium hydroxide gives R 2 This leads to the substituted imidazole AI-4. 4 Examples of the -L-bond 5-1 or 5-2 are shown. Nitration of imidazole AI-4 under conditions known to those skilled in the art (e.g., nitric acid / concentrated sulfuric acid at temperatures ranging from 0°C to 100°C) affords nitroimidazole BI-9. BI-9 is converted to a mixture of CI-8 and CI-9 by alkylation (5-1) or Mitsunobu reaction (5-2). In some embodiments, substituted nitroimidazoles CI-8 and CI-9 are available from AI-4 by either alkylation (5-1) or Mitsunobu reaction (5-2) to give BI-10. Subsequent nitration of BI-10 then affords CI-8 and CI-9. These two regioisomers, CI-8 and CI-9, can be separated by SFC purification, crystallization, or chromatography. Reduction of each nitro-imidazole CI-6 and CI-7 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding imidazole-amines DI-8 and DI-9, respectively.

[0191] [000190] In Scheme 7, examples of LG include Cl and Br, and R 2 Examples of alkyl and cycloalkyl, wherein alkyl and cycloalkyl may be optionally fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -wherein m can be 2 or 3 and L is N-bonded to the imidazole ring. [ka]

[0192] [000191] As illustrated in Scheme 8, in some embodiments, substituted thiazoles Amines DI-10 can be prepared from appropriately substituted thiazoles AI-5 (readily available to those skilled in the art). This method is described in WO 2006 / 072436, the contents of which are incorporated herein by reference in their entirety. Nitration of bromothiazole AI-5 using fuming nitric acid or nitric acid with sulfuric acid provides bromo-nitrothiazoles BI-11. The bromo functionality on BI-11 can be converted to various amines R using conditions familiar to those skilled in the art, such as Buchwald, Ullmann, or nucleophilic aromatic substitution reactions in the presence of TEA or KCO to provide CI-10. 4 -H, wherein R 4 is N-bonded. Suzuki reaction of commercially available or synthetic boronates T, including but not limited to other boronate salts (see Scheme 16), with BI-11 can be used to provide CI-10, where R 4is C-bonded. Finally, reduction of CI-10 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding thiazole-amine DI-10.

[0193] [000192] In Scheme 8, R 2 Examples of the alkyl, cycloalkyl, alkoxy, halides are alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of may independently be an alkyl group. [ka]

[0194] [000193] As illustrated in Scheme 9, in some embodiments, substituted thiazoles Amines DI-11 can be prepared from appropriately substituted thiazoles AI-5 (easily available to those skilled in the art). This method is described in WO 2009 / 158373, WO 2016 / 135163, and WO 2011 / 075515, the contents of which are incorporated herein by reference in their entireties. Nitration of bromothiazole AI-5 using fuming nitric acid or nitric acid with sulfuric acid affords bromo-nitrothiazole BI-11. The bromo functionality on BI-11 can be replaced with various linker (L) synthons using conditions familiar to those skilled in the art, such as carbonylation (CI-11a), Negishi (zinc-mediated coupling conditions, (CI-11b)), Sonogashira, or Heck coupling followed by appropriate reduction to give C—C bond CI-11c. CI-11a, CI-11b, and CI-11c can be reduced to the primary alcohol and then mesylated or tosylated to form CI-12. 4 Nucleophilic substitution of CI-12 with -H affords CI-13. Finally, reduction of CI-13 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride affords the corresponding thiazole-amine DI-11.

[0195] [000194] In Scheme 9, examples of LG include OT and OM, and examples of R include methyl and and ethyl, R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of the compounds have suitable optional substituents as illustrated by the table of intermediates below. heterocyclyl, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 1, 2, or 3. [ka]

[0196] [000195] In a similar reaction sequence as shown in Scheme 10, bromothiazole Synthesis of AI-6 (readily available to one skilled in the art) affords the thiazol-amine DI-12 shown in Scheme 10 (Science of Synthesis, 627, 2002).

[0197] [000196] In Scheme 10, R 2 Examples of are alkyl, cycloalkyl, alkoxy, halogen, or CN, alkyl, cycloalkyl, or alkoxy may optionally be fluorinated, R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of may independently be an alkyl group. [ka]

[0198] [000197] As illustrated in Scheme 11, in some embodiments, substituted thiazolidinyl groups are Bromothiazole DI-13 can be prepared from appropriately substituted thiazole AI-6 (readily available to those skilled in the art). This method is described in WO 2009 / 158373, WO 2016 / 135163, and WO 2011 / 075515, the contents of which are incorporated herein by reference in their entirety. Nitration of bromothiazole AI-6 using fuming nitric acid or nitric acid with sulfuric acid affords bromo-nitrothiazole BI-12. The bromo functionality on BI-12 can be converted to various R groups using conditions familiar to those skilled in the art, such as carbonylation (CI-15a), Negishi (zinc-mediated coupling conditions), Sonogashira or Heck coupling reactions, followed by reduction to afford C-C bond CI-15c. 4 CI-15a, CI-15b, and CI-15c can be reduced to primary alcohols and then mesylated or tosylated to form CI-16. 4 Nucleophilic substitution of CI-16 with -H affords CI-17. Finally, reduction of CI-17 in the presence of a hydrogen catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride affords the corresponding thiazole-amine DI-13.

[0199] [000198] In Scheme 11, examples of LG include OT and OM, and examples of R include methyl. and ethyl, R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of the compounds have suitable optional substituents as illustrated by the table of intermediates below. Heterocyclyl, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 1, 2, or 3. [ka]

[0200] [000199] Scheme 12 shows the substituted oxazolidinyl groups reported in WO2014 / 078378. The synthesis of various acid chlorides AI-7 is described in the literature, the contents of which are incorporated herein by reference in their entirety. 2 Reaction with substituted aminoalkylnitrile 12-1 (readily available to one skilled in the art) affords AI-8, which is converted to oxazole-amine DI-14 under acidic conditions such as acetic acid, sulfuric acid, or hydrochloric acid.

[0201] [000200] In Scheme 12, R 2 Examples of alkyl include alkyl and cycloalkyl. alkyl, cycloalkyl, or alkoxy may be optionally fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 0, 1, 2, or 3. [ka]

[0202] [000201] As shown in Scheme 13, some substituted oxazoles can be prepared by the reaction of Synl The diazoester AI-9 can be prepared from the 2-diazo-3-oxo-substituted carboxylic acid ester AI-9 as reported in [Edward] et al., 1996, 1171, the contents of which are incorporated herein by reference in their entirety. The diazoester AI-9, after treatment with primary amide 14-1 (readily available to those skilled in the art) under Rh-catalyzed coupling conditions, gives the amide BI-13. The intermediate BI-13 can be subjected to cyclodehydration conditions using a dehydrating reagent (e.g., POCl3, T3P, or Burgess's reagent) to give the oxazole ester CI-18. Hydrolysis of the oxazole-ester CI-18 affords the carboxylic acid CI-19, which is converted to the oxazole-amine DI-15 under a Curtius rearrangement using sodium azide or DPPA.

[0203] [000202] In Scheme 13, R 2 Examples of are alkyl, cycloalkyl, and alkoxy. alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 0, 1, 2, or 3. [ka]

[0204] [000203] In other embodiments, as shown in Scheme 14, oxazole-amines are DI-16 can be prepared from 2-haloxazole CI-20 as described in WO2012 / 033195, the contents of which are incorporated herein by reference in their entirety. C-I-20Reaction with affords 2-aminoalkyl substituted oxazoles CI-21, where R 4 is N-bonded. Suzuki reaction of CI-20 with commercially available or synthetic boronates T, including but not limited to other boronate salts (see Scheme 16), can be used to provide CI-21, where R 4 is C-bonded. Hydrolysis of the oxazole-ester CI-21 affords the carboxylic acid, which can be converted to the oxazole-amine DI-16 under a Curtius rearrangement using sodium azide or DPPA.

[0205] [000204] In Scheme 15, R 2 Examples of are alkyl, cycloalkyl, or alkoxy. alkyl, cycloalkyl, or alkoxy may be optionally fluorinated; R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of R can independently be an alkyl group; 6 and R 9 Each of may independently be an alkyl group. [ka]

[0206] [000205] In some embodiments, the general triazole-amine DI-17 and DI-18 and DI-19 are prepared as shown in Scheme 15. In this scheme, R 4Examples of the -L-bond 5-1 or 5-2 are shown. Triazole BI-14 can be prepared from dinitro-ester AI-10 by reaction with aldehyde 15-1 (easily available to those skilled in the art) using the procedures described in Asian J. of Chem., 2014, 26, 4744 and Hanneng Cailliao, 2008, 16, 49, the contents of which are incorporated herein by reference in their entirety. Alternatively, BI-14 can be prepared by nitration of AI-11. BI-14 is converted to a mixture of CI-22 and CI-23 by alkylation (5-1) or Mitsunobu reaction (5-2). These two regioisomers, CI-22 and CI-23, can be separated by SFC purification, crystallization, or chromatography. Reduction of nitro-triazoles CI-22 or CI-23 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding triazole-amines DI-17 and DI-18, respectively.

[0207] [000206] In Scheme 15, R 2 Examples of are alkyl, cycloalkyl, alkoxy, halogen, or CN, alkyl, cycloalkyl, or alkoxy may optionally be fluorinated, R 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 wherein R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 2 or 3. [ka]

[0208] [000207] Scheme 16 illustrates the general synthesis of commercially unavailable boronic acids / boronic esters T. We demonstrate a convenient preparation of these compounds. These compounds can be readily prepared from substituted carboxylic acids. The carboxylic acid can be activated with 2-hydroxyisoindoline-1,3-dione in the presence of a coupling reagent (e.g., DCI or EtN / HATU) to give Q. Intermediate Q is converted to the boronic ester T by nickel-catalyzed decarboxylative borylation with methyllithium and the [B2pin2Me]Li complex premixed with B2pin2 (Science, 2107, 356, 1045 and JACS, 2016, 138, 2174, the contents of which are incorporated herein by reference in their entirety).

[0209] [000208] In Scheme 16, R 4 Examples of suitable intermediates are illustrated by the table of intermediates below. Examples of L include alkyl, cycloalkyl, and heterocyclyl, each having an optional substituent such as -(CH2) m wherein m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the boronic ester, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L. [ka]

[0210] [000209] Scheme 17 shows the general preparation of LI-1 and LI-2. 2,4-Dichloro-5-iodopyrimidine reacts with TMSCHF in the presence of CuI and CsF in a solvent such as NMP or DMF to produce difluoromethylpyrimidine L-II-1 (US 2015 / 0284341, the contents of which are incorporated herein by reference in their entirety). Difluoromethylpyrimidine L-II-1 can be obtained by heating at temperatures below 10°C. The methylthiopyrimidine LI-1 can be converted to methylthiopyrimidine LI-1 by treatment with sodium thiomethoxide and zinc chloride in diethyl ether at temperatures below 200°C (WO 2012 / 110773, the contents of which are incorporated herein by reference in their entirety). In a manner similar to that of LI-1, trifluoromethylpyrimidine LI-2 can be prepared from commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine, L-II-2. [ka]

[0211] [000210] Scheme 18 shows the R 1 wherein the sulfonylpyrimidine L can be cycloalkyl A general preparation of -III (t=2) is shown. Treatment of 5-bromo-2-chloro-4-(methylthio)pyrimidine with commercially available boronic esters / boronic acids / trifluoroborates in the presence of a palladium catalyst (Suzuki coupling) affords R 1 Substituted thiopyrimidine L-III (t=0) is obtained. 1 includes cycloalkyl, such as cyclopropyl. The intermediate thiopyrimidine L-III (t=0) is converted to the sulfonylpyrimidine L-III (t=2) by standard oxidation, for example with mCPBA. [ka]

[0212] [000211] Scheme 19 shows the general preparation of H(I-XIII) by known methods. Treatment of commercially available lactams / cyclic carbamates / oxolactams / cyclic ureas / diazepanones E (ZH) with Boc (tert-butoxycarbonyl group) protected bromo compound F in the presence of a base, e.g., sodium hydride or potassium tert-butoxide, affords G. The Boc group in G is a protecting group that is removed upon exposure to an acid, e.g., HCl or TFA. Compounds H-I through H-XIII are prepared by this method.

[0213] [000212] In Scheme 19, 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 wherein R 6 is alkyl, n can be 2, 3, or 4, and each R 34 can independently be H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl. [ka]

[0214] [000213] In another embodiment, lactam H-XIV can be prepared as illustrated in Scheme 20. H-XIV can be prepared via a one-step process from DBU, which is hydrolyzed with potassium hydroxide in a solution of methanol and water at ambient temperature to give H-XIV. [ka]

[0215] [000214] Scheme 21 shows the general preparation of key intermediates J and K. Intermediate J can be prepared from H (either the free base or the HCl salt) and methylthiopyrimidine LI in the presence of an organic base (e.g., triethylamine or DIEA), optionally with heating, to afford key intermediate J. Similarly, key intermediate K can be prepared from H using either L-II or L-III.

[0216] [000215] In Scheme 21, 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 wherein R 6 is alkyl, n can be 2, 3, or 4, and each R 34 can independently be H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl group. [ka]

[0217] [000216] Scheme 22 shows a general preparation of the key pyrimidine intermediate M. Treatment of H with commercially available chloroiodopyridine under Buchwald-Hartwig coupling conditions (CsCO, Xantphos, and Pd(OAc)), performed in an aprotic solvent (e.g., DME, DMF, DMSO, or NMP) at temperatures ranging from 80°C to 140°C, affords the key intermediate M.

[0218] [000217] In Scheme 22, R 1 is optionally composed of Br, Cl, one or more fluorine atoms q can be 0, 1, 2, or 3; r can be 2, 3, or 4; and V can be C(R 34 )2, O, or NR 6 R 6 is alkyl, n can be 2, 3, or 4, and each R34 can independently be H, C1-C6 alkyl, or two R 34 can be taken together to form a cycloalkyl. [ka]

[0219] [000218] Scheme 23 shows the general preparation of compounds of formula IA from substituted DIs. The preparation of formula IA can be achieved from key intermediates K and J. The nucleophilic substitution reaction of amine D with K is typically carried out in a polar solvent, optionally in the presence of an acid, such as, for example, 4N HCl in 1,4-dioxane, at temperatures ranging from ambient to 150°C, in some embodiments using microwave heating, to provide compounds of formula IA. The commercially unavailable compound DI can be readily prepared (see Schemes 1-16). An alternative general synthesis of formula II is via a two-step process by first converting J (t=0) to sulfoxide J (t=1) by oxidation using various oxidizing agents, such as mCPBA. The sulfoxide reacts with amine DI via a nucleophilic substitution reaction, typically carried out in a polar solvent, optionally in the presence of an acid, such as, for example, 4N HCl or pTSA in 1,4-dioxane, at temperatures ranging from ambient to 150°C, in some embodiments using microwave heating, to provide compounds of formula IA. If formula IA contains a protecting group, such as a Boc group, the protecting group can be deprotected under acidic conditions to provide formula IA (free amine or salt). Further treatment of formula IA (free base or 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) provides 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 provide N-substituted formula IA. [ka]

[0220] [000219] Scheme 24 shows the general preparation of compounds of formula IB. Preparation of Formula IB can be achieved by a Buchwald-Hartwig coupling reaction with DI and M. Many amines DI that are not commercially available can be readily prepared (see Schemes 1-16). Similar to that shown in Scheme 24, reductive alkylation, acylation, and sulfonylation can be carried out to afford formula IB after deprotection of formula IB containing a protecting group such as a Boc group.

[0221] General Method A: Mitsunobu Reaction: Intermediate C1. [ka] [000220] tert-Butyl 4-hydroxypiperidine in dry THF (300 mL) A solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (29 g, 146 mmol) and 4-nitro-1H-pyrazole (15 g, 132 mmol) was treated with triphenylphosphine (52 g, 199 mmol). The mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (40 mL, 199 mmol) was added dropwise and stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was then quenched with water (200 mL). The resulting solution was extracted with EtOAc (3 × 100 mL), and the combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–5% MeOH / DCM, 10 CV) to afford tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (8.0 g, 20% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.94(s, 1H),8.27(s,1H),4.42-4.48(m,1H),3.97-4.10(m,2H),2.89(brs,2H),2 .02(d,J=12.5Hz,2H),1.80(m,2H),1.40(s,9H);MS(ESI)m / z:297.4(M+H + ).

[0222] General Method B: Boc Group Deprotection and Reductive Amination: Intermediate C4. [ka] [000221] (A) tert-Butyl 4-(4-nitro-1H- A solution of 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (17 g, 57 mmol) was treated with 4 N HCl in 1,4-dioxane (90 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with EtO (100 mL) followed by pentane (100 mL). The solid was filtered and dried under vacuum to give 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (12.5 g, 94% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.89(s,1H),8.25(s,1H),4.28(m,1H),3.21(m,2H),2.55(m,2H),1.93(m,2H),1.76(m,2H);MS(ESI)m / z:197.34(M+H + )

[0223] [000222] (B) 4-(4-nitro-1H-pyrazoline)-2 ... A solution of 1-isopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (12.5 g, 54 mmol) was treated with acetone (24 g, 323 mmol). The reaction mixture was continuously stirred at 0° C. for 15 minutes, then sodium cyanoborohydride (22 g, 323 mmol) was added in small portions and stirred at room temperature for 24 hours. The reaction mixture was concentrated, and then the residue was treated with a saturated solution of NaHCO (100 mL). The solution was extracted with DCM (3×100 mL), and the combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-isopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (11.5 g, 90% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 9.92(s,1H),8.27(s,1H),4.20(m,1H),2.86(m,2H),2.72(m,1H),2.24(m,2) H),2.01(m,2H),1.89(m,2H),0.98(d,J=6.4Hz,6H);MS(ESI)m / z:239.3(M+H + ).

[0224] General Method C: Boc Group Deprotection and Alkylation: Intermediate C7. [ka] [000223] (A) tert-Butyl 4-(4-nitro-1H- A solution of 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (17 g, 57 mmol) was treated with 4 N HCl in 1,4-dioxane (90 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with EtO (100 mL) followed by pentane (100 mL). The solid was filtered and dried under vacuum to give 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (12.5 g, 94% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6):δ 8.89(s,1H),8.25(s,1H),4.28(m,1H),3.21(m,2H),2.55(m,2H),1.93(m,2H),1.76(m,2H);MS(ESI)m / z:197.34(M+H + ).

[0225] [000224] (B) 4-(4-nitro-1H-pyrazole-1-) in MeCN (5 mL) A mixture of 4-(4-nitro-1H-pyrazol-1-yl)-1-(propan-2-yl)piperidine hydrochloride (0.24 g, 0.96 mmol), 2-iodopropane-1,1,1,2,3,3,3-d7 (0.22 g, 1.2 mmol), and potassium carbonate (0.66 g, 4.8 mmol) was heated to 90 °C for 2 h. The mixture was cooled to room temperature, treated with water and brine, and extracted with EtOAc (3 × 15 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified via silica gel column chromatography (2–8% MeOH / DCM, 16 CV) to afford 4-(4-nitro-1H-pyrazol-1-yl)-1-(propan-2-yl)piperidine (0.18 g, 76% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.91(s,1H),8.25(s,1H),4.15-4.21(m,1H),2.86(d,J=11.5Hz,2H),2.22 (m,2H),2.01(d,J=11.9Hz,2H),1.85-1.93(m,2H);MS(ESI)m / z:246.2(M+H + ).

[0226] General Method D: Alkylation and Mesylation: Intermediate C29. [ka] [000225] (A) 3-methyl-4-nitro-1H- in acetonitrile (200 mL) A solution of pyrazole (15 g, 118 mmol) was treated with 2-bromoethan-1-ol (16 g, 130 mmol) and potassium carbonate (48.8 g, 354 mmol). The reaction mixture was heated at 90° C. for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by SFC purification to give 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol. 1 H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 4.96 (t, J = 5.2, Hz, 1 H), 4.12 (t, J = 5.2 Hz, 2 H), 3.73 (t, J = 5.2 Hz, 2 H), 2.42 (s, 3 H); MS (ESI) m / z: 172.13 (M + 1).

[0227] [000226] (B) 2-(3-methyl-4-nitro-1H-pyrazol-2-yl)propanol in DCM (50 mL) A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol (5.0 g, 29 mmol) was treated with triethylamine (5.8 g, 58 mmol) followed by methanesulfonyl chloride (5.0 g, 44 mmol) under a N atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with cold water (20 mL). The solution was extracted with DCM (2 × 200 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate (6.0 g, 83% yield) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.88(s,1H),4.57(t,J=5.2,Hz,2H),4.46(t,J=5.2Hz,2H),3.32(s,3H),2.45(s,3H);MS(ESI)m / z:250.19(M+H) + ).

[0228] General Method E: Nucleophilic Substitution Reaction: Intermediate C30. [ka] [000227] 2-(3-methyl-4-nitro-1H-pyrazoline) in dry THF (70 mL) A solution of N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate (C29, 5.0 g, 20 mmol) was treated with potassium carbonate (3.8 g, 28 mmol) and 2N dimethylamine in THF (60 mL, 12 mmol) under a N atmosphere at 10 °C. The reaction mixture was quenched with cold water (20 mL). The solution was extracted with ethyl acetate (3 × 100 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-amine (1.9 g, 48% yield). 1 H NMR (400 MHz,DMSO-d6):δ 8.77(s,1H),4.17(t,J=6.4,Hz,2H),2.64(t,J=6.4Hz,2H),2.41(s,3H),2.15(s,6H);LC-MS(ESI)m / z:199.2(M+H + ). [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

[0229] Preparation of intermediate C38: [ka] [000228] (A) 5-methyl-4-nitro-1H-pyrazole in DMF (15 mL) A solution of (2.0 g, 16 mmol) was treated with sodium hydride (0.94 g, 24 mmol) in small portions under Ar at 0 °C for 15 min. The mixture was stirred at room temperature for 2 h, and then methyl 2-bromo-2-methylpropanoate (4.3 g, 24 mmol) was added. The reaction mixture was continued stirring at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (100 mL), and the solution was extracted with EtOAc (2 x 80 mL). The combined organics were washed with water (80 mL), 10% aqueous LiCl solution (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (2.9 g, 81% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.98(s,1H),3.65(s,3H),2.42(s,4H),1.78(s,6H);LC-MS m / z:228.2(M+H + ).

[0230] [000229] (B) 2-Methyl-2-(3-methyl-4-nitro)propanol in THF (40 mL) A solution of methyl 1H-pyrazol-1-yl)propanoate (2.9 g, 13 mmol) was treated with a solution of lithium hydroxide hydrate (0.54 g, 13 mmol) in water (10 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with water (60 mL), and acidified to pH 4 with 1N aqueous HCl. The resulting suspension was filtered and resuspended in water (2 × 10 mL). The solid was washed with 10 mL of HCl and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.2 g, 81% yield) as a white solid. LC-MS m / z: 214.2 (M+H + ).

[0231] [000230] (C) 2-Methyl-2-(3-methyl-4-nitro)propanol in DCM (30 mL) A suspension of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.3 g, 11 mmol) was treated dropwise with DMF followed by oxalyl chloride (2.8 mL, 32 mmol). The suspension was stirred at room temperature for 3 hours, and then the clear solution was concentrated. The residue was dissolved in THF (30 mL), and the solution was slowly added to a solution of NH4OH (10 mL / water (40 mL)). The suspension was stirred at room temperature for 1 hour, and then concentrated. The suspension (approximately 10 mL) was diluted with water (50 mL), and the solid was filtered, washed with water, and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.1 g, 92% yield). LC-MS m / z: 213.2 (M+H) + ).

[0232] General Method F: Reduction to give intermediate D9. [ka] [000231] N,N-dimethyl-2-(3-methyl-4-dimethylamino)-N ... A solution of 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-amine (C30, 1.9 g, 9.5 mmol) was treated with Pd / C (1.9 g, 10% w / w, 50% water). The reaction mixture was stirred at room temperature under hydrogen balloon pressure (1 atm) for 6 hours. The mixture was filtered through a pad of Celite and washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to give 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-amine (1.5 g, 94% yield). 1 H NMR(400 MHz,DMSO-d6):δ 7.02(s,1H),6.86(s,1H),4.99(m,2H),3.78(brs,2H),2.51(m,2H),2.13(s,6H);LC-MS m / z:155.2(M+H + ). [Table B-1] [Table B-2] [Table B-3] [Table B-4] [Table B-5] [Table B-6] [Table B-7]

[0233] General Method G: Alkylation and deprotection of the Boc protecting group: Intermediate H-VIII-1. [ka] [000232] 1,4-oxazepan-5-one ( A solution of 10 g (87 mmol) of 1,2-dichloromethane (1.0 g, 87 mmol) was treated in portions with sodium hydride (3.0 g, 130 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes, and then tert-butyl (3-bromopropyl)carbamate (21 g, 87 mmol) was added. The solution was continued to stir from 0° C. to room temperature for 16 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (200 mL), and 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 product was purified by silica gel column chromatography (40-50% EtOAc / hexane, 15 CV) to afford 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 4 N HCl in 1,4-dioxane (4 equiv.). The mixture was stirred at room temperature for 3 h, concentrated, and dried under high vacuum to afford 4-(3-aminopropyl)-1,4-oxazepan-5-one HCl salt (100% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.09(brs,3H),3.62(m,4H),3.49(m,2H),3.35(t,J=6.8Hz,2H),2.73(m,2H),2.62(t,J=4.8Hz,2H),1.78(m,2H). LC-MS(ESI)m / z:173.2(M+H + ). [Table C]

[0234] Preparation of Intermediate H-XIV: 1-(3-aminopropyl)azepan-2-one [ka] [000233] DBU (22 g, 145 m) in MeOH:HO (1:1) (130 mL) A suspension of 1-(3-aminopropyl)azepan-2-one (21 g, 85% yield) was treated with KOH (12 g, 217 mmol) at 0° C. under a N atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The solution was extracted with 10% MeOH in DCM (3×250 mL), and the combined organic extracts were 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=3.5Hz,2H),3.31(t,J=4.4Hz,2H),2.68(t,J=6.5Hz,2H),2.51(t,J=5.8Hz,2H),1.70(m,2H),1.65(m,8H);LC-MS(ESI)m / z:171.4(M+H) + ).

[0235] Intermediate L-III-1: Preparation of 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine [ka] [000234] 5-Bromo-2-chloro- in toluene:H2O (9:1) (650 mL) A suspension of 4-(methylthio)pyrimidine (25.0 g, 105 mmol) and cyclopropylboronic acid (13.7 g, 158 mmol) was treated with KPO (66.7 g, 315 mmol) and added. The reaction mixture was purged with nitrogen for 20 minutes, and then tricyclohexylphosphine (5.9 g, 21 mmol) and Pd(OAc) (2.35 g, 10.50 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product 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. 1H 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 + ). 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 NaHCO (2 × 40 mL). The organic layer was dried over anhydrous NaSO, 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 + ).

[0236] Intermediate LI-2: Preparation of 4-chloro-2-(methylthio)-5(trifluoromethyl)pyrimidine [ka] [000235] 2,4-Dichloro-5-(trifluoromethyl) A solution of 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, 0.46 mol) was treated dropwise with ZnCl (1.0 N in ether) (555 mL, 0.56 mol) at 0 °C, and the reaction mixture was stirred for 2 h. Sodium thiomethoxide (49 g, 0.94 mol) was added at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 48 h. The reaction mixture was quenched with 2 N HCl in an ice-water bath, and then the solution was extracted with EtO (3 × 500 mL). The combined organic extracts were washed with water (500 mL), dried over anhydrous NaSO, 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, DM SO-d6): δ 9.01(s 1H), 2.62(s 3H).

[0237] [000236] These three intermediates are commercially available. [ka]

[0238] General Method H: Substitution Reaction: Intermediate J-7. [ka] [000237] 4-(3-aminopropyl) 1,4-oxazepane in DMF (60 mL) A solution of 1,3-dichloro-5-methyl-pyrimidine hydrochloride (H-VIII-1, 3.0 g, 17.4 mmol) was treated with DIEA (15.5 ml, 87.2 mmol) at 0 °C and stirred for 15 minutes. 4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (LI-2, 0.0 g, 26.2 mmol) was then added and stirring was continued from 0 °C to room temperature for 16 hours. The reaction mixture was quenched with ice water (120 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40-50% EtOAc / hexane, 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(400MHz,DMSO-d6):δ 8.25(s,1H),7.52(brs,1H),3.64(m,4H),3.47(m,2H),3.42(m,2H),3.32(m,2H) ),2.63(t,J=4.8Hz,2H),2.47(s,3H),1.68(m,2H);LC-MS(ESI)m / z:365.3(M+H + ). [Table D-1] [Table D-2] [Table D-3]

[0239] General Method I: Pd Coupling Reaction Intermediate M-1. [ka] [000238] 1-(3-aminopropyl)piperidine-2- in toluene (180 mL) A mixture of PdCl(dppf) hydrochloride (9.0 g, 29 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (6.2 g, 32 mmol) was treated with cesium carbonate (23.9 g, 73 mmol). The mixture was purged with nitrogen gas for 15 minutes. . DCM (2.4 g, 2.9 mmol) was added, and the mixture was purged with nitrogen gas for an additional 5 min. The seal tube was closed and heated conventionally in a preheated oil bath at 90 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40–45% EtOAc / hexane, 10 CV) to give a brown solid. To the residue was obtained 1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one (2.6 g, 26% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ8.18(s,1H),6.99(brs,1H),6.88(s,1H),3.29(m,2H),3.24(m,4H),2.22(m,2H),1.70(m,6H);LC-MS(ESI)m / z:336.1(M+H)+ ). [Table E]

[0240] General method J: Oxidation: Intermediate J-14. [ka] [000239] 4-(3-((2-(methylthio)-5-methyl ... A solution of 4-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one (J-7, 3.0 g, 8.2 mmol), m-CPBA (2.0 g, 11.5 mmol) was added and stirred from 0 °C to room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2 × 90 mL). The organic layer was dried over anhydrous NaSO 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 semi-solid. 1 H NMR(400 MHz,DMSO-d6):δ8.59(s,1H),7.94(brs,1H),3.60(m,4H),3.45(m,4H),3.3 6(m,2H),2.88(s,3H),2.63(m,2H),1.70(m,2H);LC-MS(ESI)m / z:381.3(M+H + ). [Table F]

[0241] General Method K: Substitution Reaction A: Example 80. [ka] [000240] 1-(3-(((2,5-dichloropyrimidine-4) in EtOH (3 mL) A mixture of methyl-1-(1-methylpiperidin-4-yl)amino)propyl)azepan-2-one (K-16, 0.06 g, 0.19 mmol) and methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine hydrochloride (D11, 0.044 g, 0.19 mmol) was treated with 4.0 N HCl in 1,4-dioxane (0.047 mL), and the reaction mixture was then heated at 90° C. for 15 hours. The solution was concentrated under reduced pressure. The residue was treated with EtOAc and sonicated. The solid was filtered, treated with CH3CN, and stirred at room temperature for 3 hours. The solid was filtered and washed with CH3CN to give the desired product, which was treated with MP carbonate resin (150 mg, 3.14 mmol / g loading, 0.47 mmol, 2.5 equiv.) in MeOH (5 mL). The solution was stirred at room temperature for 2 hours. The resin was removed by filtration and washed with MeOH. The filtrate was concentrated, and the residue was treated with CHCN:HO (1:1, 3 mL) and lyophilized to give 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one (42 mg, 46% yield). 1 H NMR (400 MHz,DMSO-d6):δ8.28(brs,H),7.81(s,1H),7.79(s,1H),7.04(s,1H),3.95(m,1H),3.31-3.30(m,4H),2.80(m,2H),2 .42(m,2H),2.17(s,3H),2.08(s,3H),1.75-2.00(m,8H),1.63-1.68(m,4H),1.53(m,4H);LC-MS(ESI)m / z:476.4(M+H + ).

[0242] General Method L: Substitution Reaction B and Deprotection of the Boc Nitrogen Protecting Group: Example 83. [ka] [000241] 1-(3-(((2-(methylsulfonyl)methyl)-2-methylpropional in dry DMF (7 mL, in molecular sieves 3 Å) A solution of 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (D-10, 0.43 g, 1.5 mmol) and tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (J-12, 0.53 g, 1.4 mmol) was treated with 4.0 N HCl in 1,4-dioxane (0.11 mL), and the reaction mixture was heated at 80° C. for 15 hours. The mixture was concentrated under high vacuum, and the residue was dissolved in 1,4-dioxane (5 mL). 4.0 N HCl in 1,4-dioxane (0.35 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the crude product was purified by reverse-phase column chromatography (0-40% CHCN / HO (0.1% FA), 15 CV) to give 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)piperidin-4-yl)amino)propyl)azepan-2-one (0.57 g, 82% yield). 1 H NMR(400 MHz,DMSO-d6):δ8.94(brs,1H),8.30(s,1H),8.08(s,1H),7.84(brs,1H),7.07(brs,1H),4.18(brm,1H),3.31(brm,4H),3.17(m,2H) ,2.77(m,2H),2.42(s,3H),2.26(m,2H),2.11(m,4H),1.97(m,2H),1.84(m,2H),1.67(m,4H),1.54(m,4H);LC-MS(ESI)m / z:495.4(M+H + ).

[0243] General Method M: Reductive Alkylation: Example 90. [ka] [000242] (1-(3-((2-((3-methyl-1- A mixture of (piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one (83, 0.10 g, 0.20 mmol), acetaldehyde (0.1 mL, 1.8 mmol), and acetic acid (2 drops) was treated with sodium cyanoborohydride (0.025 g, 0.40 mmol). The mixture was stirred at room temperature for 16 hours. The solution was quenched with brine and then extracted with EtOAc (2 × 25 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (0-40% CHCN / HO (0.1% FA), 15 CV) to give 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one (46 mg, 43% yield). 1 H NMR(400 MHz,DMSO-d6):δ8.91(brs,1H),8.08(s,1H),7.85(brs,1H),7.06(brs,1H),4.02(brm,1H),3.32(m,7H),2.99(m,2H),2.43 (m,4H),2.10(m,4H),1.92(m,2H),1.88(m,2H),1.65(m,4H),1.49(m,4H),1.04(t,J=7.4Hz,3H);LC-MS(ESI)m / z:523.4(M+H) + ).

[0244] General Method N: Pd Coupling Reaction Example 171. [ka] [000243] 4-Methyl-1-(1-methylpiperazinyl)propanol in 1,4-dioxane (2.0 mL) A mixture of (lysin-4-yl)-1H-pyrazol-3-amine (D23, 0.076 g, 0.39 mmol), 1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one (M-1, 0.12 g, 0.36 mmol), and cesium carbonate (0.23 g, 0.71 mmol) was sparged with Ar, treated with Pd(dba) (0.033 g, 0.039 mmol) and Xantphos (0.041 g, 0.071 mmol), sparged again with Ar, capped, and heated at 85 °C for 16 h. The mixture was cooled to room temperature, diluted with brine, and extracted with DCM (3 × 15 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified via reverse-phase column chromatography (5-10% MeCN / HO (0.1% FA)) to afford 1-(3-((2-((4-methyl-1-(1-ethylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one (0.043 g, 24% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ9.12(brs,1H),8.13(s,2H),7.13(brs,1H),4.10(s,2H),3.72(m,2H),3.29- 3.44(m,6H),2.17(s,3H),1.92(s,6H),1.77(m,2H),1.68(m,2H);LC-MS(ESI)m / z:481.2(M+H + ).

[0245] Synthesis of Example 172: [ka] [000244] 2-Methyl-2-(3-methyl-4-((4-( A mixture of (3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide (125, 0.11 g, 0.22 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.562 g, 0.88 mmol) was treated with triethylamine (0.12 mL, 0.88 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 solution (40 mL) and stirred for several minutes. The layers were separated, the aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0-100% EtOAc / DCM, 10 CV) to give 2-methyl-2-(3-methyl-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (0.069 g, 65% yield). 1 H NMR(400 MHz,DMSO-d6):δ8.48(s,1H),7.93(s,1H),7.45(s,1H),6.67(s,1H),6.15(t,J=6.0Hz,1H),3.89-3.95(m,1H),3.28(m,2H),3.19-3.23(m ,2H),3.08(q,J=6.2Hz,2H),2.81(d,J=11.0Hz,2H),2.20(t,J=6.2Hz,2H),2.17(s,3H),1.99(m,2H),1.92(m,4H),1.89(s,3H),1.68(m,6 H);LC-MS(ESI)m / z:494.2(M+H + ). [Table G-1] [Table G-2] [Table G-3]

Table G-4

Table G-5

Table G-6

Table G-7

Table G-8

Table G-9

Table G-10

Table G-11

Table G-12

Table G-13

Table G-14

Table G-15

Table G-16

Table G-17

Table G-18

[0246] Example 174. Biochemical assays of ULK1.2 [000245] ULK1 kinase activity is continuously monitored by the ATP hydrolysis-dependent oxidation of NADH. The ATP concentration was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 19 nM ULK1 (Eurofins catalog number 14-959), 0.25 mg / mL myelin basic protein, 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 MgCl, 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 continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. Reaction rates at each compound concentration 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) MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLH SKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPV PVPSYPSSGSGSSSSSSSTSHLAS

[0247] Example 175. Biochemical Assays of ULK1.3 [000246] ULK1 kinase activity is continuously monitored by ATP hydrolysis-dependent oxidation of NADH. The activity of ULK1 was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay (e.g., Schindler et al., Science (2000) 289:1938-1942) that monitors the activity of ULK1. The assay was performed in a 384-well plate (final volume 100 μL) using 0.1 nM ULK1 (from Beryllium), 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 assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% 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 continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. Reaction rates at each compound concentration 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 using software routines in Prism (GraphPad software). ULK1 protein sequence (residues 1-283, SEQ ID NO:2) MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKP QNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS

[0248] Example 176. Biochemical assay of ULK2 [000247] ULK2 kinase activity is continuously monitored by the ATP hydrolysis-dependent oxidation of NADH. The ATP content was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay (e.g., Schindler et al., Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (final volume 100 μL) using 9.7 nM ULK2 (Eurofins catalog number 14-772), 0.25 mg / mL myelin basic protein, 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 MgCl, 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 continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). 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 by fitting a four parameter sigmoidal curve to the data using Prism (GraphPad software). ULK2 protein sequence (N-terminal GST and His-tagged residues 1-306, SEQ ID NO: 3) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFED RLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSI NKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCG SPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH Table 1. Inhibition of biochemical activity of ULK1 and ULK2 kinases by exemplary compounds of Table G. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0249] [000248] In Table 1, "+" indicates an IC of greater than 1 nM and less than or equal to 25 nM. 50refers to "++ " is an IC greater than 25 nM and less than or equal to 100 nM 50 "+++" indicates an IC greater than 100 nM and less than or equal to 500 nM 50 "++++" indicates IC greater than 500nM 50 Refers to...

[0250] Example 177. Cellular inhibition of ULK kinase substrate ATG13 protein pATG13 levels in mutant KRas A549 cells after treatment with ULK inhibitors in combination with trametinib [000249] A549 (KRAS mutant) human lung cancer cells (6,000 cells / well) Cells were added to 50 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a 384-well tissue culture-treated plate 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 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). 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.

[0251] [000250] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured using EL Measured by ISA method. Total ATG13 antibody (Cell Signaling catalog no. The wells were coated with ELISA wash buffer (Biolegend Catalog No. 13273). The plates were incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Catalog No. 421601). The wells were then blocked with Assay Diluent (Biolegend Catalog No. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Catalog No. 600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Catalog No. 21140) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog number 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 analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. 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.

[0252] Example 178. Mutant KRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in MiaPaCa-2 cells [000251] MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were cultured at 10% Cells were added to 50 μL of prewarmed DMEM medium supplemented with characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin, and 2.5% horse serum in a 384-well tissue culture-treated plate and grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to 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 plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed 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.

[0253] [000252] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured using EL Measured by ISA. Total ATG13 antibody (Cell Signaling catalog no. 13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend catalog no. 421601). The wells were then blocked with assay diluent (Biolegend catalog no. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog no. 600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher catalog no. 21140) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. Plate We The plates were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog no. 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 analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). The signal was first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. The background-corrected absorbance at 450 nm from the 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.

[0254] Example 179. Mutant KRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in HCT-116 cells [000253] HCT-116 human colon cancer cells (10,000 cells / well) were cultured in 10% 50 μL of pre-warmed DMEM medium supplemented with characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin was added to a 384-well tissue culture-treated plate and grown overnight at 37°C, 5% CO2, and 95% humidity. The following day, 10 μL of medium containing trametinib or DMSO as a control was added to 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 well. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed 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.

[0255] [000254] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured using EL Measured by ISA. Total ATG13 antibody (Cell Signaling catalog no. 13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend catalog no. 421601). The wells were then blocked with assay diluent (Biolegend catalog no. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog no. 600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher catalog no. 21140) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. 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 first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm from blank wells was subtracted from the test wells. Data was compared to control wells to determine % ATG13 phosphorylation. IC50 values were calculated using GraphPad Prism.

[0256] Example 180. Mutant BRAF after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in A375 cells [000255] A375 human melanoma cancer cells (20,000 cells / well) were cultured in 10% 100 μL of pre-warmed DMEM medium supplemented with characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin was added to a 96-well tissue culture-treated plate 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 plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Cells were lysed 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. Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling catalog no. 13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend catalog no. 421601). The wells were then blocked with assay diluent (Biolegend catalog no. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog no. 600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher catalog number 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 catalog number 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. Next, the background-corrected absorbance at 450 nm from the blank wells was 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.

[0257] Example 181. Mutant HRas after treatment with a ULK inhibitor in combination with trametinib pATG13 levels in T24 cells [000256] T24 human bladder cancer cells (25,000 cells / well) were characterized at 10% Cells were added to 100 μL of prewarmed DMEM medium supplemented with purified fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a 96-well tissue culture-treated plate 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 plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The following day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). Contains Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO). Cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) at 4°C for 10 minutes with shaking.

[0258] [000257] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured using EL Measured by ISA. Total ATG13 antibody (Cell Signaling catalog no. 13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend catalog no. 421601). The wells were then blocked with assay diluent (Biolegend catalog no. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog no. 600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher catalog no. 21140) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. 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 first calculated for each well by subtracting the background absorbance at 540 nm from the absorbance at 450 nm. 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 2. Inhibition of ULK kinase in mutant Ras or mutant BRAF cell lines by exemplary compounds from Table G [Table 2-1] [Table 2-2]

[0259] [000258] In Table 2, "+" indicates an IC of greater than 10 nM and less than or equal to 100 nM. 50 refers to " "++" indicates IC greater than 100 nM and less than 300 nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 "++++" indicates an IC of over 600 nM 50 Refers to...

[0260] Example 182. Biochemical Assay of LRRK2 (SEQ ID NO: 4) [000259] LRRK2 kinase activity is maintained by the ATP hydrolysis-dependent oxidation of NADH. The activity of LRRK2 was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay (e.g., Schindler et al. Science (2000) 289:1938-1942) that monitors the activity of LRRK2. The assay was performed in a 384-well plate (final volume 100 μL) using 26.4 nM LRRK2 (Thermo Fisher Scientific), 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 MgCl, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100). Inhibition of LRRK2 was determined by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek). 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 50Values were calculated using software routines in Prism (GraphPad software). LRRK2 protein sequence (residues 970-2528; SEQ ID NO: 4) MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGTMHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKENKESKHKMSYS GRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE [Table 3-1] [Table 3-2]

[0261] [000260] In Table 3, "+" indicates an IC of greater than 1 nM and less than or equal to 100 nM. 50 refers to "+ +" indicates IC greater than 100nM and less than 300nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 "++++" indicates an IC of over 600 nM 50 Refers to...

[0262] Example 183. In vitro and in vivo evaluation of ULK inhibitors in pancreatic ductal adenocarcinoma (PDAC) [000261] ULK inhibitors were evaluated in the PDAC flux assay and showed Trp53 lo x / + , 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.

[0263] [000262] In vivo PD using syngeneic orthotopic models after single and multiple doses Inhibition of autophagic flux using a flux reporter in AC tumors will be assessed.

[0264] [000263] The therapeutic efficacy of ULK inhibitors in PDAC models was evaluated by: (i) increasing the tumor growth rate of PDAC; (ii) assessing tumor kinetics subcutaneously in a syngeneic model of PDAC (KPC-implanted C57 black mice) pancreas orthotopically; (iii) assessing tumor growth kinetics in a syngeneic model with ULK inhibitors and MEK inhibitors; (iv) evaluating the compounds in an autotopic model of PDAC; (v) assessing histological changes in the tumor microenvironment; (vi) assessing 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 blockade.

[0265] equivalent [000264] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. 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, their full scope of equivalents, and the specification, and such variations.

[0266] [000265] Unless otherwise indicated, the ingredients used in the specification and claims include: All numbers expressing quantities, such as reaction conditions, 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 attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

1. A compound represented by: 【Chemical 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: A is a 5-membered heteroaryl having at least one ring nitrogen, W is CH or N; R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ５ Alkyl and C ３ -C ５ 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 １ -C ５ alkyl, and 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 ４ are B, D, NR ６ R ９ , N.R. ６ -(C(R １０ ) ２ ) ｐ -NR ６ 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, and B is selected from R ７ and optionally substituted on one or more available carbons by 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, and D is selected from R ７ and optionally substituted on one or more available carbons by 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; 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 ６ R ９ and each C is selected from the group consisting of １ -C ６ Alkyl and C ３ -C ６ The 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 ,oh and D, 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 １０ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R １０ However, they bond 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 4-10 membered lactam rings, said lactam ring being attached through a nitrogen atom, and lactam ring atoms optionally being oxygen or NR when said lactam ring is a 6-10 membered ring. ６ and any available carbon atom on the 4-membered lactam ring or 6- to 10-membered lactam is selected from one or more independent occurrences of R ３６ and optionally replaced by R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, and 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, or two R ３６ However, they bond together with the carbon to which they are attached to form C ３ -C ６ forming a cycloalkyl, L is -(C(R １０ ) ２ ) ｍ - and h is 1, 2, or 3; m is 0, 1, 2, or 3; n is 2, 3, or 4; p is 2 or 3; However, when m is 0, R ４ is C-bonded to ring A, and when m is 1, R ４ is C-bonded to L, and then when m is 2 or 3, R ４ is N- or C-attached to L, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

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

3. 3. The compound of claim 1 or 2, wherein A is selected from the group consisting of pyrazolyl, triazolyl, thiazolyl, and oxazolyl. 【Request 4】 【Chemical 2】 But, 【Chemistry 3】 The compound according to any one of claims 1 to 3, selected from the group consisting of: 【Request 5】 【Chemical 4】 But, 【Chemistry 5】 The compound according to any one of claims 1 to 4, selected from the group consisting of: 【Request 6】 【Chemical 6】 but, 【Chemistry 7】 The compound according to any one of claims 1 to 5,

7. Z is, 【Chemistry 8】 is selected from During the ceremony, 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 and R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, and 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, or two R ３６ However, they bond 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; The compound according to any one of claims 1 to 6, wherein r is 2 or 4.

8. Z is as follows: 【Chemistry 9】 The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. Z is, 【Chemistry 10】 is selected from In the formula, 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 and R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, and 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, or two R ３６ However, they bond 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; The compound according to any one of claims 1 to 7, wherein r is 2 or 3.

10. Z is, 【Chemistry 11】 is selected from where V is oxygen, CH ２ , and N.R. ６ 10. The compound of claim 1, wherein q is 0, 1, 2, or 3 and r is 2 or 3.

11. Z is as follows: 【Chemistry 12】 The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. Z is selected from the group consisting of a 4-10 membered lactam ring bonded through a nitrogen atom, the lactam ring atoms optionally being oxygen or NR ６ wherein an available carbon atom on the 4- to 10-membered lactam ring is selected from one or more independent occurrences of R ３６ The compound of any one of claims 1 to 6, optionally substituted by

13. R ４ The compound according to any one of claims 1 to 12, wherein is D.

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

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

16. R ４ The compound according to any one of claims 1 to 12, wherein is B.

17. R ４ But, 【Chemistry 15】 is selected from the group consisting of 13. The compound according to any one of claims 1 to 12, wherein u is 1 or 2.

18. R ４ But, 【Chemistry 16】 The compound according to any one of claims 1 to 12 and claims 16 to 17, selected from the group consisting of:

19. R ４ But, 【Chemistry 17】 The compound according to any one of claims 1 to 12 and claims 16 to 18, selected from the group consisting of:

20. The compound according to any one of claims 1 to 15, wherein m is 0.

21. The compound according to any one of claims 1 to 15, wherein m is 1.

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

23. The compound according to any one of claims 1 to 19, wherein m is 3.

24. R １ But halogen, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl and C ３－ C ５ 24. The compound of any one of claims 1 to 23, wherein the cycloalkyl is optionally substituted with 1, 2, or 3 independent occurrences of fluorine.

25. R １ But CF ３ The compound according to any one of claims 1 to 24,

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

27. R １ The compound of any one of claims 1 to 24, wherein is bromo.

28. R １ The compound of any one of claims 1 to 24, wherein is cyclopropyl.

29. R ２ But C １ -C ５ Alkyl, H, and C ３ -C ４ The compound of any one of claims 1 to 28, wherein the compound is selected from the group consisting of cycloalkyl.

30. R ２ But C １ -C ２ Alkyl and C ３ -C ４ 30. The compound of any one of claims 1 to 29, wherein the compound is selected from the group consisting of cycloalkyl.

31. R ２ The compound of any one of claims 1 to 28, wherein is halogen.

32. R ２ The compound of any one of claims 1 to 28, wherein is bromo.

33. R ２ The compound of any one of claims 1 to 28, wherein is chloro.

34. The compound of any one of claims 1 to 33, wherein n is 3.

35. A compound represented by: 【Chemistry 18】 or a pharmaceutically acceptable salt thereof, wherein: A-1 is as follows: 【Chemistry 19】 is selected from the group consisting of R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one, two, or three independent occurrences of fluorine; R ２ is a halogen, C １ -C ２ Alkyl, and C ３ -C ４ cycloalkyl; R ４ is as follows: 【Chemistry 20】 is selected from the group consisting of R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 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, 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, and C ３ -C ６ cycloalkyl, and 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; Z is as follows: 【Chemical 21】 is selected from the group consisting of R ３４ Each occurrence of is independently H and R ３６ and R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, and 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, or two R ３６ However, they bond together with the carbon to which they are attached to form C ３ -C ６ forming a cycloalkyl, L is -(C(R １０ ) ２ ) ｍ - and R １０ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R １０ However, they bond together with the carbon to which they are attached to form C ３ -C ５ forming a cycloalkyl, m is 0, 1, 2, or 3; n is 2, 3, or 4; However, when m is 0, R ４ is C-bonded to the pyrazole ring, and m is 1, then R ４ is C-bonded to L and m is 2 or 3, then R ４ is N- or C-attached to L, or a pharmaceutically acceptable salt thereof.

36. A-1, 【Chemical 22】 36. The compound of claim 35, wherein:

37. 37. The compound of claim 35 or 36, wherein n is 3.

38. The compound according to any one of claims 35 to 37, wherein m is 0.

39. The compound of any one of claims 35 to 37, wherein m is 1.

40. The compound of any one of claims 35 to 37, wherein m is 2.

41. The compound of any one of claims 35 to 37, wherein m is 3.

42. Z is as follows: 【Chemical 23】 42. The compound of any one of claims 35 to 41, selected from the group consisting of:

43. Z is as follows: 【Chemistry 24】 43. The compound of any one of claims 35 to 42, selected from the group consisting of:

44. R １ But CF ３ , C.F. ２ 44. The compound of any one of claims 35 to 43, wherein the compound is selected from the group consisting of H, chloro, bromo, and cyclopropyl.

45. R ４ but, 【Chemistry 25】 The compound according to any one of claims 35 to 43, wherein

46. A compound represented by: 【Chemical Formula 26】 or a pharmaceutically acceptable salt thereof, wherein: A-1 is as follows: 【Chemical 27】 is selected from the group consisting of R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one, two, or three independent occurrences of fluorine; R ２ is C １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and halogen; R ４ is as follows: 【Chemical Formula 28】 is selected from the group consisting of R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 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, 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, and C ３ -C ６ cycloalkyl, and 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; Z is as follows: 【Chemical 29】 is selected from the group consisting of R ３４ Each occurrence of is independently H and R ３６ and R ３６ Each occurrence of is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl, and 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, or two R ３６ However, they bond together with the carbon to which they are attached to form C ３ -C ６ forming a cycloalkyl, L is -(C(R １０ ) ２ ) ｍ - and R １０ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl, and each C １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R １０ However, they bond together with the carbon to which they are attached to form C ３ -C ５ forming a cycloalkyl, m is 0, 1, 2, or 3; n is 2, 3, or 4; However, when m is 0, R ４ is C-bonded to the pyrazole ring, and m is 1, then R ４ is C-bonded to L, and then when m is 2 or 3, R ４ is N- or C-attached to L, or a pharmaceutically acceptable salt thereof.

47. A-1, 【Chemistry 30】 47. The compound of claim 46, wherein:

48. 48. The compound of claim 46 or 47, wherein n is 3.

49. The compound of any one of claims 46 to 48, wherein m is 0.

50. 49. The compound of any one of claims 46 to 48, wherein m is 1.

51. The compound of any one of claims 46 to 48, wherein m is 2.

52. The compound of any one of claims 46 to 48, wherein m is 3.

53. Z is as follows: 【Chemical Formula 31】 53. The compound of any one of claims 46 to 52, selected from the group consisting of:

54. Z is as follows: 【Chemical 32】 54. The compound of any one of claims 46 to 53, selected from the group consisting of:

55. R １ But CF ３ , C.F. ２ 55. The compound of any one of claims 46 to 54, wherein the compound is selected from the group consisting of H, chloro, bromo, and cyclopropyl.

56. R ４ but, 【Chemical 33】 The compound according to any one of claims 46 to 55,

57. A compound represented by a formula selected from the group consisting of: 【Chemical 34】 During the ceremony, R １ Each occurrence of is independently bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ Each occurrence of is independently １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, and halogen; R ９ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ３４ Each occurrence of is independently H, C １ -C ２ Alkyl, and C ３ -C ５ cycloalkyl; The compound wherein n is 3.

58. The compound is 【Chemical 35】 58. The compound of claim 57, represented by:

59. The compound is 【Chemical 36】 58. The compound of claim 57, represented by:

60. A compound represented by a formula selected from the group consisting of: 【Chemical Formula 37】 During the ceremony, R １ Each occurrence of is independently bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ Each occurrence of is independently １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, and halogen; R ９ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ３４ Each occurrence of is independently H, C １ -C ２ Alkyl, and C ３ -C ５ cycloalkyl; The compound wherein n is 3.

61. A compound represented by a formula selected from the group consisting of: 【Chemical 38】 During the ceremony, R １ Each occurrence of is independently bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ Each occurrence of is independently １ -C ２ Alkyl, C ３ -C ４ cycloalkyl, and selected from the group consisting of halogens; R ９ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ３４ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; The compound wherein n is 3.

62. A compound represented by a formula selected from the group consisting of: 【Chemical 39】 During the ceremony, R １ Each occurrence of is independently bromo, chloro, CF ３ , C.F. ２ H, and cyclopropyl; R ２ Each occurrence of is independently １ -C ２ Alkyl, C ３ -C ４ is selected from the group consisting of cycloalkyl, and halogen; R ９ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ３４ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; The compound wherein n is 3.

63. The compound is 【Chemistry 40】 63. The compound of claim 62, represented by:

64. The compound is 【Chemistry 41】 63. The compound of claim 62, represented by:

65. 1-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-(cyclopropylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5 -chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(piperidine-4 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3 1-(3-((2-((1-(1-isopropyl-d7-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropyl-d7-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-(( (2-((1-(1-(cyclopropylmethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidine-2- 1-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one , 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-d3-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazole 1-(3-((2-((3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin 1-(3-((2-((1-(3-(dimethylamino)propyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-isopropylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazole 1-(3-((2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl- 1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl-1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propionate, propyl)piperidin-2-one, 1-(3-((5-iodo-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-d3-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((1-(1-ethylpiperidin-4-yl)-3-methyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-methyl-d3-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(1-methyl-d3-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-ethyl-1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-ethyl-1-(1-methylpiperidin-4-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-(methyl-d3)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((1-(1-(2-fluoroethyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2- ((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((5-bromo-2-((1-(1-ethylpyrrolidin-3-yl) -3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, rac-(R)-1-(3-((2-((1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazolin-4-yl)amino)propyl)piperidin-2-one 2-methyl-2-(3-methyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 3-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4 1-(3-((5-cyclopropyl-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-5,5-dimethylpyrrolidin-2-one, 3-(3-((2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidine 3-(3-((5-bromo-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 3-(3- ((5-chloro-2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 4-(3-((5-cyclopropyl-2-((1-(1-isopropylpiperidin-4-yl)-3- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 4-(3-((5-cyclopropyl-2-((3-ethyl-1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one,1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl) )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one , 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazole 1-(3-((5-chloro-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one,1-(3-((2-((1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-, (1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-(( 2-((1-(1-cyclobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-cyclopentylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(1-(sec-butyl)piperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, (S)-1-(3-((2-((1-(1-isopropylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one , 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3 -((2-((3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((2-((3-methyl-1-(3-morpholino ... -(3-((2-((3-methyl-1-(1-methyl-d3-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1, 4-oxazepan-3-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(, trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, (R)-4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(3-morpholinopropyl) 4-(3-((5-cyclopropyl-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one )-1,4-oxazepan-3-one, (R)-4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1 -(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(2-(diethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 2-methyl-2-(3-methyl-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl) 3-(3-((2-((4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)amino)propyl)pyrrolidin-2-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidine- (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-oxazepan-5-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, (R)-4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)- 1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one Zepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepam 4-(3-((5-chloro-2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-bromo-2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 4-(3-((2-((1-(2-(diethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((1-(1- 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylimidazolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylimidazolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylimidazolidin-2-one, amino)propyl)-5,5-dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-5-methylpyrrolidin-2-one, 1-methyl-3-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)imidazolidin-2-one, 1-methyl-3-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)imidazolidin-2-one, (3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)imidazolidin-2-one, 1-(3-((5-bromo-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol 1-(3-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methylpyrrolidin-2-one, rac-(R)-1-(4-((5-chloro-2-((1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)butan-2-yl)pyrrolidin-2-one,rac-(R)-1-(4-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)butan-2-yl)pyrrolidin-2-one, (R)-1-(3-((5-chloro-2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-1H (R)-1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (R)-1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one 1-(3-((5-chloro-2-((3-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (R)-1-(3-((5-bromo-2-((3-methyl-1-(pyrrolidin-3-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,(S)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, (S)-1-(3-((2-(, (1-(1-ethylpyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, rac-(R)-1-(3-((2-((3-methyl-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 2-methyl-2-(3-methyl-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile, 1-(3-((2-((4-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidine-2- 1-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3- ((2-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((1-(1-methylpiperidine- 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3 ... thiazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino )propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2- (4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)oxazo 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1, 4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino) 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepane-3, -on, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-( (2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3 ... 3-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5 -methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxaze, Pan-5-one, 3-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, -5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazol pan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-methyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-methyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)propyl) 3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(8-, methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 1- Methyl-4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)- 1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one, 4-methyl-1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-1H-pyrazol-4-yl)amino)propyl)-1,3-diazepan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-diazepan-2-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, 4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3 ... 6,6-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) amino)propyl)-1,4-oxazepan-3-one, 6,6-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 6,6-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 6,6-dimethyl-3-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(8 -methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 6,6-dimethyl-4-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((2-((3-methyl-1-(8-methyl-8-azoline 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H -pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazole-, 4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1 -(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-5-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan- 2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxo Sazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5- (difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-3-one Zepan-5-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-( 8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((1 -(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-bromo-2-((3-methyl- 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)amino)propyl)piperidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl), 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, ...pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-Oxazepan-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine- 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4 ... (3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one , 3-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepane -3-one, 4-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-Dimethylazetidin-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one , 3-(3-((5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl) 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino )propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-Oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-di Azepan-5-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3- ((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-Oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6, -dimethyl-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-3-one azepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3 -((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4- (3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-Oxazepan-5-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octyl) 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one azetidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxo, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5 -carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxopiperidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, -((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine -5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholino)propyl)amino)pyrimidine pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino) 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2, 1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-(( 3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile 2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3 -(2,2-dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(2,2-dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo so-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-2-oxo-1,3-oxazinan-3-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(2,2-dimethyl-3-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-dimethyl-5-oxo-1,4-oxazepan-4-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpyrrolidine-3- 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxoazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl-2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl-2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl- 2-oxoazetidin-1-yl)propyl)amino)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-(( 3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-1,3-oxazinan-2-one, pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one, 3-(3-((5-cyclopropyl-2-(( 3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol- 4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)amino)propyl)piperidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl, )-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)morpholin-3-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl tetrahydropyrimidin-2(1H)-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl) propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one, 4-(3-((5-cyclopropyl cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrimidin-4-yl )amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl, 3-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one, [3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((5-cyclopropyl-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 1-(3-((2-((3-methyl 1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)pyrrolidin-2-one 1-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 3,3-dimethyl-1-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one pyrolidin-2-one, 1-(3-((5-(difluoromethyl)-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(tri, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one Lysin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)amino) ... 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-(3-((5-chloro-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 1-( 3-((5-chloro-2-((1-(1-isobutylazetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one, 4-(3-((2-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2- (2-(dimethylamino)ethyl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((5-ethyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-( (4-methylpiperazin-1-yl)methyl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(azetidin-1-ylmethyl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, N-(1-methylpiperidin-4-yl)-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)thiazole-2-carboxamide, 4-(3-((2-((2-(3-(dimethylamino)propyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepane-, 3-one, 4-(3-((2-((2-(2-(dimethylamino)ethyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(4-methylpiperazine-1-carbonyl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-(4-(dimethylglycyl)piperazine-1 4-(3-((2-((2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1,1-dioxidethiomorpholino)thiazol-4-yl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((2-morpholinooxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3- ((2-((2-((dimethylamino)methyl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-((2-(dimethylamino)ethyl)(methyl)amino)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 2-(dimethylamino)-N-methyl-N-(5-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)oxazol-2-yl)acetamide, 1-(3-((2-((1-(1-(dimethylglycyl)pyrrolidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one, 3,3-dimethyl-1-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)amino)propyl) 4-(3-((2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one, 4-(3-((2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(3-(pyrrolidin-1-yl ...azetidin-2-one, 3-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-fluoro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-fluoro-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((3-methoxy-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-Oxazinan-2-one, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4-(3-((2-((3-ethynyl-1-(1-, 3-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4 8-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-oxa-8-azaspiro[2.6]nonan-9-one, ... 9-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonan-9-one, 9-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-9-azaspiro[3.6]decan-10 ... 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-oxazepan-3-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one, 3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 2,2-dimethyl-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4- Oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl) amino)propyl)-1,4-oxazepan-5-one, (S)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1 (R)-4-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)tetrahydropyrimidin-2(1H)-one, 1-methyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-diazepan-2-one, (R)-4-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H 4-(3-((2-((1-(1-((dimethylamino)methyl)azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-((dimethylamino)methyl)azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazo 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((5-chloro-2-((3-ethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((3-methoxy-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-((3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((1-(1-methylpiperidin-4-yl)-3-vinyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-((3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)propyl)-1,4-oxazepan-5-one amino)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonitrile, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile, 6-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)nicotinonitrile, 4-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 4-(3-((2-((1-(1-ethylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4-(3-((2-((2-(1-methylpiperidin-4-yl, )-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((5-(difluoromethyl)-2-((2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 3-(3-((2-((2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridine- 4-yl)amino)propyl)-1,3-oxazinan-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)pyrrolidin-2-one, 1-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-methyl-1- (1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azetidin-2-one, 2-methyl-2-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, 4-(3-((2-((2-(4-(dimethylglycyl)piperazin-1-yl)-5-methylthiazol-4-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one, 4-(3-((2-((5-methyl-2-(methyl(2-(methylsulfonyl)ethyl)amino)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((2-((2-(1,1-dioxidethiomorpholino)-5-methylthiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-Oxazinan-2-one, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-3-carbonitrile, 4-(3-((5-(difluoromethyl)-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one, 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )amino)propyl)-1,3-oxazinan-2-one, 1-methyl-4-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one, and 4-methyl-1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-2-one, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

66. 66. A pharmaceutical composition comprising a compound according to any one of claims 1 to 65 and a pharmaceutically acceptable excipient.

67. 66. A pharmaceutical composition comprising a compound of any one of claims 1 to 65, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.

68. 68. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition comprises one additional therapeutic agent.

69. 69. The method of claim 67 or 68, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor. Pharmaceutical compositions.

70. 70. The pharmaceutical composition of claim 69, 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.

71. 71. The pharmaceutical composition of claim 70, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.

72. 71. The pharmaceutical composition of claim 70, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof.

73. 71. The pharmaceutical composition of claim 70, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof.

74. 71. The pharmaceutical composition of claim 70, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

75. 69. The pharmaceutical composition of claim 67 or 68, wherein the additional therapeutic agent is a chemotherapeutic agent.

76. 69. The pharmaceutical composition of claim 67 or 68, wherein the additional 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.

77. 66. A method of treating a tumor in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 65.

78. 66. A method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 65.

79. 79. The method of claim 78, 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 that metastasizes to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.

80. 80. The method of claim 78 or 79, wherein the cancer is metastatic.

81. 66. A method of treating a disorder selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer metastatic to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-65.

82. 63. The method of any one of claims 77-62, further comprising administering to the patient one or more additional therapeutic agents.

83. 83. The method of claim 82, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

84. 84. The method of claim 83, 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.

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

86. 84. The method of claim 83, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, lavoxertinib, VX-11e, and pharmaceutically acceptable salts thereof.

87. 84. The method of claim 83, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof.

88. 84. The method of claim 83, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

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

90. 90. The method of claim 89, 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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