Heteroaryl aminopyrimidine amide autophagy inhibitors and methods of use thereof

Abstract

Described herein are compounds that are autophagy inhibitors and their use for the treatment of conditions such as cancer. I) # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with application number 2020800497431, application date May 8, 2020, and invention title "Heteroaryl Aminopyrimidine Amide Autophagy Inhibitors and Methods of Use Thereof".

[0002] Cross - reference to related applications

[0003] This application claims priority to U.S.S.N. 62 / 846,260 filed May 10, 2019, U.S.S.N. 62 / 846,264 filed May 10, 2019, U.S.S.N. 62 / 911,733 filed October 7, 2019, and U.S.S.N. 62 / 911,736 filed October 7, 2019, the respective contents of which are incorporated herein by reference in their entireties.

[0004] Sequence listing

[0005] This application contains a sequence listing that has been electronically submitted in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on May 5, 2020, has the file name DCP - 080WO_SL.txt, and is 27,200 bytes in size. Background of the invention

[0006] Autophagy (literally "self - eating") is the process by which cells can recycle organelles, proteins, stored lipids, glucagon, and other substances for the purpose of generating nutrients during periods of stress. These cellular contents are recycled by being engulfed in vesicles called autophagosomes. Subsequently, the autophagosomes fuse with lysosomes that degrade the autophagosome contents to recycle nutrients to the cell. Tumor cells tend to activate autophagy because these cells have high metabolic demands, experience cellular stress, and are typically in a hypoxic environment with limited blood flow and nutrient supply. In addition, chemotherapy and targeted therapies have been shown to induce autophagy as an anti - therapeutic mechanism, and autophagy inhibition (either through loss - of - function mutations in autophagy genes or by pharmacological means) in combination with chemotherapeutic regimens has been shown to inhibit tumor growth and trigger tumor cell apoptosis to a greater extent than single - agent chemotherapy.

[0007] Mutant Ras proteins drive approximately 30% of all human cancers - including 95% of pancreatic cancers and 45% of colorectal cancers, and the treatment of these mutant Ras cancers is a currently highly unmet area of medical need. Mutant Ras cancers are highly proliferative and depend on basal autophagy levels for survival, suggesting that autophagy inhibition is a viable therapeutic approach in these "autophagy - addicted" cancers.

[0008] Currently, the most widely used autophagy inhibitors are chloroquine and hydroxychloroquine, which are well-known antimalarial agents. These antimalarial drugs are thought to block autophagy by chelating in the lysosomal compartment, raising the pH of these lysosomes, and thus inactivating the proteases that degrade and recycle nutrients. In addition to inhibiting lysosomes, these antimalarial agents also have multiple mechanisms of action and are known to induce retinopathy in patients. Therefore, there is a need for more targeted agents that selectively block autophagy and do not exhibit the toxicity of these antimalarial agents. The ULK1 kinase is an autophagy initiation protein and a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stress, including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity by inhibiting mTORC1, and energy depletion activates ULK kinase activity by activation by the AMP-activated protein kinase AMPK. Importantly, kinase-inactivating mutants of the ULK kinase block canonical autophagy initiation, indicating that small molecule inhibitors of ULK kinase activity should be able to block autophagy.

[0009] Additional mechanistic studies have shown that ULK1 gene deletion inhibits autophagy in cancer cells, alleviating FOX3A conversion 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 (damaged mitochondrial autophagy). It has also been confirmed that ULK1 and ULK2 kinases remodel cancer cell glucose metabolism. ULK inhibitors can also be used to block these non-canonical pro-tumor ULK activities.

[0010] Autophagy is also upregulated in the host cells and tissues of cancer. Autophagy in pancreatic tissue stellate cells has been confirmed to support tumor growth. Pancreatic stellate cells have been shown to support pancreatic cancer tumor metabolism through autophagic alanine secretion. Host tissue autophagy inhibition has been confirmed to cause depletion of arginine (an amino acid required for tumor metabolism and growth) in the circulation through increased hepatic-mediated arginase secretion. It has also been shown that ULK1 kinase activation inactivates the STING pathway in immune cells by inhibitory phosphorylation of STING, regulating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Therefore, autophagy is activated not only in tumor cells (spontaneously in cancer cells), but also in other cells in the tumor microenvironment or host tissues (non-spontaneously in cancer cells) to support tumor survival and growth.

[0011] Mutant Ras cancers are dependent on autophagy. In pancreatic cancer, mutant Ras signaling mainly occurs through the MAPKAP pathway. Mutant Ras activates RAF kinase, which then activates MEK kinase, and finally activates ERK kinase: mutant Ras → RAF → MEK → ERK. Although mutant Ras signal transduction occurs through the MAPKAP pathway, inhibitors of this pathway do not provide or provide very little clinical benefit when used as single agents in clinical trials. It has recently been reported that MAPKAP pathway inhibition induces autophagy as a compensatory survival mechanism. When a MEK inhibitor is combined with the autophagy inhibitor hydroxychloroquine, there is synergistic activity that causes regression of various mutant Ras cancers or mutant BRAF cancers. Similarly, when an ERK inhibitor is combined with the autophagy inhibitor hydroxychloroquine or chloroquine, there is synergistic activity that causes inhibition of mutant Ras pancreatic cancer. It has been demonstrated that genetic depletion of RAF kinases (CRAF and BRAF) causes synergistic anti-tumor activity in mutant Ras cancer cell lines when autophagy is also genetically depleted. Recent publications have emphasized that dual inhibition of the MAPKAP pathway and the autophagy pathway in mutant Ras cancers in complex is a promising treatment option for patients with mutant Ras cancers. It has also been demonstrated that other targeted therapies and chemotherapeutic agents activate tumor autophagy as a resistance mechanism; thus, there is a theoretical basis for combining such targeted therapeutic agents or chemotherapeutic agents with autophagy inhibitors.

[0012] Genetic mutations encoding the LRRK2 kinase lead to Parkinson’s disease. LRRK2 point mutations are seen in both patients with familial (hereditary) Parkinson’s disease and patients with sporadic Parkinson’s disease. The most common LRRK2 mutation in Parkinson’s disease is LRRK2G2019S. These LRRK2 mutations are gain-of-function mutations that result in overactivation of LRRK2 signal transduction. Constitutive autophagy is a process by which brain neuronal cells maintain health and homeostasis. Autophagy is a process that enables cells to recognize, target, and destroy intracellular aged organelles and structural components, and specifically, in the case of proteins known to aggregate in neurons, autophagy eliminates such toxic protein aggregates to maintain neuronal health. LRRK2 activity inhibits autophagy, and the LRRK2G2019S gain-of-function mutation even more potently inhibits autophagy and has been associated with an aggressive form of Parkinson’s disease.

[0013] Increased LRRK2 kinase activity is also associated with immune-inflammatory diseases including colitis and Crohn’s disease and inflammatory bowel disease. In the gastrointestinal tract, LRRK2 is present in antigen-presenting cells including dendritic cells. LRRK2 activity has been shown to be crucial in lectin-1-mediated innate immune responses including NFkB pathway activation and increased TNF-α production in dendritic cells of patients with Crohn’s disease.

[0014] LRRK2 inhibitors have been explored for the treatment of neurodegenerative diseases including Parkinson's disease and have also been explored for the treatment of gastrointestinal diseases including Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0015] There is a need for novel targeted therapies that inhibit autophagy and can be used in combination with MAPKAP pathway inhibitors, chemotherapeutic agents, and / or other targeted therapeutic agents. SUMMARY OF THE INVENTION

[0017] Compounds, pharmaceutical compositions thereof, their use as medicaments in the treatment of conditions such as cancer, methods for their preparation, and pharmaceutical compositions containing them as active ingredients are described herein. The pharmaceutical compositions may contain the compounds as a single active agent or in combination with other active agents in the presence of a pharmaceutically acceptable excipient. In one embodiment, the compounds described are inhibitors of ULK kinase activity including ULK1 and ULK2 activity.

[0018] For example, the compounds provided herein may be described by Formula I

[0019]

[0020] 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 selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines; 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 with one, two, or three independently occurring fluorines or cyanos; R 4 is selected from the group consisting of B, D, NR 6 R 9 、NR 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 heterocyclic groups and heteroaryls having at least one nitrogen and optionally having additional ring nitrogens or oxygens, wherein B is optionally substituted with R on one or more available carbons7 substituted and optionally substituted on available nitrogen by R 9 ; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and optionally having additional ring nitrogen or oxygen, wherein D is optionally substituted on one or more available carbons by R 7 substituted and optionally substituted on available nitrogen by R 9 ; R 5 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic group in each occurrence, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by one or more independently occurring fluorines; R 7 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 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 independently occurring fluorines, or two R 7 join together with the atom to which they are attached to form a bridging oxy group; R 6 and R 9 are independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 , and D in each occurrence, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by one or more independently occurring fluorines; R 10 is independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl in each occurrence, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted by one or more independently occurring fluorines, or two R 10 join together with the carbon to which they are attached to form a C3-C5 cycloalkyl; Z is selected from: 4-10 membered lactam rings, wherein the lactam rings are bonded through nitrogen atoms, wherein when the lactam rings are 6-10 membered rings, the lactam ring atoms are optionally oxygen or NR 6 , and the available carbon atoms on the 4 membered lactam ring or 6-10 membered lactam are optionally substituted by one or more independently occurring R 36 ; R 36 is independently selected from: C1-C6 alkyl and C3-C6 cycloalkyl in each occurrence, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by one or more independently occurring fluorines, or two R 36 join together with the carbon to which they are attached to form a C3-C6 cycloalkyl; 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; provided that when m is 0, R 4 is C-linked to ring A; when m is 1, R 4 is C-linked to L; and subsequently when m is 2 or 3, R 4 is N-linked or C-linked to L. DETAILED DESCRIPTION OF THE INVENTION

[0022] The features and other details of the present invention will now be described more clearly. The specific terms used in this specification, the examples and the appended claims for patent are collected herein. These definitions should be read in light of the remainder of the present invention and 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 one of ordinary skill in the art.

[0023] Definitions

[0024] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon. Exemplary alkyls include, but are not limited to: straight-chain or branched-chain hydrocarbons having 1-6, 1-4, 1-3 or 1-2 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl and C1-C2 alkyl, respectively. Exemplary alkyls 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0025] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyls include, but are not limited to: straight-chain or branched-chain groups having 2-6 or 3-4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyls include, but are not limited to: vinyl, allyl, butenyl, pentenyl, etc.

[0026] As used herein, the term "alkoxy" refers to a straight-chain or branched-chain alkyl linked to oxygen (alkyl-O-). Exemplary alkoxys include, but are not limited to: alkoxys having 1-6 or 2-6 carbon atoms, referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxys include, but are not limited to: methoxy, ethoxy, isopropoxy, etc.

[0027] As used herein, the term "alkoxyalkyl" refers to a straight or branched alkyl group (alkyl-O-alkyl-) that is attached to oxygen and attached to a second straight or branched alkyl group. Exemplary alkoxyalkyls include, but are not limited to: alkoxyalkyls in which the alkyl groups, referred to herein as C1-C6 alkoxy-C1-C6 alkyl and C1-C6 alkoxy-C2-C6 alkyl, each independently contain 1-6 carbon atoms. Exemplary alkoxyalkyls include, but are not limited to: methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

[0028] As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyls include, but are not limited to: straight or branched groups having 2-6 or 3-6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyls include, but are not limited to: ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0029] As used herein, the term "cyano" refers to the group -CN.

[0030] As used herein, the term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group having, for example, 3-6 or 4-6 carbons, referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyls include, but are not limited to: cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0031] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to oxygen (cycloalkyl-O-). Exemplary cycloalkoxys include, but are not limited to: cycloalkoxys having 3-6 carbon atoms, referred to herein as C3-6 cycloalkoxy. Exemplary cycloalkoxys include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0032] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0033] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 5- or 6-membered ring system containing one or more heteroatoms such as nitrogen, oxygen, and sulfur, for example, one to three heteroatoms. Where possible, the heteroaryl ring may be attached to an adjacent group through carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to: furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, or pyrimidine, and the like.

[0034] The term "heterocyclyl or heterocyclic group" is recognized in the art and refers to a saturated or partially unsaturated 4- to 10-membered ring structure, including monocyclic, bridged-ring or fused-ring, and such a ring structure includes one to three heteroatoms such as nitrogen, oxygen and sulfur. Where possible, the heterocyclyl ring may be attached to an adjacent group through carbon or nitrogen. Examples of heterocyclyl include, but are not limited to: pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, etc.

[0035] As used herein, the term "lactam" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkan-2-one structure, or an analogue having a heteroatom that unsaturates or replaces one or more carbon atoms of the ring. "α-Lactam" refers to a lactam composed of a 3-membered ring. "β-Lactam" refers to a lactam composed of a 4-membered ring. "γ-Lactam" refers to a lactam composed of a 5-membered ring. "δ-Lactam" refers to a lactam composed of a 6-membered ring. "ε-Lactam" refers to a lactam composed of a 7-membered ring.

[0036] As used herein, the term "bridging oxygen group" refers to the group =O.

[0037] "Combination therapy" is a treatment that includes administering two or more therapeutic agents, such as a compound of Formula I and a MAPKAP pathway inhibitor, to a patient in need thereof.

[0038] "Disease", "disorder" and "condition" may be used interchangeably herein.

[0039] "Individual", "patient" or "subject" may be used interchangeably and includes any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. The compounds described herein may be administered not only to mammals such as humans, but also to other mammals, such as animals in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).

[0040] "MAPKAP pathway inhibitor" refers to an inhibitor of the MAP kinase signal transduction pathway. Such pathway inhibitors include Ras inhibitors (such as AMG-510 or MRTX 849), RAF inhibitors (such as dabrafenib, vemurafenib, or LY3009120), MEK inhibitors (such as trametinib, binimetinib, selumetinib, or cobimetinib), and ERK inhibitors (such as ulixertinib, SCH772984, or LY3214996). The terms "MAPKAP pathway inhibitor" and "MAPKAP kinase inhibitor" are used interchangeably herein.

[0041] "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, the preparations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics standards.

[0042] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The compositions may also contain other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0043] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to salts having acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The 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: malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinate, fumarates, gluconates, glucuronates, glucodylates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)). Compounds included in the compositions of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts, and iron salts. Compounds included in the compositions of the present invention that include basic or acidic moieties may also form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compound may exist in the form of an acid addition salt, zwitterion, or base salt.

[0045] The compounds of the present invention may contain one or more chiral centers and thus exist in the form of stereoisomers. The term "stereoisomers" as used herein consists of all enantiomers or diastereomers. Depending on the configuration of the substituents around the chiral carbon atoms, these compounds may be designated by the symbols "(+)", "(-)", "R", or "S", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center. The compounds described in the present invention encompass the various stereoisomers of these compounds and mixtures thereof. In nomenclature, a mixture of enantiomers or diastereomers may be designated as "(±)", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center.

[0046] In the present specification, the term "therapeutically effective amount" refers to the amount of a compound of the present invention that a researcher, veterinarian, medical doctor, or other clinician is exploring to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or human). The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

[0047] "Treatment" includes any action that causes an improvement in a condition, disease, disorder, and the like, such as alleviating, reducing, modulating, or eliminating.

[0048] The invention also encompasses isotopically labeled compounds that are consistent with the compounds described herein, except that one or more atoms are replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include, for example, 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 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. For example, the compounds of the invention may have one or more H atoms replaced with deuterium.

[0049] The individual enantiomers and diastereomers of the compounds of the invention can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing a racemic mixture and then resolving it by methods well known to those skilled in the art. These resolution methods are illustrated by: (1) attaching a chiral auxiliary to a mixture of enantiomers, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the auxiliary, (2) forming salts with an optically active resolving agent, (3) directly separating a mixture of optical enantiomers on a chiral liquid chromatography column, or (4) performing kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can 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 (chemical or enzymatic reactions) in which a single reactant forms an unequal mixture of stereoisomers during the generation of a new stereogenic center or during the transformation of a pre-existing stereogenic center is well known in the art. Stereoselective synthesis encompasses both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0050] Compound

[0051] Compounds represented by Formula I are described herein:

[0052]

[0053] 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 selected from the group consisting of: halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is optionally substituted with one, two or three independently occurring fluorines; 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 with one, two or three independently occurring fluorines or cyanos; R 4 is selected from the group consisting of: B, D, NR 6 R 9 、NR 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 heterocyclic groups and heteroaryls having at least one nitrogen and optionally having additional ring nitrogens or oxygens, wherein B is optionally substituted with R 7 on one or more available carbons and optionally substituted with R 9 on available nitrogens; D is selected from C-linked heterocyclic groups and heteroaryls having at least one nitrogen and optionally having additional ring nitrogens or oxygens, wherein D is optionally substituted with R 7 on one or more available carbons and optionally substituted with R 9 on available nitrogens; R 5 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclic group in each occurrence, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; R 7 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano and (C(R 10 )2) h -NR 6 R 9 , wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 7 join together with the atom to which they are attached to form a bridging oxygen; R 6 and R 9Independently selected from the following group at each occurrence: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 and D, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; R 10 Independently selected from the following group at each occurrence: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 10 are joined together with the carbon to which they are attached to form a C3-C5 cycloalkyl; Z is selected from: 4- to 10-membered lactam rings, wherein the lactam rings are joined through a nitrogen atom, and when the lactam ring is a 6- to 10-membered ring, the lactam ring atoms are optionally oxygen or NR 6 , and the available carbon atoms on the 4-membered lactam ring or 6- to 10-membered lactam are optionally substituted with R 36 ; R 36 Independently selected from: C1-C6 alkyl and C3-C6 cycloalkyl at each occurrence, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 36 are joined together with the carbon to which they are attached to form a C3-C6 cycloalkyl; 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; provided that: when m is 0, R 4 is C-linked to ring A; when m is 1, R 4 is C-linked to L; and subsequently when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0054] In some embodiments, Z is selected from: a 4-membered lactam ring joined through a nitrogen atom or a 6- to 10-membered lactam ring joined through a nitrogen atom, wherein when the lactam ring is a 6- to 10-membered ring, the lactam ring atoms are optionally oxygen or NR 6 , and the available carbon atoms on the 4-membered lactam ring or 6- to 10-membered lactam are optionally substituted with R 36 .

[0055] In some embodiments, Z is selected from: 4- to 10-membered lactam rings joined through a nitrogen atom, wherein any available carbon atoms on the 4- to 10-membered lactam are optionally substituted with R 36 , and when the lactam ring is a 6- to 10-membered ring, the lactam ring atoms are optionally oxygen or NR 6 .

[0056] In some embodiments, W is N. In some embodiments, A is selected from the group consisting of pyrazolyl, triazolyl, thiazolyl, and oxazolyl.

[0057] In some embodiments, is selected from the group consisting of:

[0058]

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

[0060]

[0061] In some embodiments, is:

[0062]

[0063] In some embodiments, Z is selected from:

[0064]

[0065] wherein V is selected from the group consisting of oxygen, C(R 34 )2, and NR 6 , R 34 is independently selected from H and R 36 each time it appears, where R 36 is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl each time it appears, and each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 36 bond together with the carbon to which they are attached to form a C3-C6 cycloalkyl; q is 0, 1, 2, or 3; and r is 2 or 4.

[0066] In some embodiments, Z is selected from:

[0067]

[0068] wherein V is selected from the group consisting of oxygen, C(R 34 )2, and NR 6 ; R 34 is independently selected from H and R 36 each time it appears, where R 36 is independently selected from C1-C6 alkyl and C3-C6 cycloalkyl each time it appears, and each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 36 bond together with the carbon to which they are attached to form a C3-C6 cycloalkyl; q is 0, 1, 2, or 3; and r is 2 or 3.

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

[0070]

[0071] In some embodiments, Z is selected from:

[0072]

[0073] wherein V is selected from the group consisting of oxygen, CH2, and NR 6 ; q is 0, 1, 2, or 3; and r is 2 or 3.

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

[0075]

[0076] In some embodiments, R 4 is D.

[0077] In some embodiments, R 4 is selected from the group consisting of:

[0078]

[0079] In some embodiments, R 4 is selected from the group consisting of:

[0080]

[0081] In some embodiments, R 4 is B.

[0082] In some embodiments, R 4 is selected from the group consisting of:

[0083]

[0084] wherein u is 1 or 2.

[0085] In some embodiments, R 4 is selected from the group consisting of:

[0086]

[0087] In some embodiments, R 4 is selected from the group consisting of:

[0088]

[0089] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0090] In some embodiments, L is a direct bond connected to the A ring, i.e., this is the case when m is 0.

[0091] 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-.

[0092] In some embodiments, R 1 is selected from the group consisting of: halogen, C 1- C5 alkyl, and C 3- C5 cycloalkyl, wherein the C 1- C5 alkyl or C 3- C5 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines. In some embodiments, R 1 is CF3. In some embodiments, R 1 is halogen. In some embodiments, R 1 is bromine. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is CF2H.

[0093] In some embodiments, R 2 is selected from the group consisting of: C 1- C5 alkyl, H, and C3-C4 cycloalkyl, wherein the C 1- C5 alkyl or C 3- C4 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines.

[0094] 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 halogen. In some embodiments, R 2 is selected from the group consisting of chlorine and bromine. In some embodiments, R 2 is bromine. In some embodiments, R 2 is chlorine.

[0095] In some embodiments, n is 3.

[0096] In a specific embodiment, the compound is represented by:

[0097]

[0098] or a pharmaceutically acceptable salt thereof, wherein A-1 is selected from the group consisting of:

[0099]

[0100] R 1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines; R 2 is selected from the group consisting of: halogen, C1-C2 alkyl, and C3-C4 cycloalkyl, wherein each C1-C2 alkyl and C3-C4 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines; R 4 is selected from the group consisting of:

[0101]

[0102] R 7 is independently selected from the group consisting of: H, C 1- C6 alkyl, C 3- C6 cycloalkyl, wherein each C 1- C6 alkyl and C 3- C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 7 join together with the atom to which they are attached to form an oxo bridge; R 6 and R 9 are independently selected from the group consisting of: H, C 1- C6 alkyl, and C 3- C6 cycloalkyl, wherein each C 1- C6 alkyl and C 3- C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; Z is selected from the group consisting of:

[0103]

[0104] R 34 is independently selected from: H and R 36 wherein R 36 is independently selected from: C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 36 join together with the carbon to which they are attached to form a C3-C6 cycloalkyl; L is -(C(R 10 )2) m -; R 10 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 with one or more independently occurring fluorines, or two Rs 10is joined to the carbon to which it is attached to form a C3-C5 cycloalkyl; m is 0, 1, 2, or 3; and n is 2, 3, or 4; provided that when m is 0, R 4 is C-linked to the pyrazole ring; when m is 1, R 4 is C-linked to L; and then when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0105] In some embodiments, A-1 is:

[0106]

[0107] In some embodiments, n is 3.

[0108] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0109] In some embodiments, L is a direct bond.

[0110] 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-.

[0111] In some embodiments, Z is selected from the group consisting of:

[0112]

[0113] In some embodiments, Z is selected from the group consisting of:

[0114]

[0115] In some embodiments, R 1 is selected from the group consisting of: halogen, C 1- C5 alkyl, and C 3- C5 cycloalkyl, wherein the C 1- C5 alkyl is optionally substituted with one, two, or three occurrences of fluorine. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is halogen. In some embodiments, R 1 is bromine. In some embodiments, R 1 is cyclopropyl.

[0116] In some embodiments, R 2Selected from the group consisting of: H, C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl, and C2-C5 alkynyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted with one, two, or three independently occurring fluorines. In some embodiments, R 2 is selected from the group consisting of: C 1-2 alkyl and C 3-4 cycloalkyl. In some embodiments, R 2 is selected from the group consisting of chlorine and bromine.

[0117] In some embodiments, R 2 is selected from the group consisting of: C 1- 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 chlorine and bromine.

[0118] In some embodiments, R 4 is:

[0119]

[0120] In a specific embodiment, the compound is represented by a formula selected from the group consisting of:

[0121]

[0122] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H, and cyclopropyl at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen at each occurrence; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; R 34 is independently selected from the group consisting of H, C1-C2 alkyl, and C3-C5 cycloalkyl at each occurrence; and n is 3.

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

[0124] In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9 is independently selected from H and C1-C3 alkyl at each occurrence; R 34 is independently selected from the group consisting of H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0125] In some embodiments, R 1 is CHF2 at each occurrence; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9 is selected from H and C1-C3 alkyl at each occurrence; R 34 is independently selected from the group consisting of H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CHF2 at each occurrence; R 2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is selected from H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0126] In some embodiments, the compound is represented by formula IIA.1 as defined above. In some embodiments, the compound is represented by 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.

[0127] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0128]

[0129] wherein R 1independently selected from the group consisting of: bromine, chlorine, CF3, CF2H and cyclopropyl at each occurrence; R 2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl and halogen at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0130] In some embodiments, R 1 is bromine at each occurrence; R 2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine at each occurrence; R 6 selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 selected from: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF2H at each occurrence; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from: H and C1-C3 alkyl at each occurrence; and n is 3.

[0131] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0132]

[0133] wherein R 1 independently selected from the group consisting of: bromine, chlorine, CF3, CF2H and cyclopropyl at each occurrence; R 2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl and halogen at each occurrence; R 9 independently selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl at each occurrence; R 34 independently selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0134] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from the group consisting of H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 9 At each occurrence, is selected from: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0135] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from the group consisting of H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 9 Each occurrence is independently selected from: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0136] In some embodiments, R 1 CHF2 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from the group consisting of H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 CHF2 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 9 At each occurrence, is selected from: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0137] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0138]

[0139] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H and cyclopropyl each time it appears; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl and halogen each time it appears; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0140] In some embodiments, R 1 is bromine each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R 6 is selected from C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; and R 9 is selected from H and C1-C3 alkyl each time it appears. In some embodiments, R 1 is CF3 each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R 6 is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CF2H each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R 6 is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0141] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0142]

[0143]

[0144] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H and cyclopropyl each time it appears; R 2independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R 9 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R 34 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0145] In some embodiments, R 1 is bromine each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is bromine each time it appears; R 2 independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; each R 34 is H; and n is 3.

[0146] In some embodiments, R 1 is CF3 each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 independently selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CF3 each time it appears; R 2 independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R 9 independently selected from: H and C1-C3 alkyl each time it appears; each R 34 is H; and n is 3.

[0147] In some embodiments, R 1 is CHF2 each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CHF2 each time it appears; R 2independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; R 9 selected at each occurrence from: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0148] 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.

[0149] In some embodiments, the compound is represented by a formula selected from:

[0150]

[0151] wherein R 1 is independently selected at each occurrence from the group consisting of: bromine, chlorine, CF3, CF2H, and cyclopropyl; R 2 is independently selected at each occurrence from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; R 6 is independently selected at each occurrence from: C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected at each occurrence from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0152] In some embodiments, R 1 is bromine at each occurrence; R 2 is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine; R 6 is independently selected at each occurrence from: C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine; R 6 is independently selected at each occurrence from: C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected from: H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is CF2H at each occurrence; R 2 is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine; R 6 is independently selected at each occurrence from: C1-C3 alkyl and C3-C4 cycloalkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0153] In a specific embodiment, the compound is represented by the following:

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein A-1 is selected from the group consisting of:

[0156]

[0157] R 1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines; R 2 is selected from: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen; R 4 is selected from the group consisting of:

[0158]

[0159] R 7 is independently selected from the group consisting of: H, C 1- C6 alkyl, C 3- C6 cycloalkyl, wherein each C 1- C6 alkyl and C 3- C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 7 join together with the atom to which they are attached to form a bridging oxygen group; R 6 and R 9 are independently selected from the group consisting of: H, C 1- C6 alkyl, and C3-C6 cycloalkyl, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; Z is selected from the group consisting of:

[0160]

[0161] R 34 is independently selected from: H and R 36 , wherein R 36 is independently selected from: C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 36 join together with the carbon to which they are attached to form a C3-C6 cycloalkyl; L is -(C(R 10 )2) m -; R 10Independently selected from the following group at each occurrence: H, C1-C3 alkyl, and C3-C5 cycloalkyl, where each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 10 joins with the carbon to which it is attached to form a C3-C5 cycloalkyl; m is 0, 1, 2, or 3; and n is 2, 3, or 4; provided that: when m is 0, R 4 is C-linked to the pyrazole ring; when m is 1, R 4 is C-linked to L; and then when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0162] In some embodiments, A-1 is:

[0163]

[0164] In some embodiments, n is 3.

[0165] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0166] In some embodiments, L is a direct bond.

[0167] In some embodiments, L is selected from the group: -CH2-, -CH2CH2-, and -CH2CH2CH2-. In some embodiments, L is -CH2-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-.

[0168] In some embodiments, Z is selected from the group:

[0169]

[0170] In some embodiments, Z is selected from the group:

[0171]

[0172] In some embodiments, R 1 is selected from the group: halogen, C 1- C5 alkyl, and C 3- C5 cycloalkyl, where C 1- C5 alkyl or C 3- C5 cycloalkyl is optionally substituted with one, two, or three occurrences of fluorine. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1is a halogen. In some embodiments, R 1 is bromine. In some embodiments, R 1 is cyclopropyl.

[0173] 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 the C1-C5 alkyl or C3-C5 cycloalkyl is optionally substituted with one, two, or three independently occurring fluorines. In some embodiments, R 2 is selected from: C 1-2 alkyl and C 3-4 cycloalkyl. In some embodiments, R 2 is selected from chlorine and bromine.

[0174] In some embodiments, R 2 is selected from the group consisting of: C 1- C5 alkyl, H, and C3-C4 cycloalkyl. In some embodiments, R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl. In some embodiments, R 2 is selected from: chlorine and bromine.

[0175] In some embodiments, R 4 is:

[0176]

[0177] In a specific embodiment, the compound is represented by a formula selected from the group consisting of:

[0178]

[0179]

[0180] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H, and cyclopropyl at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen at each occurrence; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0181] In some embodiments, R 1 is bromine at each occurrence; R 2 is independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9is independently selected from, at each occurrence: H and C1-C3 alkyl; R 34 is independently selected from the group consisting of, at each occurrence: H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is bromine, at each occurrence; R 2 is independently selected from, at each occurrence: C1-C2 alkyl and C3-C4 cycloalkyl; R 9 is selected from, at each occurrence: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0182] In some embodiments, R 1 is CF3, at each occurrence; R 2 is independently selected from, at each occurrence: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine; R 9 is independently selected from, at each occurrence: H and C1-C3 alkyl; R 34 is independently selected from the group consisting of, at each occurrence: H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is CF3, at each occurrence; R 2 is independently selected from, at each occurrence: C1-C2 alkyl and C3-C4 cycloalkyl; R 9 is independently selected from, at each occurrence: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0183] In some embodiments, R 1 is CHF2, at each occurrence; R 2 is independently selected from, at each occurrence: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine; R 9 is selected from, at each occurrence: H and C1-C3 alkyl; R 34 is independently selected from the group consisting of, at each occurrence: H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is CHF2, at each occurrence; R 2 is independently selected from, at each occurrence: C1-C2 alkyl and C3-C4 cycloalkyl; R 9 is selected from, at each occurrence: H and C1-C3 alkyl; each R 34 is H; and n is 3.

[0184] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0185]

[0186] wherein R 1 is independently selected from the group consisting of, at each occurrence: bromine, chlorine, CF3, CF2H, and cyclopropyl;2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0187] In some embodiments, R 1 is bromine at each occurrence; R 2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 selected from: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF2H at each occurrence; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 independently selected from: C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 independently selected from: H and C1-C3 alkyl at each occurrence; and n is 3.

[0188] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0189]

[0190] wherein R 1 independently selected from the group consisting of: bromine, chlorine, CF3, CF2H, and cyclopropyl at each occurrence; R 2 independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen at each occurrence; R 9 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; R 34 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0191] In some embodiments, R1 is bromine at each occurrence; R 2 is independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9 is selected from: H and C1-C3 alkyl at each occurrence; R 34 is independently selected from the group consisting of: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is bromine at each occurrence; R 2 is independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is selected from: H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0192] In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9 is independently selected from: H and C1-C3 alkyl at each occurrence; R 34 is independently selected from the group consisting of: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from: H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0193] In some embodiments, R 1 is CHF2 at each occurrence; R 2 is independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 9 is selected from: H and C1-C3 alkyl at each occurrence; R 34 is independently selected from the group consisting of: H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CHF2 at each occurrence; R 2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is selected from: H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0194] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0195]

[0196] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H, and cyclopropyl each time it appears; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromine, chlorine, and halogen each time it appears; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0197] In some embodiments, R 1 is bromine each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 6 is selected from C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; and R 9 is selected from H and C1-C3 alkyl each time it appears. In some embodiments, R 1 is CF3 each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 6 is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CF2H each time it appears; R 2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 6 is independently selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl each time it appears; R 9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0198] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0199]

[0200]

[0201] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H, and cyclopropyl each time it appears; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R 9independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R 34 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0202] In some embodiments, R 1 is bromine each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is bromine each time it appears; R 2 independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; each R 34 is H; and n is 3.

[0203] In some embodiments, R 1 is CF3 each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 independently selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CF3 each time it appears; R 2 independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R 9 independently selected from: H and C1-C3 alkyl each time it appears; each R 34 is H; and n is 3.

[0204] In some embodiments, R 1 is CHF2 each time it appears; R 2 independently selected from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine each time it appears; R 9 selected from: H and C1-C3 alkyl each time it appears; R 34 independently selected from the group consisting of: H and C1-C3 alkyl each time it appears; and n is 3. In some embodiments, R 1 is CHF2 each time it appears; R 2 independently selected from: C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R 9is independently selected from H and C1-C3 alkyl at each occurrence; each R 34 is H; and n is 3.

[0205] In some embodiments, the compound is represented by a formula selected from:

[0206]

[0207] wherein R 1 is independently selected from the group consisting of bromine, chlorine, CF3, CF2H, and cyclopropyl at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen at each occurrence; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl at each occurrence; and n is 3.

[0208] In some embodiments, R 1 is bromine at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from H and C1-C3 alkyl at each occurrence; and n is 3. In some embodiments, R 1 is CF3 at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from H and C1-C3 alkyl; and n is 3. In some embodiments, R 1 is CF2H at each occurrence; R 2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, bromine, and chlorine at each occurrence; R 6 is independently selected from C1-C3 alkyl and C3-C4 cycloalkyl at each occurrence; R 9 is independently selected from H and C1-C3 alkyl at each occurrence; and n is 3.

[0209] In some embodiments, the compound is represented by a formula selected from the group consisting of: 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-(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-Isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, racemic-(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)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, racemic-(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, racemic-(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)pyrimidin-4-yl)amino)propyl)piperidin-2-one1-(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-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-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)piperidin-2-one, racemic-(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, 1-(3-((2-((1-(3-(dimethylamino)propyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, racemic-(R)-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-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 1-(3-((2-((3-ethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one1-(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, racemic-(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)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-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)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-((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-one1-(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, racemic-(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, racemic-(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, racemic-(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, racemic-(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, racemic-(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, 2-methyl-2-(3-methyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide3-(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)-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-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)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-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, 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-one4-(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)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-one4-(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-oxa-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)-1,4-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-one4-(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-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)imidazolidin-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-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)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-oneRacemic-(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, racemic-(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)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-oneRacemic-(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-oxabicyclo[4.1.0]hept-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)-1,4-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-oxazepan-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-oxazepan-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-5-one, 3-(3-((2-((2-(4-Methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-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-oxazepan-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)-1,3-oxazepan-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-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)-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)-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)-1,3-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)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one4-(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-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[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-one3-(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-one4-(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)-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)-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-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-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)-1,3-oxazepan-2-one2,2-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-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-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-one4-(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)-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-one1-(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)-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-oxazepan-3-one4-(3-((5-(Difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-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-(Difluoromethyl)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-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)-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-oxazepan-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)-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-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-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-one4-(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-(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)-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]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-one1-(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]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)-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)-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-one4-(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)-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)-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-oxazepan-3-one4-(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-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)-1,3-oxazepan-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-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-oxazepan-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-(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)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-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-oxazepan-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)morpholin-3-one1-(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-methylpyrrolidin-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)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one3-(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)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-one1-(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)-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-oxabicyclo[4.1.0]heptan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxabicyclo[4.1.0]heptan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[3.1.0]hexan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxabicyclo[4.1.0]heptan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxabicyclo[4.1.0]heptan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[3.1.0]hexan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxamorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxatetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((3-Methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[2.2.1]hept-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-oxabicyclo[2.2.1]heptan-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-oxabicyclo[3.2.1]oct-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-oxabicyclo[3.2.1]oct-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxapiperidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxaazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(4-methyl-2-oxabicyclo[3.2.1]oct-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[2.2.1]hept-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxamorpholino)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxatetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[2.2.1]hept-3-yl)propyl)amino)pyrimidine-5-carbonitrile2-((3-Methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxabicyclo[1.1.1]pentan-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-oxabicyclo[2.2.1]heptan-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-(3-oxabicyclo[1.1.1]pentan-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-oxabicyclo[1.1.1]pentan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[1.1.1]pentan-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-oxabicyclo[1.1.1]pentan-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-oxabicyclo[2.2.1]heptan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxabicyclo[1.1.1]pentan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxabicyclo[1.1.1]pentan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-Dimethyl-2-oxabicyclo[1.1.1]pentan-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-oxabicyclo[1.1.1]pentan-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-endo-oxido-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-endo-oxido-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-endo-oxido-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-endo-oxido-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-endo-oxido-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-endo-oxido-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-endo-oxido-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-endo-oxidopyrrolidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-endo-oxidopyrrolidin-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-endo-oxidopyrrolidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-Dimethyl-2-endo-oxidopyrrolidin-1-yl)propyl)amino)-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile4-((3-(3,3-Dimethyl-2-oxabicyclo[1.1.1]pentan-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-oxabicyclo[1.1.1]pentan-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)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-one4-(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)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)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-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)-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-one4-(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-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-oxazepan-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-oxazepan-2-one4-(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)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)-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-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-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-one1-(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)-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)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, 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-(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]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-((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)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-oxazepan-2-one4-(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-oxido-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)-1,4-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-dioxothiomorpholino)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-bridged-oxy-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)-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)-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-bridged-oxypiperidin-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-ethenyl-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-one3-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyridin-4-yl)amino)propyl)-1,3-oxazepan-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)-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-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)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, 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)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-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)pyridin-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-dioxothiomorpholino)-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-oxazepan-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.、

[0210] Treatment method

[0211] The compounds described herein can act as autophagy inhibitors that can be used to treat conditions in patients in need. For example, the condition can be a tumor such as a solid tumor. The condition can also be cancer.

[0212] Exemplary conditions also include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, bone metastases, papillary thyroid cancer, non-small cell lung cancer and colorectal cancer, and the cancer treated by the methods described herein can be metastatic cancer.

[0213] In some embodiments, the compounds described herein can be used to treat cancers caused by RAS mutations. In some embodiments, the cancer is caused by a KRAS mutation. In some embodiments, the cancer has additional mutations in tumor suppressor proteins, including mutations in TP53, PTEN, CDN2A / INK4A, p16 or STAG2. In some embodiments, these additional mutations occur in one or more of TP53, PTEN, CDN2A / INK4A, p16 or STAG2. In some embodiments, the cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer.

[0214] In some embodiments, the assay of autophagic cell inhibition by the compounds described herein is determined by monitoring autophagic flux, e.g., by monitoring the inhibition of autophagy-mediated clearance of mCherry / GFP-LC3 fusion protein. In some embodiments, the assay of autophagic cell inhibition by the compounds described herein is determined by monitoring the accumulation of autophagy proteins such as p62 or LC-3. In some embodiments, the assay of autophagic cell inhibition by the compounds described herein is determined by the reduced clearance of luciferase-tagged LC3 protein. In some embodiments, the assay of autophagic cell inhibition by the compounds described herein is determined by monitoring the reduction of cellular autophagosomes, e.g., by measuring fluorescent puncta with the autophagosome marker Cyto-ID.

[0215] In some embodiments, the inhibition of ULK kinase by the compounds described herein is determined by the inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1, or STING in tumor cells or non-tumor host tissues. In some embodiments, the inhibition of ULK kinase by the compounds described herein is assayed in host tissues including immune cells.

[0216] In some embodiments, the in vivo inhibition of autophagy by the compounds described herein is determined by the inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1, or STING in tumor cells or non-tumor host tissues. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is assayed in host tissues including immune cells. In some embodiments, the in vivo inhibition of autophagic flux by the compounds described herein can be used as a pharmacodynamic model for monitoring the kinetics and extent of such ULK inhibition. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is assayed in animals with pancreatic cancer. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is assayed in animals with lung cancer. In some embodiments, the in vivo inhibition of ULK kinase is assayed in animals with colorectal cancer. In some embodiments, the in vivo inhibition of autophagy by the compounds described herein is determined by the inhibition of autophagic flux in tumor cells or non-tumor host tissues by monitoring the inhibition of autophagosome formation or by monitoring the accumulation of autophagy proteins such as p62 or LC-III. In some embodiments, the in vivo inhibition of autophagy is assayed in host tissues including immune cells. In some embodiments, the in vivo inhibition of autophagic flux can be used as a pharmacodynamic model for monitoring the kinetics and extent of such ULK inhibition.

[0217] In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in immunocompromised mice such as SCID or nude mice using human RAS mutant cell lines in xenograft studies. In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in xenograft studies in immunocompromised mice such as SCID or nude mice using human RAS mutant patient-derived tumor xenografts (PDX). In some embodiments, the xenograft studies include evaluating the compounds described herein in a pancreatic cancer model. In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in a genetically engineered mouse (GEM) model of syngeneic mutant RAS cancer. In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in a murine GEM syngeneic orthotopic pancreatic cancer model named as follows: KPC model (LSL-Kras G12D / + ; LSL-Trp53 R172H / + ; Pdx-1-Cre) or a variant of the KPC model.

[0218] In some embodiments, the compounds described herein are evaluated in combination with a MEK inhibitor in a xenograft or GEM cancer model. In some embodiments, the compounds described herein are evaluated in combination with a RAF inhibitor in a xenograft or GEM cancer model. In some embodiments, the compounds described herein are evaluated in combination with an ERK inhibitor in a xenograft or GEM cancer model. In some embodiments, the compounds described herein are evaluated in combination with a direct RAS G12C inhibitor in a xenograft or GEM cancer model.

[0219] In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in an immunocompetent mouse cancer model for assessing immunomodulatory components against the mechanism of action of ULK inhibitors. In some embodiments, the immunocompetent mouse model is a murine GEM syngeneic orthotopic pancreatic cancer model named as follows: KPC model (LSL-Kras G12D / + ; LSL-Trp53 R172H / +; Pdx-1-Cre), or variant forms of the KPC model. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with MEK inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with RAF inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with ERK inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in combination with direct RAS G12C inhibitors.

[0220] In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced innate immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced adaptive immune response. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced activity of antigen-presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced anti-tumor activity of myeloid cells including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is the enhanced activity of effector T cells including cytotoxic T cells.

[0221] In some embodiments, the present disclosure provides methods of treating the disorders described herein, which include: administering to a patient in need a therapeutically effective amount of the compounds described herein, and detecting the engagement of the compound with ULK kinase during or after the administration (e.g., at discrete time points, such as one week, two weeks, or one month after the initial administration of the compound under consideration), wherein the detection includes contacting a sample obtained from the patient (including but not limited to tumor, blood, saliva, or tissue) with a phosphorylated ATG13 antibody ELISA assay to detect, for example, ULK kinase activity inhibition based on the content of phosphorylated ATG13 in the sample. In some embodiments, the methods under consideration include optionally contacting a sample obtained from the patient (including but not limited to tumor, blood, saliva, or tissue) with a phosphorylated ATG13 antibody ELISA assay before administering the compound, and comparing the content of phosphorylated ATG13 in the sample obtained before administration with the content of phosphorylated ATG13 in the sample obtained during or after the administration. In some embodiments, the phosphorylated ATG13 is p-S318ATG13.

[0222] In some embodiments, provided herein are methods of treating the disorders described herein, which comprise: administering to a patient in need a therapeutically effective amount of a compound described herein, and detecting, during or after the administration (e.g., at discrete time points, such as one, two, or three months after the initial administration of the compound under consideration), the engagement of the compound with ULK kinase, wherein the detection comprises contacting a sample obtained from the patient (including but not limited to tumor, blood, saliva, or tissue) with a phosphorylated ATG14 antibody ELISA assay to detect, for example, inhibition of ULK kinase activity based on the content of phosphorylated ATG14 in the sample. In some embodiments, the methods under consideration comprise optionally contacting a sample obtained from the patient (including but not limited to tumor, blood, saliva, or tissue) with a phosphorylated ATG14 antibody ELISA assay prior to administering the compound, and comparing the content of phosphorylated ATG14 in the sample obtained before administration with the content of phosphorylated ATG14 in the sample obtained during or after the administration. In some embodiments, phosphorylated ATG14 is p-ATG14Ser29.

[0223] In some embodiments, provided herein are methods of treating the disorders described herein, which comprise: administering to a patient in need a therapeutically effective amount of a compound described herein, and detecting, during or after the administration (e.g., at discrete time points, such as one, two, or three months after the initial administration of the compound under consideration), the engagement of the compound with ULK kinase, 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, for example, inhibition of ULK kinase activity based on the content of p62 in the sample. In some embodiments, the methods under consideration 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 prior to administering the compound, and comparing the content of p62 in the sample obtained before administration with the content of p62 in the sample obtained during or after the administration.

[0224] In some embodiments, provided herein are methods of treating the disorders described herein, which comprise: administering to a patient in need thereof a therapeutically effective amount of a compound described herein, and detecting, during or after the administration (e.g., at discrete time points, such as one, two, or three weeks or one month after the initial administration of the compound under consideration), the engagement of the compound with ULK kinase, 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, for example, ULK kinase activity inhibition based on the amount of pBeclin in the sample. In some embodiments, the methods under consideration 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 administering the compound, and comparing the amount of pBeclin in the sample obtained before administration with the amount of pBeclin in the sample obtained during or after the administration.

[0225] The compounds provided herein can be administered to a patient (animal and human) in need of such treatment in a dose that provides optimal pharmaceutical efficacy. It will be understood that the dosage required for any particular application will vary with the patient, not only as a function of the particular compound or composition selected, but also as a function of the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent drug therapy, or the particular diet followed by the patient, as well as other factors recognized by those skilled in the art, where the appropriate dosage is ultimately at the discretion of the attending physician. For treating the clinical conditions and diseases mentioned above, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in the form of 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.

[0226] Treatment can be continued for a long or short period as needed. The composition can be administered according to a regimen, for example, one to four or more times per day. 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 1 year, or indefinitely. The treatment period can be terminated when the desired result is achieved.

[0227] Combination therapy

[0228] The compounds described herein (e.g., compounds of formula I as defined herein) can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein such as cancer. For example, the present invention provides pharmaceutical compositions comprising the compounds described herein (e.g., compounds 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 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, such as a pharmaceutical composition comprising a compound of formula I as a 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. Combination therapy also encompasses other combinations. Although two or more agents in combination therapy can be administered simultaneously, this is not necessarily the case. For example, the administration of the first agent (or combination of agents) can precede the administration of the second agent (or combination of agents) by several minutes, hours, days, or weeks. Thus, the administration of two or more agents can be within several minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or weeks of each other. In some cases, even longer intervals are possible. Although in most cases two or more agents in combination therapy need to be present in the patient's body simultaneously, this is not necessarily the case.

[0229] Combination therapy can also include two or more administrations of one or more of the agents using different sequences of the component agents. For example, if agent X and agent Y are used in combination, they can be administered in sequence one or more times in any combination, such as in the order of X - Y - X, X - X - Y, Y - X - Y, Y - Y - X, X - X - Y - Y, etc.

[0230] In some embodiments, one or more additional therapeutic agents that can be administered in combination with the compounds provided herein can be MAPKAP pathway inhibitors. Such MAPKAP pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.

[0231] Exemplary MEK inhibitors include, but are not limited to: trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to: ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof. Exemplary RAF inhibitors include, but are not limited to: LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof. Exemplary Ras inhibitors include, but are not limited to: AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

[0232] The compounds described herein can be administered in combination with other therapeutic agents known for the treatment of cancer. These other therapeutic agents include: radiotherapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, anti-estrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug conjugates (ADCs), immunotherapeutic agents including immunomodulators, targeted therapeutic agents, cancer vaccines, and CAR-T cell therapy.

[0233] In some embodiments, the additional therapeutic agent can be a chemotherapeutic agent including but not limited to: anti-tubulin agents (such as paclitaxel, albumin-bound particles of paclitaxel for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins or maytansinoids), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents or DNA topoisomerase inhibitors (including anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone or epirubicin, camptothecin such as topotecan, irinotecan or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate).

[0234] In some other specific embodiments, the additional therapeutic agent may be a kinase inhibitor including but not limited to the following: erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib; an anti-estrogen agent including but not limited to the following: tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; an anti-androgen agent including but not limited to the following: abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate; a steroid agent including but not limited to the following: prednisone and dexamethasone; a PARP inhibitor including but not limited to the following: neraparib, olaparib, talazoparib, and rucaparib; a topoisomerase I inhibitor including but not limited to the following: irinotecan, camptothecin, exatecan, and topotecan; a topoisomerase II inhibitor including but not limited to the following: anthracycline, etoposide, etoposide phosphate, and mitoxantrone;Histone deacetylase (HDAC) inhibitors including but not limited to the following: vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors including but not limited to the following: DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors including but not limited to the following: bortezomib and carfilzomib; thalidomide; lenalidomide; pomalidomide; biological agents including but not limited to the following: trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab; anti-PD-1 agents including the following: pembrolizumab, nivolumab, pidilizumab, and cemiplimab; anti-PD-L1 agents including the following: atezolizumab, avelumab, durvalumab, and BMS-936559; anti-angiogenic agents including the following: bevacizumab and aflibercept; and antibody-drug conjugates (ADCs) including the following: DM1, DM4, MMAE, MMAF, or camptothecin payload; brentuximab vedotin and trastuzumab emtansine; radiotherapy; therapeutic vaccines including but not limited to sipuleucel-T.;

[0235] In some embodiments, the additional therapeutic agent can be an immunomodulator including, but not limited to, the following: anti-PD-1 or anti-PDL-1 therapeutic agents, which include pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab; anti-TIM3 (anti-HAVcr2) therapeutic agents, which include, but are not limited to, TSR-022 or MBG453; anti-LAG3 therapeutic agents, which include, but are not limited to, relatlimab, LAG525, or TSR-033; anti-4-1BB (anti-CD37, anti-TNFRSF9) agents; CD40 agonist therapeutic agents, which include, but are not limited to, SGN-40, CP-870,893, or RO7009789; anti-CD47 therapeutic agents, which include, but are not limited to, Hu5F9-G4; anti-CD20 therapeutic agents; anti-CD38 therapeutic agents; STING agonists, which include, but are not limited to, ADU-S100, MK-1454, ASA404, or amidobenzimidazole; anthracyclines, which include, but are not limited to, doxorubicin or mitoxantrone; hypomethylating agents, which include, but are not limited to, azacitidine or decitabine; other immunomodulatory therapeutic agents, which include, but are not limited to, epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone.

[0236] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs including goserelin and leuprolide.

[0237] In some embodiments, the additional therapeutic agent is selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.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, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY317615, 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-oxa-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEGylated irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperidinomethyl)-indolyl]-quinolinone, vatalanib, AG-013736, AVE-0005, acetate 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) xwhere x = 1 to 2.4]), goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BacillusCalmette-Guerin, BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin D, daunomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, 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-vitamin A acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukindiftitox, gefitinib, bortezomib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, paclitaxel without hydrogenated castor oil, epithilone BB), 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 alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans-retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomabtiuxetan), androgen, decitabine, altretamine, bexarotene, tositumomab, arsenic trioxide, corticosterone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0238] Pharmaceutical Compositions and Kits

[0239] Another aspect of the invention provides pharmaceutical compositions comprising a compound as disclosed herein formulated with a pharmaceutically acceptable carrier. Specifically, the invention provides pharmaceutical compositions comprising a compound as 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, but the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, the disclosed compositions may be formulated in unit dosage form and / or may be formulated for oral or subcutaneous administration.

[0240] Exemplary pharmaceutical compositions can be used in pharmaceutical dosage forms, for example, in solid, semi-solid or liquid forms, which contain one or more of the compounds described herein as active components in admixture with organic or inorganic carriers or excipients suitable for external, enteral or parenteral administration. The active components can be admixed, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable forms of use. The active target compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0241] For the preparation of solid compositions such as tablets, the main active component can be mixed with a pharmaceutical carrier such as conventional tablet-making components (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate or gum) and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of the compounds provided herein or their non-toxic, pharmaceutically acceptable salts. When referring to these preformulation compositions as homogeneous preformulation compositions, it means that the active component is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0242] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the compositions of the present invention are admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dibasic calcium 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) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as ethanol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions can also contain buffering agents. Excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol and the like can also be used to use similar types of solid compositions as fillers in soft-fill and hard-fill gelatin capsules.

[0243] Tablets can be manufactured by compressing or molding, optionally with one or more auxiliaries. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or croscarmellose sodium), surfactants or dispersants. Molded tablets can be manufactured by molding a mixture of the composition of the present invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as dragees, capsules, pills and granules can optionally be scored or provided with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0244] Compositions for inhalation or insufflation include solutions, suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the composition of the present invention, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0245] In addition to the composition of the present invention, suspensions may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth and mixtures thereof.

[0246] Preparations for rectal or vaginal administration may be presented in the form of suppositories, which can be prepared by mixing the composition of the present invention with one or more suitable non - irritant excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and will thus melt in the body cavity and release the active agent.

[0247] Dosage forms for percutaneous administration of the composition of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

[0248] In addition to the composition of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0249] In addition to the compositions of the present invention, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0250] The compositions and compounds of the present invention may alternatively be administered by nebulization. This is achieved by preparing an aqueous nebulizer formulation, a liposomal formulation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used as they minimize the exposure of the medicament to shear forces that may cause degradation of the compounds contained in the compositions of the present invention. Generally, aqueous nebulizer formulations are prepared by formulating an aqueous solution or suspension of the composition of the present invention with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular composition of the present invention, but generally include non-ionic surfactants (Tweens, copolymer Pluronics, or polyethylene glycols); innocuous proteins such as serum albumin; sorbitan esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Nebulizer formulations are generally prepared from isotonic solutions.

[0251] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise the composition of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, said sterile powders may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0252] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and their analogs) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate), as well as cyclodextrins. Adequate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0253] In another aspect, enteric pharmaceutical formulations are provided, which comprise the disclosed compounds and enteric materials; and their pharmaceutically acceptable carriers or excipients. Enteric materials refer to polymers that are substantially insoluble in the gastric acidic environment and are mainly soluble in intestinal fluids at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5.

[0254] Thus, enteric materials are insoluble, e.g., until a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8 or about 10.0. Exemplary enteric materials include: cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose acetate propionate; cellulose acetate maleate; cellulose acetate butyrate; cellulose acetate propionate; copolymer of methyl methacrylate and methyl acrylate; copolymer of methyl acrylate, methyl methacrylate and methacrylic acid; copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl acrylate chloride trimethylammonium copolymer; natural resins such as zein, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of each of the foregoing materials is known or can be readily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art who benefit from the present invention will recognize that it is not comprehensive and that there are other enteric materials that meet the objectives described herein.

[0255] Advantageously, the present disclosure provides kits for consumers, such as those in need of treating cancer. The kits include a suitable dosage form, such as the dosage forms described above; and instructions describing a method of using the dosage form to mediate, reduce, or prevent inflammation. The instructions will guide the consumer or medical personnel to administer the dosage form according to an administration pattern known to those skilled in the art. The kits may advantageously be packaged and sold in single or multiple kit units. An example of such kits is the so-called blister packaging. Blister packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packaging generally consists of a relatively rigid sheet material covered with a preferably transparent plastic foil. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the groove, and the relatively rigid sheet material is sealed against the plastic foil at the foil side opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet material. Preferably, the sheet material is strong enough such that an opening can be formed at the position of the groove in the sheet material by manually applying pressure on the groove to remove the tablet or capsule from the blister packaging. Subsequently, the tablet or capsule can be removed through the opening.

[0256] It may be necessary to provide memory aids on the kit, such as in the form of numbers adjacent to the tablets or capsules, which correspond to the days on which the tablets or capsules so specified should be taken in the dosing regimen. Another example of such a memory aid is a schedule printed on a card, such as "First week, Monday, Tuesday,... etc.; Second week, Monday, Tuesday,... etc.". Other variations of the memory aid will be obvious. The "daily dose" may be a single tablet or capsule to be taken on a specified date, or several pills or capsules. In addition, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this. Examples

[0257] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that unless otherwise indicated, all recommended reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experiment duration, and handling procedures, can be selected as the standard conditions for the reaction. Those familiar with organic synthesis techniques should understand that the functional groups present on various parts of the molecule should be compatible with the recommended reagents and reactions. Substituents that are not compatible with the reaction conditions will be obvious to those skilled in the art and thus indicate alternative methods. The starting materials for the examples are commercially available or can be readily prepared from known materials by standard methods.

[0258] The following abbreviations are used in the present invention and have the following definitions: "ADP" is adenosine diphosphate, "Boc" is tert-butyl carbonate, "CDI" is carbonyldiimidazole, "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, "DMEM" is Dulbecco's Modified Eagle Media, "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, "HCl" is hydrochloric acid, "Hex" is hexane, "H2O" is water, "HOBt" is hydroxybenzotriazole, "IC 50"IC50" is the half maximal 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 referred to as "ambient temperature", which is understood to consist of a range of normal laboratory temperatures between 15 °C and 25 °C, "satd." is saturated, "T3P" is 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.

[0259] General Chemical Reactions

[0260] The exemplary compounds described herein can be obtained by the general synthetic methods, intermediate preparations, and the accompanying examples illustrated in the schemes below.

[0261] Scheme 1

[0262]

[0263] Exemplary methods for preparing pyrazoles have been disclosed in WO2006 / 071940 and WO2008 / 1311227, the contents of which are incorporated herein by reference in their entirety. In Scheme 1, R 4-L-substituted pyrazolamide D-I can be obtained by condensing hydrazine 4-1 (readily available to those skilled in the art) with 1,1,3,3-tetramethoxypropane A-I to obtain R 4 -L-substituted pyrazole B-I. The conditions for this transformation include heating in ethanol HCl. Those skilled in the art should further recognize that, in some embodiments, R 4 -L-substituted pyrazole B-I is prepared by direct alkylation of pyrazole. In some embodiments, pyrazole B-I is regioselectively nitrated under standard conditions familiar to those skilled in the art to obtain nitropyrazole C-I. Finally, nitropyrazole C-I is hydrogenated using a hydrogenation catalyst such as palladium or nickel to obtain pyrazolamide D-I.

[0264] In Scheme 1, R 4 embodiments include heterocyclic groups having suitable optional substituents as exemplified by the intermediate table below and NR 6 R 9 , where R 6 and R 9 can each independently be alkyl, embodiments of L include -(CH2) m -, where m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-linked to the pyrazole; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0265] Scheme 2

[0266]

[0267] General additional embodiments of pyrazolamide D-I-1 and D-I-2 substituted with a single R 2 (i.e., where one R 2 is not hydrogen) are prepared as described in Scheme 2. The ketoester A-I-1 is reacted with N,N-dimethylformamide dimethyl acetal or triethyl orthoformate / acetic anhydride to obtain A-I-2 (where LG is a suitable leaving group required for the subsequent cyclization / pyrazole formation reaction). In the presence of acid, A-I-2 is reacted with hydrazine 4-1 (readily available to those skilled in the art) to predominantly obtain B-I-1 or its positional isomer B-I-2. The regiochemistry of the cyclization is controlled under conditions (such as temperature and solvent) familiar to those skilled in the art. For the synthesis of B-I-1 (where R 2The conditions for (wherein LG is not hydrogen) include: when LG is OEt, in a protic solvent (such as ethanol), at a low temperature (-10 °C to RT), in the presence of an acid. The conditions for synthesizing B-I-2 include: when LG is NMe2, in a protic solvent (such as ethanol), under reflux, in the presence of an acid. Subsequently, the ester B-I-1 or B-I-2 is converted into the corresponding acid C-I-1 or C-I-2 using standard conditions known to those skilled in the art. The acid C-I-1 or C-I-2 is converted into the corresponding amine D-I-1 or D-I-2 through the Curtius rearrangement reaction.

[0268] In Process 2, examples of LG include OMe, OEt, and N(CH3)2, and examples of R 2 include alkyl and cycloalkyl, where the alkyl and cycloalkyl are optionally fluorinated, and examples of R 4 include heterocyclic groups and NR with suitable optional substituents as exemplified by the intermediate table below, and R 6 R 9 , where R 6 and R 9 can each independently be alkyl. Examples of L include -(CH2) m ]-, where m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-linked to the pyrazole; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0269] Process 3

[0270]

[0271] In a manner similar to Process 2, Process 3 illustrates the general preparation of amine D-I-3. The pyrazole ester B-I-3 is prepared by reacting hydrazine 4-1 (which can be readily obtained by those skilled in the art) with intermediate A-I-3. In some embodiments, the R 2 and R 3 moieties are independently varied such that R 3 is the same as or different from R 2 . Using standard conditions known to those skilled in the art, the ester B-I-3 is converted into the corresponding acid C-I-3. Under standard Curtius rearrangement reaction conditions known to those skilled in the art, the acid C-I-3 is converted into the amine D-I-3.

[0272] In Process 3, examples of R 2 and R 3 can independently include alkyl and cycloalkyl, where the alkyl and cycloalkyl are optionally fluorinated, and R 4Examples include a heterocyclic group having suitable optional substituents as exemplified in the intermediate table below and NR 6 R 9 wherein R 6 and R 9 each may independently be alkyl. Examples of L include -(CH2) m - where m may be 0, 1, 2 or 3, and when m is 0, R 4 is C-linked to pyrazole; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0273] Scheme 4

[0274]

[0275] In some embodiments, non-commercially available hydrazine 4-1 can be readily prepared by two methods shown in Scheme 4. One method involves diazotization of amine 4-2 followed by reduction using conditions familiar to those skilled in the art, such as treatment with Sn(II)Cl2 in the presence of a proton source. Alternatively, hydrazine 4-1 can be obtained from the corresponding N-tert-butoxycarbonyl hydrazine 4-3 by acid-catalyzed removal of the tert-butoxycarbonyl group. Those skilled in the art will recognize that in some embodiments, the conversion of carbamate 4-3 to hydrazine 4-1 is also achieved in situ within the reaction sequence. Thus, in all schemes where hydrazine 4-1 is typically used in the presence of an acid, carbamate 4-3 serves as a substitute for hydrazine 4-1. N-tert-butoxycarbonyl hydrazine 4-3 can be prepared by reductive amination of a commercially available aldehyde or ketone 4-4 and tert-butyl hydrazinecarboxylate.

[0276] In Scheme 4, examples of R 4 include a heterocyclic group having suitable optional substituents as exemplified in the intermediate table below and NR 6 R 9 wherein R 6 and R 9 each may independently be alkyl. Examples of L include -(C(R 10 )2) m - where examples of R 10 are H, and wherein m may be 0, 1, 2 or 3; and when m is 0, R 4 is C-linked to nitrogen; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0277] Scheme 5

[0278]

[0279] In some embodiments, the general pyrazolamines D-I-4 or D-I-5 are prepared by two methods shown in Scheme 5. In this scheme, examples of R are shown 4 -L-linked 5-1 or 5-2. One method involves alkylating B-I-4 (readily available to those skilled in the art) with commercially available 5-1 in the presence of a base (such as potassium carbonate, cesium carbonate, or sodium hydride) and a polar aprotic solvent (dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, or the like) at a temperature between ambient temperature and 150 °C to obtain nitro pyrazoles C-I-4 and / or C-I-5. An alternative preparation of D-I-4 or D-I-5 involves the Mitsunobu reaction of B-I-4 with commercially available 5-2 to obtain nitro pyrazoles C-I-4 and C-I-5. Those skilled in the art will understand that when C-I-4 and C-I-5 are produced as a mixture, they are separated by SFC purification, crystallization, or chromatography. Finally, the nitro pyrazoles C-I-4 and C-I-5 are reduced 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) to obtain pyrazolamines D-I-4 and D-I-5.

[0280] In Scheme 5, examples of LG include Cl and Br, and examples of R 2 include alkyl, cycloalkyl, alkoxy, halogen, and CN, where the alkyl, cycloalkyl, or alkoxy may optionally be fluorinated, and examples of R 4 include heterocyclic groups, C(O)NR 6 R 9 and NR 6 R 9 with suitable optional substituents as exemplified by the intermediate table below, where R 6 and R 9 may each independently be H or alkyl, and examples of L include -(CH2) m -, where m may be 0, 1, 2, or 3; and when m is 0, R 4 is C-linked to the pyrazole; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L.

[0281] Scheme 6

[0282]

[0283] In some embodiments, the general pyrazolamines D-I-6 and D-I-7 are prepared as shown in Scheme 6. Examples of R are shown in this scheme 4-L-linked 6-1 embodiment. Alkylate B-I-4 (readily available to those skilled in the art) with 6-1 to obtain a mixture of nitropyrazoles B-I-5 and B-I-6. These two isomers B-I-5 and B-I-6 are separated by SFC purification, crystallization or chromatography. Activate each isomer B-I-5 or B-I-6 using MsCl or TsCl to obtain B-I-7 or B-I-8 (R is Ms or Ts), respectively. Replace OMs or OTs with amine R 4 -H to obtain C-I-6 or C-I-7, respectively. Finally, reduce nitropyrazole C-I-6 or C-I-7 in the presence of a hydrogenation catalyst (such as palladium, nickel) or mild reduction conditions (such as zinc or iron and ammonium chloride) to obtain pyrazolamine D-I-6 or D-I-7.

[0284] In Scheme 6, examples of LG include Cl and Br, examples of R include mesylate and tosylate, and examples of R 2 include alkyl, cycloalkyl, alkoxy, halogen, and CN, where the alkyl, cycloalkyl, or alkoxy may optionally be fluorinated, and examples of R 4 include heterocyclic groups and NR with suitable optional substituents as exemplified by the intermediate table below, and R 6 R 9 where R 6 and R 9 can each independently be alkyl, and examples of L include -(CH2) m -, where m is 2 or 3, and R 4 is N-linked.

[0285] Scheme 7

[0286]

[0287] Scheme 7 illustrates the synthesis of general amines D-I-8 and D-I-9. Thus, condense a commercially available aldehyde with glyoxal in the presence of ammonium hydroxide to obtain imidazole A-I-4 substituted by R 2 . R is shown in this scheme 4-L-linked embodiments of 5-1 or 5-2. Under conditions known to those skilled in the art (e.g., nitric acid / sulfuric acid at a temperature in the range of 0 °C to 100 °C), imidazole A-I-4 is nitrated to obtain nitroimidazole B-I-9. By alkylation (5-1) or Mitsunobu reaction (5-2), B-I-9 is converted into a mixture of C-I-8 and C-I-9. In some embodiments, the substituted nitroimidazoles C-I-8 and C-I-9 can be obtained by alkylation (5-1) or Mitsunobu reaction (5-2) of A-I-4 to obtain B-I-10. Subsequently, B-I-10 is nitrated to obtain C-I-8 and C-I-9. These two regioisomers C-I-8 and C-I-9 can be separated by SFC purification, crystallization, or chromatography. In the presence of a hydrogenation catalyst such as palladium or nickel, or mild reducing conditions such as zinc or iron and ammonium chloride, each nitroimidazole C-I-6 and C-I-7 is reduced to obtain the corresponding imidazoleamine D-I-8 and D-I-9, respectively.

[0288] In Process 7, embodiments of LG include Cl and Br, R 2 embodiments of include alkyl and cycloalkyl, where the alkyl and cycloalkyl are optionally fluorinated, R 4 embodiments of include heterocyclic groups and NR having suitable optional substituents as exemplified by the intermediate table below 6 R 9 where R 6 and R 9 can each independently be alkyl, embodiments of L include -(CH2) m - where m can be 2 or 3, and L is N-linked to the imidazole ring.

[0289] Process 8

[0290]

[0291] As exemplified in Process 8, in some embodiments, the substituted thiazoleamine D-I-10 can be prepared from the appropriately substituted thiazole A-I-5 (which can be readily obtained by those skilled in the art). This method has been described in WO2006072436, the content of which is incorporated herein by reference in its entirety. Bromothiazole A-I-5 is nitrated using fuming nitric acid or nitric acid with sulfuric acid to obtain bromonitrothiazole B-I-11. The bromo functional group on B-I-11 can be replaced by various amines R 4 -H in the presence of TEA or K2CO3 using conditions familiar to those skilled in the art such as Buchwald, Ullmann, or nucleophilic aromatic substitution reactions to obtain C-I-10, where R 4is N-linked. The Suzuki reaction (see Scheme 16) is carried out using B-I-11 with a commercially available or synthetic borate T including but not limited to other borate salts to obtain C-I-10, where R 4 is C-linked. Finally, C-I-10 is reduced in the presence of a hydrogenation catalyst such as palladium or nickel, or mild reducing conditions such as zinc or iron and ammonium chloride to obtain the corresponding thiazolamine D-I-10.

[0292] In Scheme 8, examples of R 2 include alkyl, cycloalkyl, alkoxy, halogen, and CN, where the alkyl, cycloalkyl, or alkoxy is optionally fluorinated, and examples of R 4 include heterocyclic groups and NR 6 R 9 where R 6 and R 9 can each independently be alkyl.

[0293] Scheme 9

[0294]

[0295] As illustrated in Scheme 9, in some embodiments, the substituted thiazolamine D-I-11 can be prepared from the appropriately substituted thiazole A-I-5 (which can be readily obtained by those skilled in the art). This method has been described in WO2009158373, WO2016135163, and WO2011075515, the contents of which are incorporated herein by reference in their entirety. Nitrating bromothiazole A-I-5 with fuming nitric acid or nitric acid with sulfuric acid gives bromonitrothiazole B-I-11. The bromo functional group on B-I-11 can be replaced by various linker (L) synthons using conditions familiar to those skilled in the art such as carbonylation (C-I-11a), Negishi reaction (zinc-mediated coupling conditions, (C-I-11b)), Sonogashira or Heck coupling reactions, followed by appropriate reduction to obtain C-C-linked C-I-11c. C-I-11a, C-I-11b, and C-I-11c can be reduced to primary alcohols, followed by mesylation or tosylation to form C-I-12. Nucleophilic substitution of C-I-12 with different nucleophiles R 4 -H gives C-I-13. Finally, C-I-13 is reduced in the presence of a hydrogenation catalyst such as palladium or nickel, or mild reducing conditions such as zinc or iron and ammonium chloride to obtain the corresponding thiazolamine D-I-11.

[0296] In Scheme 9, examples of LG include OTs and OMs, examples of R include methyl and ethyl, R2 Examples of include alkyl, cycloalkyl, alkoxy, halogen, and CN, where the alkyl, cycloalkyl, or alkoxy is optionally fluorinated, R 4 Examples of include heterocyclic groups and NR having suitable optional substituents as exemplified in the intermediate table below 6 R 9 , where R 6 and R 9 can each independently be alkyl, and examples of L include -(CH2) m -, where m can be 1, 2, or 3.

[0297] Process 10

[0298]

[0299] As shown in Process 10, in a similar reaction sequence as shown in Process 10, bromothiazole A-I-6 (readily available to those skilled in the art) provides thiazolamine D-I-12 (Science of Synthesis, 627, 2002).

[0300] In Process 10, examples of R 2 can be alkyl, cycloalkyl, alkoxy, halogen, or CN, where the alkyl, cycloalkyl, or alkoxy is optionally fluorinated, and examples of R 4 include heterocyclic groups and NR having suitable optional substituents as exemplified in the intermediate table below 6 R 9 , where R 6 and R 9 can each independently be alkyl.

[0301] Process 11

[0302]

[0303] As exemplified in Process 11, in some embodiments, substituted thiazolamine D-I-13 can be prepared from appropriately substituted thiazole A-I-6 (readily available to those skilled in the art). This method has been described in WO2009158373, WO2016135163, and WO2011075515, the contents of which are incorporated herein by reference in their entireties. Nitrating bromothiazole A-I-6 using fuming nitric acid or nitric acid with sulfuric acid gives bromonitrothiazole B-I-12. The bromo functional group on B-I-12 can be replaced by various R using conditions familiar to those skilled in the art such as carbonylation (C-I-15a), Negishi reaction (zinc-mediated coupling conditions (C-I-15b), Sonogashira or Heck coupling reactions 4Group substitution is followed by reduction to give C-C-linked C-I-15c. C-I-15a, C-I-15b and C-I-15c can be reduced to primary alcohols, which are then mesylated or tosylated to form C-I-16. C-I-16 is nucleophilically substituted with different nucleophiles R 4 -H to give C-I-17. Finally, C-I-17 is reduced in the presence of a hydrogenation catalyst such as palladium or nickel, or mild reducing conditions such as zinc or iron and ammonium chloride, to give the corresponding thiazolamine D-I-13.

[0304] In Scheme 11, examples of LG include OTs and OMs, examples of R include methyl and ethyl, and examples of R 2 include alkyl, cycloalkyl, alkoxy, halogen and CN, where the alkyl, cycloalkyl or alkoxy is optionally fluorinated, and examples of R 4 include heterocyclic groups and NR 6 R 9 with suitable optional substituents as exemplified by the intermediate table below, where R 6 and R 9 can each independently be alkyl, and examples of L include -(CH2) m -, where m can be 1, 2 or 3.

[0305] Scheme 12

[0306]

[0307] Scheme 12 describes the synthesis of substituted oxazole D-I-14 as reported in WO2014078378, the content of which is incorporated herein by reference in its entirety. Various acid chlorides A-I-7 are reacted with aminoalkanenitrile 12-1 substituted with R 2 (which can be readily obtained by those skilled in the art) to give A-I-8. A-I-8 is converted to oxazolamine D-I-14 under acidic conditions such as acetic acid, sulfuric acid or hydrochloric acid.

[0308] In Scheme 12, examples of R 2 include alkyl and cycloalkyl, where the alkyl, cycloalkyl or alkoxy is optionally fluorinated, and examples of R 4 include heterocyclic groups and NR 6 R 9 with suitable optional substituents as exemplified by the intermediate table below, where R 6 and R 9 can each independently be alkyl, and examples of L include -(CH2) m -, where m can be 0, 1, 2 or 3.

[0309] Scheme 13

[0310]

[0311] As shown in Scheme 13, some substituted oxazoles can be prepared from carboxylic acid esters A-I-9 substituted with 2-diazo-3-bridged oxy as reported in Synlett, 1996, 1171, the content of which is incorporated herein by reference in its entirety. After treating the diazo ester A-I-9 with a primary amide 14-1 (readily available to those skilled in the art) under Rh-catalyzed coupling conditions, amide B-I-13 is obtained. Using a dehydrating agent (such as POCl3, T3P or Burgess reagent) under cyclization dehydration conditions, the intermediate B-I-13 is provided with oxazole ester C-I-18. Hydrolyzing the oxazole ester C-I-18 gives carboxylic acid C-I-19, which is converted into oxazolamine D-I-15 using sodium azide or DPPA under the Curtius rearrangement reaction.

[0312] In Scheme 13, examples of R 2 include alkyl, cycloalkyl and alkoxy, where the alkyl, cycloalkyl or alkoxy is optionally fluorinated, and examples of R 4 include heterocyclic groups and NR 6 R 9 with suitable optional substituents as exemplified by the intermediate table below, and where R 6 and R 9 can each independently be alkyl, and examples of L include -(CH2) m -, where m can be 0, 1, 2 or 3.

[0313] Scheme 14

[0314]

[0315] As shown in Scheme 14, in other specific embodiments, oxazolamine D-I-16 can be prepared from 2-halooxazole C-I-20 as described in WO2012033195, the content of which is incorporated herein by reference in its entirety. Under Buchwald coupling conditions, reacting C-I-20 with various amines R 4 -H gives 2-aminoalkyl-substituted oxazole C-I-21, where R 4 is N-linked. Performing a Suzuki reaction (see Scheme 16) using C-I-20 with a commercially available or synthetic borate T including but not limited to other borate salts gives C-I-21, where R 4 is C-linked. Hydrolyzing the oxazole ester C-I-21 gives a carboxylic acid, which can be converted into oxazolamine D-I-16 using sodium azide or DPPA under the Curtius rearrangement reaction.

[0316] In Scheme 15, R 2Examples of may be alkyl, cycloalkyl or alkoxy, where the alkyl, cycloalkyl or alkoxy is optionally fluorinated, and R 4 Examples of include heterocyclic groups and NR having suitable optional substituents as exemplified by the intermediate table below 6 R 9 where R 6 and R 9 can each independently be alkyl, where R 6 and R 9 can each independently be alkyl.

[0317] Process 15

[0318]

[0319] In some embodiments, the general triazoleamines D-I-17 and D-I-18 are prepared as shown in Process 15. Examples of R 4 -L-linked 5-1 or 5-2 are shown in this process. By using the procedures described in Asian J. of Chem, 2014, 26, 4744 and Hanneng Cailliao, 2008, 16, 49, which are incorporated herein by reference in their entireties, the triazole B-I-14 is prepared by reacting with aldehyde 15-1 (readily available to those skilled in the art). Alternatively, B-I-14 can be prepared by nitrating A-I-11. By alkylation (5-1) or Mitsunobu reaction (5-2), B-I-14 is converted into a mixture of C-I-22 and C-I-23. These two regioisomers C-I-22 and C-I-23 can be separated by SFC purification, crystallization or chromatography. In the presence of a hydrogenation catalyst such as palladium or nickel, or mild reducing conditions such as zinc or iron and ammonium chloride, the nitro triazoles C-I-22 or C-I-23 are reduced to give the corresponding triazoleamines D-I-17 and D-I-18, respectively.

[0320] In Process 15, examples of R 2 can be alkyl, cycloalkyl, alkoxy, halogen or CN, where the alkyl, cycloalkyl or alkoxy is optionally fluorinated, examples of R 4 include heterocyclic groups and NR having suitable optional substituents as exemplified by the intermediate table below 6 R 9 where R 6 and R 9 can each independently be alkyl, examples of L include -(CH2) m -, where m can be 2 or 3.

[0321] Process 16

[0322]

[0323] Scheme 16 illustrates the general preparation of non-commercially available boronic acid / boronate T. 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 agent (e.g., DCI or Et3N / HATU) to give Q. The intermediate Q is converted to boronate T by nickel-catalyzed decarboxylative borylation with a [B2pin2Me]Li complex pre-mixed with methyllithium and B2pin2 (Science, 2017, 356, 1045 and JACS, 2016, 138, 2174), the contents of which are incorporated herein by reference in their entirety.

[0324] In Scheme 16, examples of R 4 include alkyl, cycloalkyl, and heterocyclic groups having suitable optional substituents as exemplified by the intermediate table below, and examples of L include -(CH2) m -, where m can be 0, 1, 2, or 3; and when m is 0, R 4 is C-linked to the boronate; when m is 1, then R 4 is C-linked to L; and when m is 2 or 3, then R 4 is N-linked or C-linked to L.

[0325] Scheme 17

[0326]

[0327] Scheme 17 illustrates the general preparation of L-I-1 and L-I-2. In the presence of CuI and CsF, commercially available 2,4-dichloro-5-iodopyrimidine is reacted with TMSCHF2 in a solvent such as NMP or DMF to yield difluoromethylpyrimidine L-II-1 (US20150284341, the contents of which are incorporated herein by reference in their entirety). Difluoromethylpyrimidine L-II-1 can be converted to methylthiopyrimidine L-I-1 by treatment with sodium methanethiolate and zinc chloride in diethyl ether at a temperature below 10 °C (WO2012110773, the contents of which are incorporated herein by reference in their entirety). Trifluoromethylpyrimidine L-I-2 can be prepared from commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine L-II-2 in a similar manner to L-I-1.

[0328] Scheme 18

[0329]

[0330] Scheme 18 illustrates where R 1General preparation of sulfonylpyrimidine L-III (t = 2) which may be cycloalkyl. In the presence of a palladium catalyst, commercially available 5-bromo-2-chloro-4-(methylthio)pyrimidine is treated with a boronic ester / boric acid / trifluoroborate (Suzuki coupling) to give the thiopyrimidine L-III (t = 0) substituted by R 1 Examples of R in this process 1 include cycloalkyl such as cyclopropyl. The intermediate thiopyrimidine L-III (t = 0) is converted to sulfonylpyrimidine L-III (t = 2) by standard oxidation, for example by mCPBA.

[0331] Scheme 19

[0332]

[0333] Scheme 19 illustrates the general preparation of intermediate H (I-XIII) by methods widely known. In the presence of a base such as sodium hydride or potassium tert-butoxide, commercially available lactam / cyclic carbamate / bridged lactam / cyclic urea / diazepanone E (Z-H) is treated with a Boc (tert-butoxycarbonyl) protected bromo compound F to give G. The Boc group of G is a protecting group that is removed upon exposure to an acid such as HCl or TFA. H-I to H-XIII are prepared by this method.

[0334] In Scheme 19, q can be 0, 1, 2 or 3, r can be 2, 3 or 4, V can be C(R 34 )2, O or NR 6 , where R 6 is alkyl, n can be 2, 3 or 4, each R 34 can independently be H, C1-C6 alkyl, or two R 34 can together form cycloalkyl.

[0335] Scheme 20

[0336]

[0337] In another specific embodiment, lactam H-XIV can be prepared from DBU by a one-step method as illustrated in Scheme 20. DBU is hydrolyzed with a methanol and aqueous solution containing potassium hydroxide at ambient temperature to give H-XIV.

[0338] Scheme 21

[0339]

[0340] Scheme 21 illustrates the general preparation of key intermediates J and K. Key intermediate J can be prepared from H (free base or HCl salt) and methylthio pyrimidine L-I in the presence of an organic base (such as triethylamine or DIEA) and optionally with heating to provide key intermediate J. In a similar manner, key intermediate K can be prepared from H and L-II or L-III.

[0341] In Scheme 21, q can be 0, 1, 2 or 3, r can be 2, 3 or 4, V can be C(R 34 )2, O or NR 6 , where R 6 is alkyl, n can be 2, 3 or 4, each R 34 can independently be H, C1-C6 alkyl, or two R 34 can together form cycloalkyl.

[0342] Scheme 22

[0343]

[0344] Scheme 22 illustrates the general preparation of key pyridine intermediate M. The treatment of H with commercially available chloroiodo pyridine is carried out under Buchwald-Hartwig coupling conditions (Cs2CO 3、 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and Pd(OAc)2) in an aprotic solvent (such as DME, DMF, DMSO or NMP) at a temperature in the range of ambient temperature to 140 °C to give key intermediate M.

[0345] In Scheme 22, R 1 can be Br, Cl, alkyl optionally substituted with one or more fluorine atoms, or cycloalkyl, q can be 0, 1, 2 or 3, r can be 2, 3 or 4, V can be C(R 34 )2, O or NR 6 , where R 6 is alkyl, n can be 2, 3 or 4, each R 34 can independently be H, C1-C6 alkyl, or two R 34 can together form cycloalkyl.

[0346] Scheme 23

[0347]

[0348] Scheme 23 illustrates the general preparation of substituted D-I propargylic I-A compounds. The preparation of formula I-A can be achieved by key intermediates K and J. The nucleophilic substitution reaction of K with amine D-I is usually carried out in a polar solvent at a temperature ranging from ambient temperature to 150 °C, with microwave heating in some embodiments, and optionally carried out in the presence of an acid (such as 1,4-dioxane containing 4N HCl), to obtain the compound of formula I-A. Non-commercial compounds D-I can be easily prepared (see Schemes 1-16). The alternative general synthesis of formula II is carried out by a two-step method, by oxidation using various oxidants such as mCPBA, first converting J (t = 0) into sulfoxide J (t = 1). At a temperature ranging from ambient temperature to 150 °C, with microwave heating in some embodiments, and optionally in the presence of an acid (such as 1,4-dioxane containing 4N HCl or pTSA), the sulfoxide is usually subjected to a nucleophilic substitution reaction with amine D-I in a polar solvent to obtain the compound of formula I-A. When the compound of formula I-A contains a protecting group such as a Boc group, this protecting group can be deprotected under acidic conditions to obtain formula I-A (free amine or salt). In the presence of a catalytic amount of a polar solvent containing acetic acid such as MeOH (reductive amination conditions), the compound of formula I-A (free base or salt) is further treated with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone to obtain N-substituted formula I-A. For acylation and sulfonylation, the free amine (or salt) can be treated with commercially available acyl chlorides or sulfonyl chlorides to obtain N-substituted formula I-A.

[0349] Scheme 24

[0350]

[0351] Scheme 24 illustrates the general preparation of formula I-B compounds. The preparation of formula I-B can be achieved by Buchwald-Hartwig coupling reaction of D-I and M. Many non-commercial amines D-I can be easily prepared (see Schemes 1-16). Reductive alkylation, acylation and sulfonylation can be carried out in a similar manner as shown in Scheme 24, and after deprotecting formula I-B containing a protecting group such as a Boc group, formula I-B is obtained.

[0352] General method A: Mitsunobu reaction:

[0353] Intermediate C1.

[0354]

[0355] Treat a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (29 g, 146 mmol) and 4-nitro-1H-pyrazole (15 g, 132 mmol) in anhydrous THF (300 mL) with triphenylphosphine (52 g, 199 mmol). Cool the mixture to 0 °C, and add diisopropyl azodicarboxylate (40 mL, 199 mmol) dropwise and stir at RT for 16 h. Remove the solvent under reduced pressure, and then quench the residue with water (200 mL). Extract the resulting solution with EtOAc (3 × 100 mL), and dry the combined organic matter over anhydrous Na2SO4, filter and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (0% to 5% MeOH / DCM, 10 CV’s) to obtain tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (8.0 g, yield 20%) as a white solid. 1 1H 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 = 12.5 Hz, 2H), 1.80 (m, 2H), 1.40 (s, 9H); MS (ESI) m / z: 297.4 (M+H + )。

[0356] General method B: Deprotection of the Boc group and reductive amination:

[0357] Intermediate C4.

[0358]

[0359] (A) At 0 °C, treat a solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (17 g, 57 mmol) in DCM (90 mL) with 1,4-dioxane (90 mL) containing 4N HCl, and stir the mixture at RT for 2 h. Evaporate the solvent under reduced pressure, and triturate the residue with Et2O (100 mL), then pentane (100 mL). Filter and dry the solid under vacuum to obtain 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (12.5 g, yield 94%) as a white solid. 1 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 + )。

[0360] (B) At 0 °C, a solution of 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (12.5 g, 54 mmol) in MeOH (250 mL) was treated with acetone (24 g, 323 mmol). The reaction mixture was stirred continuously at 0 °C for 15 min, then sodium cyanoborohydride (22 g, 323 mmol) was added in portions and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated and the residue was then treated with saturated NaHCO3 solution (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 Na2SO4, filtered and concentrated under reduced pressure to give 1-isopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine as a white solid (11.5 g, 90% yield). 1 H NMR (400 MHz, 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, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 0.98 (d, J = 6.4 Hz, 6H); MS (ESI) m / z: 239.3 (M+H + )。

[0361] General method C: Deprotection of the Boc group and alkylation:

[0362] Intermediate C7.

[0363]

[0364] (A) At 0 °C, a solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (17 g, 57 mmol) in DCM (90 mL) was treated with 1,4-dioxane containing 4N HCl (90 mL), and the mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was triturated with Et2O (100 mL), then pentane (100 mL). The solid was filtered and dried in vacuo to give 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride as a white solid (12.5 g, 94% yield). 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 + )。

[0365] (B) A mixture of 4-(4-nitro-1H-pyrazol-1-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) in MeCN (5 mL) was heated to 90 °C for 2 h. The mixture was cooled to RT, treated with water and brine, and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (2% to 8% MeOH / DCM, 16 CV's) to give 4-(4-nitro-1H-pyrazol-1-yl)-1-(propan-2-yl-d7)piperidine as a white solid (0.18 g, 76% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.25 (s, 1H), 4.15 - 4.21 (m, 1H), 2.86 (d, J = 11.5 Hz, 2H), 2.22 (m, 2H), 2.01 (d, J = 11.9 Hz, 2H), 1.85 - 1.93 (m, 2H); MS (ESI) m / z: 246.2 (M+H + ).

[0366] General method D: Alkylation and mesylation:

[0367] Intermediate C29.

[0368]

[0369] (A) A solution of 3-methyl-4-nitro-1H-pyrazole (15 g, 118 mmol) in acetonitrile (200 mL) was treated with 2-bromoethanol (16 g, 130 mmol) and potassium carbonate (48.8 g, 354 mmol). The reaction mixture was heated at 90 °C for 16 h. 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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by SFC purification to afford 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethanol-1-ol. 1 H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 4.96 (t, J = 5.2, Hz, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.73 (t, J = 5.2 Hz, 2H), 2.42 (s, 3H); MS (ESI) m / z: 172.13 (M+1).

[0370] (B) 2-(3-Methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol (5.0 g, 29 mmol) in DCM (50 mL) was treated with triethylamine (5.8 g, 58 mmol) and then methanesulfonyl chloride (5.0 g, 44 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at RT for 4 h. The reaction mixture was quenched with ice-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 Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-(3-methyl-4-nitro-1H-pyrazol-1-yl) methanesulfonate as an off-white solid (6.0 g, 83% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.88 (s, 1H), 4.57 (t, J = 5.2, Hz, 2H), 4.46 (t, J = 5.2 Hz, 2H), 3.32 (s, 3H), 2.45 (s, 3H); MS (ESI) m / z: 250.19 (M+H + )。

[0371] General method E: Nucleophilic substitution reaction:

[0372] Intermediate C30.

[0373]

[0374] Ethyl 2-(3-methyl-4-nitro-1H-pyrazol-1-yl) methanesulfonate (C29, 5.0 g, 20 mmol) in anhydrous THF (70 mL) was treated with potassium carbonate (3.8 g, 28 mmol) and 2N dimethylamine in THF (60 mL, 12 mmol) at 10 °C under N2 atmosphere. The reaction mixture was quenched with ice-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 Na2SO4, filtered and concentrated under reduced pressure to afford N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-amine (1.9 g, 48% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 4.17 (t, J = 6.4, Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H), 2.15 (s, 6H); LC-MS (ESI) m / z: 199.2 (M+H + )。

[0375] Table A. Examples of Intermediate C prepared by General Methods A-E above.

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382] Preparation of Intermediate C38:

[0383]

[0384] (A) A solution of 5-methyl-4-nitro-1H-pyrazole (2.0 g, 16 mmol) in DMF (15 mL) was treated portionwise with sodium hydride (0.94 g, 24 mmol) over a 15 min period at 0 °C under Ar. The mixture was stirred at RT for 2 h, then methyl 2-bromo-2-methylpropionate (4.3 g, 24 mmol) was added. The reaction mixture was stirred at RT for an additional 16 h. The reaction mixture was quenched with saturated NH4Cl solution (100 mL), and the solution was extracted with EtOAc (2 × 80 mL). The combined organic layers 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 afford methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate (2.9 g, 81% yield) as a white solid. 1 1H 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 + )

[0385] (B) A solution of methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate (2.9 g, 13 mmol) in THF (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.54 g, 13 mmol) in water (10 mL). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated, diluted with water (60 mL), and acidified to pH ~4 with 1N aqueous HCl. The resulting suspension was filtered, washed with water (2 × 10 mL), and air dried to afford 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+ )。

[0386] (C) Treat a suspension of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.3 g, 11 mmol) in DCM (30 mL) with a drop of DMF, followed by oxalyl chloride (2.8 mL, 32 mmol). Stir the suspension at RT for 3 h, then concentrate the clear solution. Dissolve the residue in THF (30 mL), and slowly add the solution to an NH4OH solution (10 mL / water (40 mL)). Stir the suspension at RT for 1 h, then concentrate. Dilute the suspension (about 10 mL) with water (50 mL), filter the solid, wash with water and air dry to obtain 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 + )。

[0387] General method F: Reduction to obtain intermediate D9.

[0388]

[0389] Treat a solution of N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-amine (C30, 1.9 g, 9.5 mmol) in EtOAc (50 mL) with Pd / C (1.9 g, 10% w / w, 50% humidity). Stir the reaction mixture at RT under a hydrogen balloon pressure (1 atm) for 6 h. Filter the mixture through a Celite pad and wash with EtOAc (200 mL). Concentrate the filtrate under reduced pressure to obtain 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 + )。

[0390] Table B. Examples of intermediate D prepared by the above general method F.

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] General method G: Alkylation and deprotection of Boc protecting group:

[0399] Intermediate H-VIII-1.

[0400]

[0401] Under a nitrogen atmosphere, a solution of 1,4-oxazepan-5-one (10 g, 87 mmol) in anhydrous THF (400 mL) at 0 °C was treated portionwise with sodium hydride (3.0 g, 130 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then (3-bromopropyl) tert-butylcarbamate (21 g, 87 mmol) was added. The solution was continued to be stirred from 0 °C to RT for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (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% to 50% EtOAc / hexane, 15 CV’s) to obtain tert-butyl 3-(5-oxo-1,4-oxazepan-4-yl)propylcarbamate (12 g, yield 50%) as a yellow liquid. The product was dissolved in DCM (50 mL) and treated with 1,4-dioxane containing 4N HCl (4 eq). The mixture was stirred at RT for 3 h and concentrated, and dried under high vacuum to obtain 4-(3-aminopropyl)-1,4-oxazepan-5-one HCl salt (yield 100%). 1 H NMR (400 MHz, DMSO-d6): δ 8.09 (brs, 3H), 3.62 (m, 4H), 3.49 (m, 2H), 3.35 (t, J = 6.8 Hz, 2H), 2.73 (m, 2H), 2.62 (t, J = 4.8 Hz, 2H), 1.78 (m, 2H). LC-MS (ESI) m / z: 173.2 (M+H + )

[0402] Table C. Examples of Intermediate H that can be prepared by General Method G.

[0403]

[0404]

[0405] Preparation of Intermediate H-XIV: 1-(3-aminopropyl)azepan-2-one

[0406]

[0407] At 0 °C under a N2 atmosphere, DBU (22 g, 145 mmol) in MeOH:H2O (1:1) (130 mL) was treated with KOH (12 g, 217 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The above 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 obtain 1-(3-aminopropyl)azepan-2-one as a liquid oil (21 g, 85% yield). 1 H NMR (400 MHz, CDCl3): δ 3.45 (t, J = 3.5 Hz, 2H), 3.31 (t, J = 4.4 Hz, 2H), 2.68 (t, J = 6.5 Hz, 2H), 2.51 (t, J = 5.8 Hz, 2H), 1.70 (m, 2H), 1.65 (m, 8H); LC-MS (ESI) m / z: 171.4 (M+H + )

[0408] Preparation of Intermediate L-III-1: 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine

[0409]

[0410] In the presence of K3PO4 (66.7 g, 315 mmol), a suspension of 5-bromo-2-chloro-4-(methylthio)pyrimidine (25.0 g, 105 mmol) and cyclopropylboronic acid (13.7 g, 158 mmol) in toluene:H2O (9:1) (650 mL) was treated. The reaction mixture was purged with nitrogen for 20 min, and then tricyclohexylphosphine (5.9 g, 21 mmol) and Pd(OAc)2 (2.35 g, 10.50 mmol) were added. The reaction mixture was stirred at 90 °C for 16 h. 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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0% to 10% EtOAc / hexane) to obtain 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine as a yellow oil (14.0 g, 66% yield). 11H 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 + )。The solution of 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (4.0 g, 20 mmol) in DCM (60 mL) was treated with m-CPBA (4.8 g, 28 mmol) at 0 °C. The reaction mixture was warmed to RT and stirred for 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (2 × 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine as a yellow solid (3.6 g, 86% yield). 1 1H NMR (400 MHz, DMSO-d6): 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 + )。

[0411] Preparation of Intermediate L-I-2: 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine.

[0412]

[0413] A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 g, 0.46 mol) in diethyl ether (2 L) was treated dropwise with ZnCl2 (1.0 N in ether) (555 mL, 0.56 mol) at 0 °C, and the reaction mixture was stirred for 2 h. Sodium methanethiolate (49 g, 0.94 mol) was added at 0 °C, and the reaction mixture was warmed to RT and stirred for 48 h. The reaction mixture was quenched with 2 N HCl in an ice-water bath, and the solution was then extracted with Et2O (3 × 500 mL). The combined organic extracts were washed with water (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 35 °C to afford 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine as a colorless liquid (100 g, 95% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s 1H), 2.62 (s 3H).

[0414] These three intermediates are commercially available.

[0415]

[0416] General Method H: Substitution reaction:

[0417] Intermediate J-7.

[0418]

[0419] At 0 °C, a solution of 4-(3-aminopropyl)-1,4-oxazepan-5-one hydrochloride (H-VIII-1, 3.0 g, 17.4 mmol) in DMF (60 mL) was treated with DIEA (15.5 mL, 87.2 mmol) and stirred for 15 min. Subsequently, 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (L-I-2, 0 g, 26.2 mmol) was added and stirring was continued from 0 °C to RT for 16 h. The reaction mixture was quenched with ice water (120 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40% to 50% EtOAc / hexane, 15 CV’s) to afford 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one as a yellow liquid (3.0 g, 47% yield). 1 H NMR (400 MHz, 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 = 4.8 Hz, 2H), 2.47 (s, 3H), 1.68 (m, 2H); LC-MS (ESI) m / z: 365.3 (M+H + )。

[0420] Table D. Examples of Intermediate K that can be prepared by General Method H.

[0421]

[0422]

[0423]

[0424]

[0425] General Method I: Pd Coupling Reaction:

[0426] Intermediate M-1.

[0427]

[0428] Treat a mixture of 1-(3-aminopropyl)piperidin-2-one hydrochloride (9.0 g, 29 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (6.2 g, 32 mmol) in toluene (180 mL) with cesium carbonate (23.9 g, 73 mmol). Purge the mixture with nitrogen for 15 min. Add PdCl2(dppf).DCM (2.4 g, 2.9 mmol), and purge the mixture with nitrogen again for 5 min. Seal the sealed tube and routinely heat it in a preheated oil bath at 90 °C for 16 h. Cool the reaction mixture to RT, pour it into water (100 mL), and extract with EtOAc (3 × 100 mL). Wash the combined organic extracts with brine, dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (40% to 45% EtOAc / hexane, 10 CV’s) to obtain 1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one as a brown solid (2.6 g, yield 26%). 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (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 + )。

[0429] Table E. Examples of Intermediate J that can be prepared by General Method I.

[0430]

[0431] General Method J: Oxidation

[0432] Intermediate J-14.

[0433]

[0434] Add a solution of 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one (J-7, 3.0 g, 8.2 mmol) in DCM (60 mL) and m-CPBA (2.0 g, 11.5 mmol) at 0 °C, and stir from 0 °C to room temperature for 3 h. Wash the reaction mixture with saturated aqueous sodium bicarbonate (2 × 90 mL). Dry the organic layer over anhydrous Na2SO4 and filter. Concentrate the filtrate under reduced pressure to obtain 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 as a pale yellow semi-solid (3.0 g, 95%, 9:1). 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.94 (brs, 1H), 3.60 (m, 4H), 3.45 (m, 4H), 3.36 (m, 2H), 2.88 (s, 3H), 2.63 (m, 2H), 1.70 (m, 2H); LC-MS (ESI) m / z: 381.3 (M+H + )

[0435] Table F. Additional examples of Intermediate J that can be prepared by General Method J.

[0436]

[0437] General Method K: Substitution Reaction A

[0438] Example 80

[0439]

[0440] A mixture of 1-(3-((2,5-dichloropyrimidin-4-yl)amino)propyl)azepan-2-one (K-16, 0.06 g, 0.19 mmol) and methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-amine hydrochloride (D11, 0.044 g, 0.19 mmol) in EtOH (3 mL) was treated with 1,4-dioxane (0.047 mL) containing 4.0 N HCl, and then the reaction mixture was heated at 90 °C for 15 h. 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 RT for 3 h. The solid was filtered and washed with CH3CN to obtain the desired product, which was treated with a solution of MP carbonate resin (150 mg, 3.14 mmol / g loading, 0.47 mmol, 2.5 eq) in MeOH (5 mL). The solution was stirred at RT for 2 h. The resin was filtered off and washed with MeOH. The filtrate was concentrated, and the residue was treated with CH3CN:H2O (1:1, 3 mL) and lyophilized to obtain 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, yield 46%). 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (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 + )

[0441] General method L: Substitution reaction B and deprotection of Boc nitrogen protecting group

[0442] Example 83.

[0443]

[0444] Treat a solution of 1-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one (J-12, 0.53 g, 1.4 mmol) and tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (D-10, 0.43 g, 1.5 mmol) in anhydrous DMF (7 mL, over molecular sieves ) with 1,4-dioxane (0.11 mL) containing 4.0 N HCl, and then heat the reaction mixture at 80 °C for 15 h. Concentrate the mixture under high vacuum and dissolve the residue in 1,4-dioxane (5 mL). Add 1,4-dioxane (0.35 mL) containing 4.0 N HCl and stir the mixture at RT for 2 h. Concentrate the mixture under reduced pressure and purify the crude product by reverse-phase column chromatography (0% to 40% CH3CN / H2O (0.1% FA), 15 CV’s) to obtain 1-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one (0.57 g, 82% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.94 (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 + ).

[0445] General method M: Reductive alkylation:

[0446] Example 90.

[0447]

[0448] Treat a mixture of (1-(3-((2-((3-methyl-1-(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) in methanol (0.5 mL) with sodium cyanoborohydride (0.025 g, 0.40 mmol). Stir the mixture at RT for 16 h. Quench the solution with brine and then extract with EtOAc (2 × 25 mL). Dry the combined organic layers over anhydrous Na2SO4, filter and concentrate. Purify the crude product by reverse phase column chromatography (0% to 40% CH3CN / H2O (0.1% FA), 15 CV’s) to afford 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, yield 43%). 1 H NMR (400 MHz, DMSO-d6): δ 8.91 (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 = 7.4 Hz, 3H); LC-MS (ESI) m / z: 523.4 (M+H + )

[0449] General method N: Pd coupling reaction

[0450] Example 171.

[0451]

[0452] A mixture of 4-methyl-1-(1-methylpiperidin-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) in 1,4-dioxane (2.0 mL) was purged with Ar gas, treated with Pd2(dba)3 (0.033 g, 0.039 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.041 g, 0.071 mmol), purged again with Ar gas, capped tightly, and heated at 85 °C for 16 h. The mixture was cooled to RT, diluted with brine, and extracted with DCM (3 × 15 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (5% to 10% MeCN / H2O (0.1% FA)) to afford 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 as a white solid (0.043 g, yield 24%). 1 H NMR (400 MHz, DMSO-d6): δ 9.12 (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 + )。

[0453] Synthesis Example 172:

[0454]

[0455] Treat 2-methyl-2-(3-methyl-4-((4-((3-(3-bridged oxy-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) in a mixture of EtOAc (5 mL) with triethylamine (0.12 mL, 0.88 mmol). Stir the reaction mixture at RT for 16 h. Quench the reaction mixture with saturated NaHCO3 solution (40 mL) and stir for a few minutes. Separate the layers, extract the aqueous layer with EtOAc (2 × 30 mL), wash the combined organic matter with brine, dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by flash column chromatography (0% to 100% EtOAc / DCM, 10 CV’s) to obtain 2-methyl-2-(3-methyl-4-((4-((3-(3-bridged oxy-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (0.069 g, yield 65%). 1 H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.93 (s, 1H), 7.45 (s, 1H), 6.67 (s, 1H), 6.15 (t, J = 6.0 Hz, 1H), 3.89 - 3.95 (m, 1H), 3.28 (m, 2H), 3.19 - 3.23 (m, 2H), 3.08 (q, J = 6.2 Hz, 2H), 2.81 (d, J = 11.0 Hz, 2H), 2.20 (t, J = 6.2 Hz, 2H), 2.17 (s, 3H), 1.99 (m, 2H), 1.92 (m, 4H), 1.89 (s, 3H), 1.68 (m, 6H); LC-MS (ESI) m / z: 494.2 (M + H + )。

[0456] Table G. Exemplary compounds that can be prepared by general methods K to N.

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] Example 174. Biochemical Analysis of ULK1.2

[0486] The activity of ULK1 kinase was spectrophotometrically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289:1938-1942). In a 384-well plate (100 μL final volume), an assay buffer (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100) containing 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 was used for the assay. ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). Absorbance decrease at 340 nm was continuously monitored for up to 6 hours at 30 °C on a multimode microplate reader (BioTek). The reaction rate was calculated using a 2-3 h time period. Using controls (i.e., reactions without test compounds and reactions with known inhibitors), the reaction rate at each concentration of the compound was converted to a percentage of inhibition, and the IC 50 value was calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software).

[0487] ULK1 protein sequence (residues 1-314 with an N-terminal His tag; SEQ.ID NO:1)

[0488] MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPVPVPSYPSSGSGSSSSSSSTSHLAS

[0489] Example 175. Biochemical analysis of ULK1.3

[0490] The activity of ULK1 kinase was spectrophotometrically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289:1938-1942). In a 384-well plate (100 μL final volume), an assay buffer (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100) containing 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 was used for the assay. ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). Absorbance decrease at 340 nm was continuously monitored for up to 6 h at 30 °C on a multimode microplate reader (BioTek). The reaction rate was calculated using a 2-3 h time period. Using controls (i.e., reactions without test compounds and reactions with known inhibitors), the reaction rate at each concentration of the compound was converted to a percentage of inhibition, and the IC 50 value was calculated using a software routine in Prism (GraphPad software).

[0491] ULK1 protein sequence (residues 1-283; SEQ.ID NO:2)

[0492] MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS

[0493] Example 176. Biochemical analysis of ULK2

[0494] The activity of ULK2 kinase was spectrophotometrically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289:1938-1942). In a 384-well plate (100 μL final volume), an assay buffer (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100) containing 9.7 nM ULK2 (Eurofins 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 was used for the assay. ULK2 inhibition was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). Absorbance decrease at 340 nm was continuously monitored for up to 6 h at 30 °C on a multimode microplate reader (BioTek). The reaction rate was calculated using a 2-3 h time period. Using controls (i.e., reactions without test compounds and reactions with known inhibitors), the reaction rate at each concentration of the compound was converted to a percentage of inhibition, and the IC 50 value was calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software).

[0495] ULK2 protein sequence (residues 1-306 with N-terminal GST and His tags; SEQ.ID NO:3)

[0496] MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSINKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCGSPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH

[0497] Table 1. Inhibition of the biochemical activities of ULK1 and ULK2 kinases by the exemplary compounds in Table G.

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] For Table 1, “+” refers to an IC 50 that is greater than 1 nM and less than or equal to 25 nM; “++” refers to an IC 50 that is greater than 25 nM and less than or equal to 100 nM; “+++” refers to an IC 50 that is greater than 100 nM and less than or equal to 500 nM; and “++++” refers to an IC 50 .

[0504] Example 177. Cellular Inhibition of ULK Kinase Substrate ATG13 Protein

[0505] pATG13 Content in Mutant KRas A549 Cells after Treatment with a Combination of ULK Inhibitor and Trametinib

[0506] A549 (KRAS mutant) human lung cancer cells (6,000 cells / well) were added to 50 μL of pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a tissue culture-treated 384-well plate and allowed to grow 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 / well) was added. DMSO (0.6 μL) was added to the control wells. The plate was briefly shaken to mix the wells and then incubated overnight at 37 °C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed for 10 minutes using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) with shaking at 4 °C.

[0507] The cellular content of phosphoserine 318 ATG13 (pATG13) was measured by ELISA method. The wells were coated with the total ATG13 antibody (Cell Signaling Catalog No. 13273). The plate was incubated overnight at 4 °C and washed with ELISA wash buffer (Biolegend Catalog No. 421601). Subsequently, the wells were blocked with assay diluent (Biolegend Catalog No. 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. The cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. The 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. The high-sensitivity TMB substrate (Biolegend Catalog No. 421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate reader measuring absorbance at 450 nm and 540 nm (background). For each well, the signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm of the blank wells was subtracted from the test wells. The data was compared to the control wells to determine the percentage of ATG13 phosphorylation. GraphPad Prism was used to calculate the IC 50 value.

[0508] Example 178. pATG13 content in mutant KRas MiaPaCa-2 cells after treatment with a combination of ULK inhibitor and trametinib

[0509] MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were added to 50 μL of pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin, and 2.5% horse serum in a tissue culture-treated 384-well plate and allowed to grow 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 / well) was added. DMSO (0.6 μL) was added to the control wells. The plate was shaken briefly to mix the wells and then incubated overnight at 37 °C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed for 10 minutes using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) with shaking at 4 °C.

[0510] The cellular content of phosphoserine 318 ATG13 (pATG13) was measured by ELISA method. The wells were coated with the full-length ATG13 antibody (Cell Signaling catalog number 13273). The plate was incubated overnight at 4 °C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked with assay diluent (Biolegend catalog number 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. The cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. The biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog number 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, added to each well and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. The high-sensitivity TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate reader measuring absorbance at 450 nm and 540 nm (background). For each well, the signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm of the blank group wells was subtracted from the test wells. The data was compared to the control wells to determine the percentage of ATG13 phosphorylation. GraphPad Prism was used to calculate the IC 50 values.

[0511] Example 179. pATG13 content in mutant KRas HCT-116 cells after treatment with a combination of ULK inhibitor and trametinib

[0512] HCT-116 human colorectal cancer cells (10,000 cells / well) were added to 50 μL of pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a tissue culture-treated 384-well plate and allowed to grow 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 / well) was added. DMSO (0.6 μL) was added to the control wells. The plate was briefly shaken to mix the wells and then incubated overnight at 37 °C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed for 10 minutes at 4 °C with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0513] The cellular content of phospho-serine 318 ATG13 (pATG13) was measured by ELISA. The wells were coated with a pan-ATG13 antibody (Cell Signaling catalog number 13273). The plate was incubated overnight at 4 °C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked for 1 hour at room temperature with assay diluent (Biolegend catalog number 421203). 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. The biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog number 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, added to each well and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. High sensitivity TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate reader measuring absorbance at 450 nm and 540 nm (background). For each well, the signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm of the blank group wells was subtracted from the test wells. The data were compared to the control wells to determine the percentage of ATG13 phosphorylation. GraphPad Prism was used to calculate the IC50 value.

[0514] Example 180. pATG13 content in mutant BRAF A375 cells after treatment with a combination of ULK inhibitor and trametinib

[0515] A375 human malignant melanoma cancer cells (20,000 cells / well) were added to 100 μL of pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a tissue culture-treated 96-well plate and allowed to grow overnight at 37 °C, 5% CO2, and 95% humidity. The next day, 100 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.5 μL / well) was added. DMSO (0.5 μL) was added to the control wells. The plate was briefly shaken to mix the wells and then incubated overnight at 37 °C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed for 10 minutes at 4 °C with shaking using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0516] The cellular content of phospho-serine 318 ATG13 (pATG13) was measured by ELISA method. The wells were coated with a pan-ATG13 antibody (Cell Signaling catalog number 13273). The plate was incubated overnight at 4 °C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked for 1 hour at room temperature with assay diluent (Biolegend catalog number 421203). 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. The biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog number 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, added to each well and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. High-sensitivity TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate reader measuring absorbance at 450 nm and 540 nm (background). For each well, the signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm of the blank group wells was subtracted from the test wells. The data was compared to the control wells to determine the percentage of ATG13 phosphorylation. GraphPad Prism was used to calculate the IC 50 value.

[0517] Example 181. pATG13 content in mutant HRas T24 cells after treatment with a combination of ULK inhibitor and trametinib

[0518] T24 human bladder cancer cells (25,000 cells / well) were added to 100 μL of pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a tissue culture-treated 96-well plate and allowed to grow overnight at 37 °C, 5% CO2, and 95% humidity. The next day, 100 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.5 μL / well) was added. DMSO (0.5 μL) was added to the control wells. The plate was briefly shaken to mix the wells and then incubated overnight at 37 °C. The next day, the medium was aspirated and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed for 10 minutes at 4 °C with agitation using MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO).

[0519] The cellular content of phosphoserine 318 ATG13 (pATG13) was measured by ELISA method. The wells were coated with the full-length ATG13 antibody (Cell Signaling catalog number 13273). The plate was incubated overnight at 4 °C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked with assay diluent (Biolegend catalog number 421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. The cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. The biotinylated pS318-ATG13 antibody (Rockland Immunochemicals catalog number 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, added to each well and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. The high-sensitivity TMB substrate (Biolegend catalog number 421101) was added to each well and incubated for 20 minutes at room temperature. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate reader measuring absorbance at 450 nm and 540 nm (background). For each well, the signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm. Next, the background-corrected absorbance at 450 nm of the blank group wells was subtracted from the test wells. The data was compared with the control wells to determine the percentage of ATG13 phosphorylation. GraphPad Prism was used to calculate the IC 50 value.

[0520] Table 2. ULK kinase inhibition in mutant Ras or mutant BRAF cell lines by exemplary compounds from Table G.

[0521]

[0522]

[0523] For Table 2, "+" refers to an IC 50 of greater than 10 nM and less than or equal to 100 nM; "++" refers to an IC 50 of greater than 100 nM and less than or equal to 300 nM; "+++" refers to an IC 50 of greater than 300 nM and less than or equal to 600 nM; and "++++" refers to an IC 50 of greater than 600 nM.

[0524] Example 182. Biochemical analysis of LRRK2 (SEQ.ID NO.4)

[0525] The activity of the LRRK2 kinase was spectrophotometrically determined using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289:1938-1942). The assay was performed in a 384-well plate (100 μL final volume) using an assay buffer (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100) containing 26.4 nM LRRK2 (Thermo Fisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP. LRRK2 inhibition was measured by adding serially diluted test compounds (final assay concentration of 1% DMSO). Absorbance decrease at 340 nm was continuously monitored for up to 6 hours at 30 °C on a multimode microplate reader (BioTek). The reaction rate was calculated using a 2-3 h time period. Using controls (i.e., reactions without test compounds and reactions with known inhibitors), the reaction rate at each concentration of the compound was converted to a percentage of inhibition, and the IC 50 value was calculated using a software routine in Prism (GraphPad software).

[0526] LRRK2 protein sequence (residues 970 - 2528; SEQ.ID NO.4)

[0527]

[0528] Table 3. LRRK2IC 50 Data.

[0529]

[0530]

[0531] For Table 3, "+" refers to an IC that is greater than 1 nM and less than or equal to 100 nM 50 ; "++" refers to an IC that is greater than 100 nM and less than or equal to 300 nM 50 ; "+++" refers to an IC that is greater than 300 nM and less than or equal to 600 nM 50 ; and "++++" refers to an IC that is greater than 600 nM 50 .

[0532] Example 183. Evaluation of ULK Inhibitors in In Vitro and In Vivo Pancreatic Ductal Adenocarcinoma (PDAC)

[0533] ULK inhibitors were evaluated in a PDAC flux assay, and the IC of compounds in a panel of multiple PDAC cell lines (including cells from primary tumors of Trp53 lox / + , LSL-Kras G12D , Rosa-rtTA LSL , p48Cre + ) will be determined using colony formation 2D assays and 3D organoid assays in the absence or presence of trametinib. 50

[0534] Evaluation of autophagy flux inhibition using a flux reporter gene in in vivo PDAC tumors after single and multiple doses using a syngeneic orthotopic model.

[0535] The therapeutic efficacy of ULK inhibitors in the PDAC model will be evaluated by: (i) evaluating the tumor kinetics of PDAC subcutaneously; (ii) evaluating the tumor kinetics of PDAC orthotopically in the pancreas (C57BL / 6 mice implanted with KPC) in a syngeneic model; (iii) evaluating the tumor growth kinetics in a syngeneic model using ULK inhibitors and MEK inhibitors; (iv) evaluating the compounds in a PDAC orthotopic model; (v) evaluating histological changes in the tumor microenvironment; (vi) evaluating changes in immune cell infiltration in the tumor after inhibition by ULK inhibitors; (vii) evaluating the efficacy of the combination of ULK inhibitors and immune checkpoint blockade.

[0536] Equivalent protocol

[0537] ​Although specific embodiments have been discussed, the foregoing specification is exemplary and not restrictive. After reading this specification, many variations of the embodiments will be apparent to those skilled in the art. The full scope of the disclosure should be determined with reference to the claims and their equivalents and the full scope of this specification and such variations.

[0538] All numbers expressing quantities of ingredients, reaction conditions, and so forth, used in the specification and claims, are to be understood as being modified in all instances by the term "about" unless otherwise indicated. 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 method for preparing a compound of formula I-A, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein formula I-A is represented by: Wherein: A is a 5-membered heteroaryl having at least one ring nitrogen; R 1 selected from the group consisting of halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein each C1-C5 alkyl and C3-C5 cycloalkyl is optionally substituted with one, two or three independently occurring fluorines; R 2 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 one, two or three independently occurring fluorine or cyano; R 4 Selected from the group consisting of: B, D, NR 6 R 9 , NR 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 heterocyclic groups and heteroaryl groups having at least one nitrogen and optionally having additional ring nitrogen or oxygen, wherein B is optionally substituted by R on one or more available carbons 7 and optionally substituted by R on available nitrogen 9 ; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and optionally having additional ring nitrogen or oxygen, where D is optionally substituted with R on one or more available carbons 7 and optionally substituted with R on available nitrogen 9 ; R 7 Independently selected from the following group at each occurrence: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , where each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 7 join together with the atom to which they are attached to form a bridging oxy group; R 6 and R 9 is independently selected, at each occurrence, from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 and a C-linked heterocyclic group and heteroaryl having at least one nitrogen and optionally additional ring nitrogen or oxygen, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; R 5 independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic group, each C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted with one or more independently occurring fluorines; R 10 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two Rs 10 are joined to the carbon to which they are attached to form a C3-C5 cycloalkyl; Z is q is 0, 1, 2 or 3; r is 2, 3 or 4; V is C(R 34 )2, oxygen or NR 6 , where R 6 is an alkyl group; R 34 independently at each occurrence is H or a C1-C6 alkyl group, or two R's 34 are joined to the carbon to which they are attached to form a cycloalkyl group; 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; The condition is that when m is 0, R 4 is C-linked to ring A; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L; The method comprises: Reacting a compound of formula K or formula J (t = 1) With a compound of formula D-I 2. The method according to claim 1, comprising reacting a compound of formula K or formula J (t = 1) with a compound of formula D-I in a polar solvent at ambient temperature to 150 °C.

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

4. The method according to claim 2 or 3, wherein for formula K, the reaction comprises the presence of an acid.

5. The method according to claim 4, wherein the acid is 1,4-dioxane containing 4N HCl.

6. The method according to claim 2 or 3, wherein for formula J (t = 1), the reaction comprises the presence of an acid.

7. The method according to claim 6, wherein the acid is 1,4-dioxane containing 4N HCl or p-toluenesulfonic acid.

8. The method according to claim 1, wherein when formula I-A further comprises a protecting group, the method further comprises deprotecting the protecting group under acidic conditions to form the compound of formula I-A.

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

10. The method according to any one of claims 1-9, further comprising: i) Reacting a compound of formula H: Wherein n and Z are as defined in formula I-A, With a compound of formula L-II or formula L-III: wherein R of formula L-II 1 is Cl, Br or I, and R of formula L-III 1 is cyclopropyl, Thereby forming a compound of formula K; or ii) Reacting a compound of formula J: With an oxidant, optionally wherein the oxidant is meta-chloroperoxybenzoic acid (mCPBA), Thereby forming a compound of formula J (t = 1), and further comprising: Reacting a compound of formula H: Wherein n and Z are as defined in formula I-A, With a compound of formula L-I: Wherein the compound of formula L-I is CHF2, CF3 or CN, Thereby forming the compound of formula J.

11. The method according to claim 1, wherein the compound of formula I-A is selected from the group consisting of: 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-(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-(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-((5-bromo-2-((1-(1-isobutylazetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,racemic-(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-((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-((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, racemic-(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, racemic-(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)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-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-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, racemic-(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, 1-(3-((2-((1-(3-(dimethylamino)propyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one, racemic-(R)-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-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one, 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, racemic-(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-one1-(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)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-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)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-((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,Racemic-(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, racemic-(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, racemic-(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, racemic-(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, racemic-(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, 2-methyl-2-(3-methyl-4-((4-((3-(2-bridged-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-oxazepan-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-oxazepan-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-oxazepan-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-oxazepan-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-oxazepan-2-one4-(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-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-one1-(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-((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, 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)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-one4-(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-oxabicyclo[1.1.1]pentan-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide3-(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-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)amino)propyl)-1,4-oxazepan-5-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, (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)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one1-(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, racemic-(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-oxabicyclo[4.1.0]heptan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile, 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-one3-(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-oxazepan-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-oxazepan-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)-1,3-oxazepan-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-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-oxazepan-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-oxazepan-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)-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-((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)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-oxazepan-2-one1-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)-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-oxazepan-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)-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)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-diazepan-5-one4-(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-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)-1,3-oxazinan-2-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-one6,6-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-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-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-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-oxazepan-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)-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]oct-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]oct-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]oct-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]oct-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one4-(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-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-one4-(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)-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)-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-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-one1-(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-(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-oxazepan-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-oxazepan-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-one1-(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-(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)-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]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-oxazepan-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)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)-one3-(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)-6,6-dimethyl-1,3-oxazepan-2-one4-(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)-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-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-one1-(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)-1,3-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-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)-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-one4-(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-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)morpholin-3-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-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-one4-(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)-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)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-oxazepan-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-oxazepan-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-(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)-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-oxabicyclo[1.1.1]pentan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxabicyclo[1.1.1]pentan-1-yl)propyl)amino)pyrimidine-5-carbonitrile2-((3-Methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[2.2.1]heptan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxabicyclo[3.2.2]nonan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-oxabicyclo[3.2.2]nonan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxabicyclo[2.2.1]heptan-3-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxomorpholin-4-yl)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-oxabicyclo[2.2.1]heptan-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-diazabicyclo[3.2.2]nonan-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-diazabicyclo[3.2.2]nonan-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-diazabicyclo[3.2.2]nonan-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-(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-oxabicyclo[1.1.1]pentan-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-oxabicyclo[1.1.0]butan-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-oxamorpholino)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-oxatetrahydropyrimidin-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-oxa-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-oxa-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-oxa-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-(3-oxa-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-oxa-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-oxa-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile2-((3-Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-methyl-2-oxabicyclo[3.2.1]octan-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-oxabicyclo[4.2.1]nonan-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-Methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-4-((3-(3-oxa-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-oxa-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(6,6-Dimethyl-2-oxa-1,3-oxahexan-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-oxa-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-oxa-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-oxa-1,3-oxahexan-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-oxa-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-oxa-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-oxa-1,3-oxahexan-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-carbonitrile4-((3-(2,2-dimethyl-3-oxabicyclo[3.2.1]octan-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-oxabicyclo[3.2.1]octan-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-oxaazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(2-oxaazetidin-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-oxaazetidin-1-yl)propyl)amino)pyrimidine-5-carbonitrile, 4-((3-(3,3-dimethyl-2-oxaazetidin-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-oxaazetidin-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-oxaazetidin-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)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)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)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-one4-(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-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)-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[3.2.1]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-2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one4-(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-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)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)-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-one1-(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-(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-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, 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, 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-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)pyrrolidin-2-one1-(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-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]oct-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)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, 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, N-(1-methylpiperidin-4-yl)-4-((4-((3-(2-oxido-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, 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-one4-(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)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-oxabicyclo[2.2.1]heptan-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-ethenyl-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-one9-(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-(3-morpholinopropyl)-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-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)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, 1-(1-methylpiperidin-4-yl)-4-((4-((3-(3-oxa-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.

12. A method for preparing a compound of formula I-B or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein formula I-B is represented by: Wherein: A is a 5-membered heteroaryl having at least one ring nitrogen; R 1 selected from the group consisting of Br, Cl, an alkyl group optionally substituted with one or more fluorine atoms, and a cycloalkyl group; R 2 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 with one, two or three independently occurring fluorine or cyano groups; R 4 selected from the group consisting of: B, D, NR 6 R 9 , NR 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 heterocyclic groups and heteroaryl groups having at least one nitrogen and optionally having additional ring nitrogen or oxygen, wherein B is optionally substituted by R on one or more available carbons 7 and optionally substituted by R on available nitrogen 9 ; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and optionally having additional ring nitrogen or oxygen, where D is optionally substituted on one or more available carbons by R 7 and optionally substituted on available nitrogen by R 9 ; R 7 independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano and (C(R 10 )2) h -NR 6 R 9 , where each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 7 join with the atom to which they are attached to form a bridging oxygen group; R 6 and R 9 is independently selected, at each occurrence, from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 and a C-linked heterocyclic group and heteroaryl having at least one nitrogen and optionally additional ring nitrogen or oxygen, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; R 5 independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic group each time it appears, wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with one or more independently occurring fluorines; R 10 independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears, wherein each C1-C3 alkyl and C3-C5 cycloalkyl is optionally substituted with one or more independently occurring fluorines, or two R 10 join together with the carbon to which it is attached to form a C3-C5 cycloalkyl; Z is q is 0, 1, 2 or 3; r is 2, 3 or 4; V is C(R 34 )2, oxygen or NR 6 , where R 6 is an alkyl group; R 34 independently at each occurrence is H or a C1-C6 alkyl group, or two Rs 34 are joined to the carbon to which they are attached to form a cycloalkyl group; 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; The condition is: when m is 0, R 4 is C-linked to ring A; when m is 1, R 4 is C-linked to L; and when m is 2 or 3, R 4 is N-linked or C-linked to L; The method comprises: Reacting a compound of formula M: With a compound of formula D-I:

13. The method according to claim 12, wherein when formula I-B further comprises a protecting group, the method further comprises deprotecting the protecting group under acidic conditions to form the compound of formula I-B.

14. The method of claim 13 further comprises reacting the compound of formula I-B with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or a ketone in the presence of a catalytic amount of a polar solvent containing acetic acid to form an N-substituted compound of formula I-B.

15. The method of any one of claims 12-14 further comprises: reacting a compound of formula H: with a compound represented by the following formula: where n, Z and R 1 as defined in Formula I-B to thereby form the compound of formula M.

16. The method of claim 12, wherein the compound of formula I-B is selected from the group consisting of: 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-((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-((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-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-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)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, 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-((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-bridged-oxy-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-bridged-oxy-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propionitrile, 6-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-4-((3-(5-bridged-oxy-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-Bridged oxy-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)pyridin-4-yl)amino)propyl)-1,3-oxazepan-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, and 2-Methyl-2-(3-methyl-4-((4-((3-(5-bridged oxy-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propanamide, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof., 17. The method of claim 1 or claim 12, wherein the compound of formula D-I is a compound of formula D-I-1, formula D-I-2, formula D-I-3, formula D-I-4, formula D-I-5, formula D-I-6, formula D-I-7, formula D-I-8, formula D-I-9, formula D-I-10, formula D-I-11, formula D-I-12, formula D-I-13, formula D-I-14, formula D-I-15, formula D-I-16, formula D-I-17 or formula D-I-18:

18. A compound selected from the group consisting of:

19. A compound selected from the group consisting of:

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