Aminopyrimidine amide autophagy inhibitors and methods of use thereof

Abstract

This article describes compounds as inhibitors of autophagy and their use in treating conditions such as cancer.

Description

Prior Technology

[0001] Autophagy (literally meaning "self-eating") is the process by which cells recycle organelles, proteins, stored lipids, glucagon, and other materials in order to generate nutrients during periods of stress. These cellular contents are recycled by being engulfed in vesicles called autophagosomes. Subsequently, the autophagosomes merge with lysosomes, which degrade their contents to recycle nutrients back into the cell. Tumor cells tend to activate autophagy because they have high metabolic demands, experience cellular stress, and are often in hypoxic environments with limited blood flow and nutrient supply. Furthermore, chemotherapy and targeted therapy have been shown to induce autophagy as a mechanism of treatment resistance, and the combination of autophagy inhibition (through loss-of-function mutations in autophagy genes or through pharmacological means) with chemotherapy has been shown to inhibit tumor growth and trigger tumor cell apoptosis to a greater extent than single-agent chemotherapy.

[0002] Mutated Ras protein drives approximately 30% of all human cancers—including 95% of pancreatic cancers and 45% of colorectal cancers—and the treatment of these mutant Ras cancers represents a significant unmet medical need. Mutated Ras cancers are highly proliferative and dependent on the amount of autophagy required for survival, suggesting that autophagy inhibition is a viable treatment approach in these "autophagy-dependent" cancers.

[0003] Currently, the most widely used autophagy inhibitors are chloroquine and hydroxychloroquine, recognized antimalarial agents. These antimalarial drugs are believed to block autophagy by chelating in lysosomal compartments, increasing the pH of these lysosomes, and thus inactivating proteases that degrade and recycle nutrients. These antimalarial agents have multiple mechanisms of action besides lysosomal inhibition and are known to induce retinopathy in patients. Therefore, there is a need for more selective targets that block autophagy without exhibiting the toxicity of these antimalarial agents. 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 via AMP-activated protein kinase AMPK. Importantly, kinase death mutants of ULK kinase block typical autophagy initiation, indicating that small-molecule inhibitors of ULK kinase activity should be able to block autophagy.

[0004] Other mechanistic studies have shown that deletion of the ULK1 gene inhibits autophagy in cancer cells, eliminates FOX3A conversion, and upregulates the pro-apoptotic protein PUMA. In addition to classical activation of typical autophagy, ULK1 kinase activity has also been shown to require Bcl-2-L-13-mediated mitochondrial autophagy (autophagy of damaged mitochondria). ULK1 and ULK2 kinases have also been shown to remodel glucose metabolism in cancer cells. ULK inhibitors have also been found to be effective in blocking these atypical pro-tumorigenic ULK activities.

[0005] Autophagy is also upregulated in cancer host cells and tissues. It was confirmed that autophagy in pancreatic astrocytes supports tumor growth. Pancreatic astrocytes support pancreatic cancer tumor metabolism through autophagic alanine secretion. It was confirmed that inhibition of autophagy in host tissues leads to a depletion of circulating arginine (an amino acid required for tumor metabolism and growth) through increased liver-mediated arginase secretion. It was also shown that ULK1 kinase activation inactivates the STING pathway in immune cells via STING inhibitory phosphorylation, regulating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Therefore, autophagy is activated not only in tumor cells (spontaneous in cancer cells) but also in other cells in the tumor microenvironment or host tissues (non-spontaneous in cancer cells) to support tumor survival and growth.

[0006] Mutant Ras cancers are autophagy-dependent. In pancreatic cancer, mutant Ras signaling primarily occurs via the MAPKAP pathway. Mutant Ras activates RAF kinase, followed by MEK kinase, and finally ERK kinase: mutant Ras → RAF → MEK → ERK. Although mutant Ras signaling occurs via the MAPKAP pathway, inhibitors of this pathway have provided little or no clinical benefit when used as monotherapy in clinical trials. Recently, MAPKAP pathway inhibition has been reported to induce autophagy as a compensatory survival mechanism. When MEK inhibitors are combined with the autophagy inhibitor hydroxychloroquine, there is synergistic activity in inducing regression in various mutant Ras or mutant BRAF cancers. Similarly, when ERK inhibitors are combined with the autophagy inhibitors hydroxychloroquine or chloroquine, there is synergistic activity in inhibiting mutant Ras pancreatic cancer. Gene depletion of RAF kinases (CRAF and BRAF) has been shown to induce synergistic antitumor activity in mutant Ras cancer cell lines, particularly in cases of autophagy depletion. Recent published findings emphasize that dual inhibition of the MAPKAP and autophagy pathways in mutant Ras cancers within the complex represents a promising treatment option for patients with mutant Ras cancers. It has also been confirmed that other targeted therapies and chemotherapy agents activate tumor autophagy as a resistance mechanism; therefore, there is a theoretical basis for combining such targeted therapies or chemotherapy agents with autophagy inhibitors.

[0007] Mutations in the gene encoding the LRRK2 kinase cause Parkinson's disease. Point mutations in LRRK2 are found in both familial (hereditary) and sporadic Parkinson's disease. The most common LRRK2 mutation in Parkinson's disease is LRRK2 G2019S. These LRRK2 mutations are gain-of-function mutations that cause excessive activation of LRRK2 signaling. Autophagy is a process used by brain neurons to maintain health and homeostasis. Autophagy is the process by which cells recognize, locate, and destroy aging organelles and structural elements within the cell; specifically, it eliminates toxic protein aggregates known to accumulate in neurons to maintain neuronal health. LRRK2 activity inhibits autophagy, and the LRRK2 G2019S gain-of-function mutation is even more inhibitory of autophagy and has been associated with the aggressive forms of Parkinson's disease.

[0008] Elevated LRRK2 kinase activity is also associated with immune-inflammatory diseases, including colitis, 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 patients with Crohn's disease, including NF-κB pathway activation and lectin-1-mediated innate immune responses mediated by TNF-α production in elevated dendritic cells.

[0009] LRRK2 inhibitors are sought for the treatment of neurodegenerative diseases, including Parkinson's disease, and also for the treatment of gastrointestinal diseases, including Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0010] Novel targeted therapies that require inhibition of autophagy and can be used in combination with MAPKAP pathway inhibitors, chemotherapeutic agents and / or other targeted therapies. Summary of the Invention

[0011] This document describes compounds of autophagy inhibitors, pharmaceutical compositions thereof, their use as medicaments in the treatment of conditions such as cancer, methods of their preparation, and pharmaceutical compositions containing them as active ingredients. Such pharmaceutical compositions may comprise compounds as a single active agent or in combination with other active agents in the presence of pharmaceutically acceptable excipients. In one embodiment, the described compound is an inhibitor of ULK kinase activity including ULK1 and ULK2 activities.

[0012] For example, the compounds presented herein can be described as Formula I: [formula] [I] Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: A series is selected from the group consisting of phenyl and 5 or 6 heteroaryl groups; W is CH or N; R1 series is selected from the group consisting of halogens, cyano groups, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted by one, two, or three independently occurring fluorine groups, as appropriate; R2 series is selected from the group consisting of halogens, cyano groups, C1-C5 alkyl groups, C3-C6 cycloalkyl groups, and C2-C5 olefins. The R3 group is selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein each C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkoxy, and C1-C5 alkoxy may be substituted by one, two, or three independently occurring fluorine or cyano groups, as appropriate; the R4 group is selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine groups, as appropriate; Group: B, D, NR6R9, NR6-(C(R10)2)p-NR6R9, C(O)-NR6R9, 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, depending on the case, another ring nitrogen or oxygen, wherein B may be R7 substituted on one or more usable carbons and R9 substituted on usable nitrogen; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the case, another ring nitrogen or oxygen, wherein D may be R7 substituted on one or more usable carbons and R9 substituted on usable nitrogen; Or multiple substituted carbon atoms via R7 and, if applicable, substituted nitrogen atoms via R9; R7, each time it appears, is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, if applicable, be substituted by one or more independently appearing fluorine atoms, or two R7 atoms may be linked together with the atoms to which they are attached to form a side oxygen group; R6 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1 -C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted with one or more independently occurring fluorine groups; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted with one or more independently occurring fluorine groups;R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine groups as appropriate; R10 is independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorine groups as appropriate, or two R10s may be attached to a carbon atom to form a C3-C5 cycloalkyl group; RL is selected from the group consisting of: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12, and; Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R13 is selected from H and C1-C3 alkyl; R34 is selected from each occurrence of... The R4 group is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted by one or more independently occurring fluorines, or two R34 groups may be connected to their attached carbons to form C3-C6 cycloalkyl groups; L is -(C(R10)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 limiting conditions are that when m is 0, R4 group C is connected to ring A, when m is 1, R4 group C is connected to L, and when m is 2 or 3, R4 group N is connected or C is connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0013] This article also describes a compound, which is represented by the following: [Mode] [IA] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: W is CH or N; X is CH or N; Y is C(R33) or N; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorines, as appropriate; R2 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl. R1-C5 alkoxy and C1-C5 alkoxy-C2-C5 alkyl, wherein each C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be substituted by one, two or three independently occurring fluorine or cyano groups as appropriate; R3 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine groups as appropriate; R33 is selected from the group consisting of: H, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C5 alkoxy groups may be substituted by one, two or three independently occurring fluorine groups as appropriate; -C6 alkoxy groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R4 groups are selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p-NR6R9, C(O)-NR6R9, C(O)-B, C(O)-D, and CN; B groups are selected from N-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the situation, another ring nitrogen or oxygen, wherein B may be substituted with R7 on one or more usable carbons and, depending on the situation, with R9 on usable nitrogen; D groups are selected from C-linked heterocyclic groups having at least one nitrogen and, depending on the situation, another ring nitrogen or oxygen. The group consists of alkyl and heteroaryl groups, wherein D may be substituted with R7 on one or more available carbons and with R9 on available nitrogen, depending on the situation; R7 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, or two R7s may be linked together with the atom to which they are attached to form a side oxygen group; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, depending on the situation, another cyclic nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, depending on the situation;The R9 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted by one or more independently occurring fluorine groups; the R5 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted by one or more independently occurring fluorine groups. Multiple independently occurring fluorine substitutions; R10 is independently selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine substitutions, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL series is selected from the group consisting of: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12 and; Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation. Substitution; R13 is selected from H and C1-C3 alkyl; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently appearing fluorines, or two R34s are connected to the carbon to which they are attached to form C3-C6 cycloalkyl; L is -(C(R10)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 restriction is that X and Y are not N, and when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0014] In another state, the compound described in this paper is ID. [Mode] [ID] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: The DD series is selected from the following groups: ; W is CH or N; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two or three independently occurring fluorines, as appropriate; R2 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkoxy, and C1-C5 alkoxy-C2-C5 alkyl, wherein each C1- C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy groups may be substituted with one, two, or three independently occurring fluorine or cyano groups, depending on the situation; R3 groups are selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R4 groups are selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p -NR6R9, C(O)-NR6R9, 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, depending on the case, another ring nitrogen or oxygen, wherein B may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on the usable nitrogen; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the case, another ring nitrogen or oxygen, wherein D may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on the usable nitrogen; As appropriate, nitrogen may be substituted with R9; R7, each time appearing, is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines, or two R7s may be attached to the atoms to form a side oxygen group; R6 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1 -C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups;R10 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorines, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12 and; Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2, and q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R13 is selected from H and C1-C3 alkyl; R34 is selected each time it appears. The components are independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorines, or two R34s may be connected to their attached carbons to form C3-C6 cycloalkyls; L is -(C(R10)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 limiting conditions are that when m is 0, R4 is C connected to the pyrazolyl ring, when m is 1, R4 is C connected to L, and when m is 2 or 3, R4 is N connected or C connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6. Implementation

[0015] [Cross-reference to related applications] This application claims priority to USSN 62 / 862,469, filed June 17, 2019; USSN 62 / 862,470, filed June 17, 2019; USSN 62 / 911,739, filed October 7, 2019; and USSN 62 / 911,740, filed October 7, 2019, the contents of which are incorporated herein by reference in their entirety.

[0016] The features and other details of this disclosure will now be described more clearly. Specific terms used in this specification, examples, and the appended claims are collected herein. These definitions should be read in accordance with the remainder of this disclosure and as understood by one skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art. definition

[0017] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons having 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms, referred to herein as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tributyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0018] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups having 2-6 or 3-4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0019] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group (alkyl-O-) attached to an oxygen atom. Exemplary alkoxy groups include, but are not limited to, alkoxy groups having 1-6 or 2-6 carbon atoms, referred to herein as C1-C6 alkoxy groups and C2-C6 alkoxy groups, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0020] As used herein, the term "alkoxyalkyl" refers to a straight-chain or branched alkyl group (alkyl-O-alkyl-) attached to an oxygen atom or to a second straight-chain or branched alkyl group. Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups in which each of the alkyl groups independently contains 1-6 carbon atoms, referred to herein as C1-C6 alkoxy-C1-C6 alkyl groups. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, etc.

[0021] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups having 2-6 or 3-6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, and methylpropynyl.

[0022] As used in this article, the term "cyano" refers to the group -CN.

[0023] As used herein, the terms "cycloalkyl" or "carbocyclic" refer 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 cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0024] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to an oxygen atom (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups having 3-6 carbon atoms, referred to herein as C3-C6 cycloalkoxy groups. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0025] As used herein, the terms "halogen" or "halogen" refer to F, Cl, Br, or I.

[0026] 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 linked to an adjacent group via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furans, thiophenes, pyrroles, thiazoles, oxazoles, isothiazoles, isoxazoles, imidazoles, pyrazoles, triazoles, pyridines, or pyrimidines.

[0027] The term "heterocyclyl / heterocyclic group" is a recognized term in the field referring to saturated or partially unsaturated 4-10 member ring structures, including monocyclic, bridging, or fused rings, and such ring structures include one to three heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be connected to an adjacent group via carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azabutane, tetrahydrofuran, or dihydrofuran.

[0028] As used herein, the term "endoamide" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkyl-2-one structure, or an analogue having one or more carbon atoms of an unsaturated or substituted ring. "α-endoamide" refers to an amide composed of a 3-membered ring. "β-endoamide" refers to an amide composed of a 4-membered ring. "γ-endoamide" refers to an amide composed of a 5-membered ring. "δ-endoamide" refers to an amide composed of a 6-membered ring. "ε-endoamide" refers to an amide composed of a 7-membered ring.

[0029] As used in this article, the term "side oxygen group" refers to the =O group.

[0030] "Combination therapy" refers to treatment that involves administering two or more therapeutic agents, such as a compound of formula I and a MAPKAP pathway inhibitor, to a patient in need.

[0031] The terms "disease," "symptom," and "symptom" are used interchangeably in this article.

[0032] The terms "person," "patient," or "individual" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and preferably humans. The compounds described herein may be administered to mammals, such as humans, but may also be administered to other mammals, such as animals requiring veterinary care, such as livestock (e.g., dogs, cats, and similar animals), agricultural animals (e.g., cattle, sheep, pigs, horses, and similar animals), and laboratory animals (e.g., rats, mice, guinea pigs, and similar animals).

[0033] "MAPKAP pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. These inhibitors include Ras inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996). The terms "MAPKAP pathway inhibitor" and "MAPKAP kinase inhibitor" are used interchangeably in this document.

[0034] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other adverse reactions when administered to animals or humans as needed. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0035] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonics, absorption delay agents, and the like that are compatible with pharmaceutical administration. The use of such media and pharmaceuticals for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic efficacy.

[0036] 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.

[0037] As used herein, the term "medically acceptable salt" refers to a salt having acidic or basic groups that can be present in a compound used in a composition. Compounds included in the compositions of this invention, which are inherently basic, 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, bromines, iodines, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleate, gentianate, fumarates, gluconates, glucuronides, glucosidates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (e.g., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarboxylate)). Compounds included in the compositions of the present invention that are inherently acidic can form basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the compositions of the present invention, including basic or acidic portions, can 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 this case, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0038] The compounds of this invention may contain one or more enantiomers and thus exist in stereoisomeric form. When used herein, the term "stereoisomer" comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereoforming carbon atom, such compounds may be designated by the symbols "(+)", "(-)", "R" or "S", but those skilled in the art will recognize that the structure may implicitly represent the enantiomer. The compounds described in this invention encompass various stereoisomers of such compounds and mixtures thereof. In nomenclature, mixtures of enantiomers or diastereomers may be designated as "(±)", but those skilled in the art will recognize that the structure may implicitly refer to the enantiomer.

[0039] In this specification, the term "therapeuticly effective amount" means the amount of the compound of the invention that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds described herein are administered in therapeutically effective amounts to treat a condition.

[0040] "Treatment" includes any action that causes improvement of symptoms, diseases, conditions and similar ones, such as relief, reduction, regulation or elimination.

[0041] This disclosure also covers isotopically labeled compounds consistent with those described herein, differing in that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, the compounds of this invention may have one or more H atoms substituted with deuterium.

[0042] Individual enantiomers and diastereomers of the compounds of the present invention can be prepared by synthesis from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by analytical methods well known to those skilled in the art. Such analytical methods are exemplified by: (1) attaching a mixture of enantiomers to a palmitic auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the auxiliary agent; (2) salt formation using an optically active analytical agent; (3) direct separation of the mixture of optically enantiomers on a palmitic liquid chromatography column; or (4) kinetic analysis using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their constituent enantiomers by well-known methods such as palmitic liquid chromatography or crystallization of the compound in a palmitic solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms a distinct mixture of stereoisomers during the formation of a new stereocenter or during the transformation of one of the pre-existing components, is well known in this art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of antagonistic auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. compound

[0043] In one state, the compounds presented herein can be described by the following formula I: [Mode] [I] Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: A is selected from the group consisting of phenyl and 5 or 6 heteroaryl groups; W is CH or N; R1 is selected from the group consisting of halogens, cyano groups, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted by one, two, or three independently occurring fluorine groups, as appropriate; R2 is selected from the group consisting of halogens, cyano groups, C1-C5 alkyl groups, C3-C6 cycloalkyl groups, C2-C5 alkenyl groups, C2-C5 alkynyl groups, C1-C5 alkoxy groups, and C1-C5 alkyl groups. Oxy-C2-C5 alkyl, wherein each of the C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy groups may be substituted by one, two or three independently occurring fluorine or cyano groups, depending on the situation; R3 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups, depending on the situation; R4 is selected from the group consisting of: B, D, NR6R9, NR 6-(C(R10)2)p-NR6R9, C(O)-NR6R9, 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, depending on the case, another ring nitrogen or oxygen, wherein B may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on the usable nitrogen; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the case, another ring nitrogen or oxygen, wherein D may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on one or more usable carbons. R7 is substituted and may be substituted with R9 on available nitrogen, depending on the situation; R7 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, or two R7s may be attached to the atoms to form a side oxygen group; R6 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1 -C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted with one or more independently occurring fluorine groups; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted with one or more independently occurring fluorine groups;R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine groups as appropriate; R10 is independently selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorine groups as appropriate, or two R10s may be attached to a carbon atom to form a C3-C5 cycloalkyl group; RL is selected from the group consisting of: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12, and; Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R13 is selected from H and C1-C3 alkyl; R34 is selected from each occurrence of... The R4 group is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted by one or more independently occurring fluorines, or two R34 groups may be connected to their attached carbons to form C3-C6 cycloalkyl groups; L is -(C(R10)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 limiting conditions are that when m is 0, R4 group C is connected to ring A, when m is 1, R4 group C is connected to L, and when m is 2 or 3, R4 group N is connected or C is connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0044] For example, this article also describes compounds represented by formula IA: [Mode] [IA] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: W is CH or N; X is CH or N; Y is C(R33) or N; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorines, as appropriate; R2 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl. R1-C5 alkoxy and C1-C5 alkoxy-C2-C5 alkyl, wherein each C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be substituted by one, two or three independently occurring fluorine or cyano groups as appropriate; R3 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine groups as appropriate; R33 is selected from the group consisting of: H, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C5 alkoxy groups may be substituted by one, two or three independently occurring fluorine groups as appropriate; -C6 alkoxy groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R4 groups are selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p-NR6R9, C(O)-NR6R9, C(O)-B, C(O)-D, and CN; B groups are selected from N-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the situation, another ring nitrogen or oxygen, wherein B may be substituted with R7 on one or more usable carbons and, depending on the situation, with R9 on usable nitrogen; D groups are selected from C-linked heterocyclic groups having at least one nitrogen and, depending on the situation, another ring nitrogen or oxygen. The group consists of alkyl and heteroaryl groups, wherein D may be substituted with R7 on one or more available carbons and with R9 on available nitrogen, depending on the situation; R7 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, or two R7s may be linked together with the atom to which they are attached to form a side oxygen group; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, depending on the situation, another cyclic nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, depending on the situation;The R9 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted by one or more independently occurring fluorine groups; the R5 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may, where appropriate, be substituted by one or more independently occurring fluorine groups. Multiple independently occurring fluorine substitutions; R10 is independently selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine substitutions, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL series is selected from the group consisting of: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12 and; Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation. R13 is selected from H and C1-C3 alkyl; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently appearing fluorine, or two R34 are connected to the carbon to which they are attached to form C3-C6 cycloalkyl; L is -(C(R10)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 restriction is that X and Y are not N, when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0045] In some embodiments, W is N. In some embodiments, X is CH and Y is N. In some embodiments, X is CH and Y is C(R33).

[0046] In some embodiments, R4 is B.

[0047] In some embodiments, the R4 series is selected from the group consisting of: , Where u is 1, 2 or 3.

[0048] In some embodiments, the R4 series is selected from the group consisting of: .

[0049] In some embodiments, the R4 series is selected from the group consisting of: .

[0050] In some embodiments, the R4 series is selected from the group consisting of: .

[0051] In some embodiments, R4 is D.

[0052] In some embodiments, the R4 series is selected from the group consisting of: .

[0053] In some embodiments, L is -(CH2)m. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0054] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine compounds, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0055] In some embodiments, the R2 group is selected from the group consisting of: C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl, and C2-C5 alkynyl, wherein the C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl may be substituted with one, two, or three independently occurring fluorine groups, as appropriate. In some embodiments, the R2 group is selected from the group consisting of: C1-2 alkyl and C3-4 cycloalkyl.

[0056] In some embodiments, R3 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted with one or more independently occurring fluorines, as appropriate.

[0057] In some embodiments, the RL system is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, each of which may be substituted with one, two or three independently occurring fluorine molecules, as appropriate.

[0058] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12.

[0059] In some embodiments, RL is Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0060] In some embodiments, n is 3.

[0061] In some embodiments, the compound is represented by formula IB: [Mode] [IB] Or a pharmaceutically acceptable salt thereof, wherein: n is 2, 3 or 4; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two or three independently occurring fluorine, as appropriate; R2 is selected from the group consisting of: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein the C1-C2 alkyl and C3-C4 cycloalkyl may be substituted by one, two or three independently occurring fluorine, as appropriate; R3 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine, as appropriate; R4 is selected from the group consisting of: ; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, where appropriate, another ring nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups. C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl groups, wherein C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case, or two R7s may be attached to their attached atoms to form a side oxygen group; the RL series is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, NR11R12 and In this system, each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine groups, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, depending on the situation, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R11 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine groups, depending on the situation. One or more independently occurring fluorine substitutions; R12 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R13 is selected from H and C1-C3 alkyl; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate, or two R34s are connected to the carbon to which they are attached to form a C3-C6 cycloalkyl; the restriction is that X and Y are not N, and when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0062] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted by one, two, or three independently occurring fluorine and C3-C5 cycloalkyl groups, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from the group consisting of chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0063] In some embodiments, the R2 group is selected from the group consisting of C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, the R2 group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromine.

[0064] In some embodiments, R3 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted with one or more independently occurring fluorines, as appropriate.

[0065] In some embodiments, the R4 series is selected from the group consisting of: .

[0066] In some embodiments, the R4 series is selected from the group consisting of: .

[0067] In some embodiments, each of R6 and R9 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate.

[0068] In some embodiments, R7 is H.

[0069] In some embodiments, the RL system is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one, two or three independently occurring fluorine molecules, as appropriate.

[0070] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12.

[0071] In some embodiments, RL is Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0072] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0073] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0074] In some embodiments, n is 3.

[0075] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; R34 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0076] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0077] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0078] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0079] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0080] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0081] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0082] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0083] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0084] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0085] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0086] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0087] In some embodiments, the compound is composed of [Mode] [IC] indicates: [Mode] [IC] Or a pharmaceutically acceptable salt thereof, wherein: n is 2, 3 or 4; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two or three independently occurring fluorine, as appropriate; R2 is selected from the group consisting of: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein the C1-C2 alkyl and C3-C4 cycloalkyl may be substituted by one, two or three independently occurring fluorine, as appropriate; R3 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine, as appropriate; R4 is selected from the group consisting of: ; R9 is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups. -C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl groups, wherein C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case, or two R7s may be attached to their attached atoms to form a side oxygen group; the RL series is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, NR11R12 and In this system, each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine groups, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, depending on the situation, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R11 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine groups, depending on the situation. One or more independently occurring fluorine substitutions; R12 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R13 is selected from H and C1-C3 alkyl; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate, or two R34s are connected to the carbon to which they are attached to form a C3-C6 cycloalkyl; the restriction is that X and Y are not N, and when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0088] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted by one, two, or three independently occurring fluorine and C3-C5 cycloalkyl groups, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from the group consisting of chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0089] In some embodiments, the R2 group is selected from the group consisting of C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, the R2 group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromine.

[0090] In some embodiments, R3 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted with one or more independently occurring fluorines, as appropriate.

[0091] In some embodiments, the R4 series is selected from the group consisting of: .

[0092] In some embodiments, the R4 series is selected from the group consisting of: .

[0093] In some embodiments, each of R6 and R9 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate.

[0094] In some embodiments, R7 is H.

[0095] In some embodiments, the RL system is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one, two or three independently occurring fluorine molecules, as appropriate.

[0096] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12.

[0097] In some embodiments, RL is Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0098] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0099] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0100] In some embodiments, n is 3.

[0101] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; R34 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0102] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0103] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0104] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0105] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0106] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0107] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0108] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0109] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group of the following components each time it appears: CF3, CF2H, bromine, chlorine or cyclopropyl; R2 is independently selected from the group of the following components each time it appears: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; R3 is independently selected from the group of the following components each time it appears: H and C1-C2 alkyl; R9 is independently selected from the group of the following components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl; and n is 3.

[0110] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0111] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0112] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R9 is independently selected from H and C1-C3 alkyl each time it appears; and n is 3.

[0113] This article also describes ID compounds. [Mode] [ID] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the cyclic DD system is selected from the group consisting of: ; W is CH or N; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two or three independently occurring fluorines, as appropriate; R2 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkoxy, and C1-C5 alkoxy-C2-C5 alkyl, wherein each C1- C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy groups may be substituted with one, two, or three independently occurring fluorine or cyano groups, depending on the situation; R3 groups are selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups, depending on the situation; R4 groups are selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p -NR6R9, C(O)-NR6R9, 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, depending on the case, another ring nitrogen or oxygen, wherein B may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on the usable nitrogen; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, depending on the case, another ring nitrogen or oxygen, wherein D may, depending on the case, be substituted with R7 on one or more usable carbons and may, depending on the case, be substituted with R9 on the usable nitrogen; As appropriate, nitrogen may be substituted with R9; R7, each time appearing, is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines, or two R7s may be attached to the atoms to form a side oxygen group; R6 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1 -C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups;R10 is independently selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorines, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12 and; Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2, and q is 1, 2, or 3; R11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine molecules, depending on the situation; R13 is selected from H and C1-C3 alkyl; R34 is selected each time it appears. The components are independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorines, or two R34s may be connected to their attached carbons to form C3-C6 cycloalkyls; L is -(C(R10)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 limiting conditions are that when m is 0, R4 is C connected to the pyrazolyl ring, when m is 1, R4 is C connected to L, and when m is 2 or 3, R4 is N connected or C connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0114] In some embodiments, W is N. In some embodiments, W is CH.

[0115] In some embodiments, the ring DD system is selected from the group consisting of: .

[0116] In some embodiments, the ring DD system is selected from the group consisting of: .

[0117] In some embodiments, the ring DD is: .

[0118] In some embodiments, R4 is D.

[0119] In some embodiments, the R4 series is selected from the group consisting of: .

[0120] In some embodiments, the R4 series is selected from the group consisting of: .

[0121] In some embodiments, R4 is B.

[0122] In some embodiments, the R4 series is selected from the group consisting of: , where u is 1 or 2.

[0123] In some embodiments, the R4 series is selected from the group consisting of: .

[0124] In some embodiments, the R4 series is selected from the group consisting of: .

[0125] In some embodiments, L is -(CH2)m. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0126] In some embodiments, R4 is D and m is 0. In some embodiments, R4 is D and m is 1. In some embodiments, R4 is selected from D and B and m is 2. In some embodiments, R4 is selected from D and B and m is 3.

[0127] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine compounds, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from the group consisting of chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0128] In some embodiments, the R2 group is selected from the group consisting of: C3-C5 cycloalkyl, C1-C5 alkyl, halogen, cyano, C2-C5 alkenyl, and C2-C5 alkynyl, wherein the C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl may be substituted with one, two, or three independently occurring fluorine groups, as appropriate. In some embodiments, the R2 group is selected from the group consisting of: C1-2 alkyl and C3-4 cycloalkyl. In some embodiments, the R3 group is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate.

[0129] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12.

[0130] In some embodiments, RL is Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0131] In some embodiments, n is 3.

[0132] In some embodiments, the compound is composed of [Mode] [IE] indicates: [Mode] [IE] Or its pharmaceutically acceptable salts, wherein: the cyclic DD series is selected from the following groups: ; n is 2, 3, or 4; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorine, depending on the situation; R2 is selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, wherein the C1-C2 alkyl and C3-C4 cycloalkyl may be substituted by one, two, or three independently occurring fluorine, depending on the situation; R3 is selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine, depending on the situation; R4 is selected from the group consisting of: ; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, where appropriate, another ring nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups. C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl groups, wherein C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case, or two R7s may be attached to their attached atoms to form a side oxygen group; the RL series is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, NR11R12 and Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the case; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, having at least one nitrogen and, depending on the case, having Another ring nitrogen or oxygen C-linked heterocyclic and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R11 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R12 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R13 is selected from H and C1-C3 alkyl groups; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate, or two R34 groups are connected to the attached carbon to form a C3 group. -C6 cycloalkyl; and L is -(C(R10)2)m-; m is 0, 1, 2 or 3; the limiting condition is that when m is 0, the R4 series C is connected to the pyrazolyl ring, when m is 1, the R4 series C is connected to L, and when m is 2 or 3, the R4 series N is connected or C is connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0133] In some embodiments, the ring DD is free from the following group of components: .

[0134] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine compounds, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from the group consisting of chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0135] In some embodiments, the R2 group is selected from the group consisting of C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, the R2 group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromine.

[0136] In some embodiments, R3 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted with one or more independently occurring fluorines, as appropriate.

[0137] In some embodiments, R4 is D.

[0138] In some embodiments, the R4 series is selected from the group consisting of: .

[0139] In some embodiments, the R4 series is selected from the group consisting of: .

[0140] In some embodiments, each of R6 and R9 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate.

[0141] In some embodiments, R7 is H.

[0142] In some embodiments, the RL system is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one, two or three independently occurring fluorine molecules, as appropriate.

[0143] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12.

[0144] In some embodiments, RL is Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0145] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0146] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0147] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0148] In some embodiments, n is 3.

[0149] In some embodiments, the compound is represented by a formula selected from the group consisting of: . R1 is independently selected from the group consisting of: CF3, CF2H, bromine, chlorine, or cyclopropyl, each time it appears; R2 is independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, each time it appears; R3 is independently selected from the group consisting of: H and C1-C2 alkyl, each time it appears; R6 is independently selected from the group consisting of: H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be... R7 is selected independently from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, depending on the situation; R9 is selected independently from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears; R34 is selected independently from H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears; and n is 3.

[0150] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0151] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IE.1 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IE.2 and IE.3 as defined above.

[0152] In some embodiments, the compound is represented by a formula selected from the group consisting of: . R1 is independently selected from the group consisting of CF3, CF2H, bromine, chlorine, or cyclopropyl each time it appears; R2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl each time it appears, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines as appropriate; R9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0153] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0154] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IE.4 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IE.5 and IE.6 as defined above.

[0155] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group consisting of CF3, CF2H, bromine, chlorine, or cyclopropyl each time it appears; R2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl each time it appears, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines as appropriate; R9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0156] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0157] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0158] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IE.7 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IE.8 and IE.9 as defined above.

[0159] In some embodiments, the compound is obtained from [Mode] [IF]: [Mode] [IF] Or its pharmaceutically acceptable salts, wherein: the cyclic DD series is selected from the following groups: ; n is 2, 3, or 4; R1 is selected from the group consisting of: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorine, depending on the situation; R2 is selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, wherein the C1-C2 alkyl and C3-C4 cycloalkyl may be substituted by one, two, or three independently occurring fluorine, depending on the situation; R3 is selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently occurring fluorine, depending on the situation; R4 is selected from the group consisting of: ; R9 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, C-linked heterocyclic groups having at least one nitrogen and, where appropriate, another ring nitrogen or oxygen, and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted by one or more independently occurring fluorine groups. C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl groups, wherein C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine atoms, depending on the case, or two R7s may be attached to their attached atoms to form a side oxygen group; the RL series is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, NR11R12 and Each C1-C6 alkyl and C3-C6 cycloalkyl group may be substituted with one, two, or three independently occurring fluorine molecules, depending on the case; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2, and NR6; r is 0, 1, or 2; q is 1, 2, or 3; R6 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R5, SO2R5, having at least one nitrogen and, depending on the case, having Another ring nitrogen or oxygen C-linked heterocyclic and heteroaryl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R11 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R12 is selected from the group consisting of: H, C1-C3 alkyl and C3-C5 cycloalkyl groups, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate; R13 is selected from H and C1-C3 alkyl groups; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorine groups as appropriate, or two R34 groups are connected to the attached carbon to form a C3 group. -C6 cycloalkyl; and L is -(C(R10)2)m-; m is 0, 1, 2 or 3; the limiting condition is that when m is 0, the R4 series C is connected to the pyrazolyl ring, when m is 1, the R4 series C is connected to L, and when m is 2 or 3, the R4 series N is connected or C is connected to L; and other limiting conditions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0160] In some embodiments, the ring DD is free from the following group of components: .

[0161] In some embodiments, R1 is selected from the group consisting of halogens, C1-C5 alkyl groups, and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted with one, two, or three independently occurring fluorine compounds, as appropriate. In some embodiments, R1 is CF3. In some embodiments, R1 is CF2H. In some embodiments, R1 is selected from the group consisting of chlorine, bromine, and fluorine. In some embodiments, R1 is bromine. In some embodiments, R1 is cyclopropyl.

[0162] In some embodiments, the R2 group is selected from the group consisting of C3-C4 cycloalkyl, C1-C5 alkyl, and halogen. In some embodiments, the R2 group is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromine.

[0163] In some embodiments, R3 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted with one or more independently occurring fluorines, as appropriate.

[0164] In some embodiments, R4 is D.

[0165] In some embodiments, the R4 series is selected from the group consisting of: .

[0166] In some embodiments, the R4 series is selected from the group consisting of: .

[0167] In some embodiments, each of R6 and R9 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate.

[0168] In some embodiments, R7 is H.

[0169] In some embodiments, the RL system is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one, two or three independently occurring fluorine molecules, as appropriate.

[0170] In some embodiments, RL is cyclobutyl. In some embodiments, RL is NR11R12. In some embodiments, RL is... Each of the C1-C6 alkyl and C3-C6 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, depending on the situation; U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl groups; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl groups each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl groups may be substituted with one or more independently occurring fluorines, depending on the situation, or two R34 groups may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl group; the restriction is that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR6.

[0171] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0172] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0173] In some embodiments, the -N(R3)-C(O)-RL system is selected from the group consisting of: .

[0174] In some embodiments, n is 3.

[0175] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group consisting of: CF3, CF2H, bromine, chlorine, or cyclopropyl, each time it appears; R2 is independently selected from the group consisting of: C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, each time it appears; R3 is independently selected from the group consisting of: H and C1-C2 alkyl, each time it appears; R6 is independently selected from the group consisting of: H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be... R7 is selected independently from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorine, depending on the situation; R9 is selected independently from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears; R34 is selected independently from H, C1-C3 alkyl, and C3-C5 cycloalkyl, each time it appears; and n is 3.

[0176] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0177] In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R7 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IF.1 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IF.2 and IF.3 as defined above.

[0178] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group consisting of CF3, CF2H, bromine, chlorine, or cyclopropyl each time it appears; R2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl each time it appears, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines as appropriate; R9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0179] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0180] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IF.4 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IF.5 and IF.6 as defined above.

[0181] In some embodiments, the compound is represented by a formula selected from the group consisting of: R1 is independently selected from the group consisting of CF3, CF2H, bromine, chlorine, or cyclopropyl each time it appears; R2 is independently selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and halogen each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl each time it appears, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines as appropriate; R9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl each time it appears; and n is 3.

[0182] In some embodiments, R1 is bromine each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, R1 is CF3 each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3.

[0183] In some embodiments, R1 is CF2H each time it appears; R2 is independently selected from C1-C2 alkyl and C3-C4 cycloalkyl each time it appears; R3 is independently selected from the group consisting of H and C1-C2 alkyl each time it appears; R6 is independently selected from the group consisting of H, C1-C6 alkyl and C3-C6 cycloalkyl each time it appears; R9 is selected from H and C1-C3 alkyl each time it appears; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears; and n is 3. In some embodiments, the compound is represented by formula IF.7 as defined above. In some embodiments, the compound represents a formula selected from the group consisting of formulas IF.8 and IF.9 as defined above.

[0184] This article also describes compounds selected from the group consisting of: N-(3-((5-cyclopropyl-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-(2-methyl-4-(4-))cyclobutanemethane, N-(3-((2-(2-methyl-4-(4-))cyclobutanemethane, N-(3-((2-(2-(2-))cyclobutanemethane, N-(3-( ...2-(2-))cyclobutanemethane, N-(3-(2-(2- Methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentylamine, N-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-(( 2-((1-(1-amino-2-methyl-1-sideoxypropyl-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((1-(2-cyanopropyl-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-methyl-6-(4-methylpiperazine)) N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperazin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)N-methylcyclobutanemethane,N-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane methylamine, N-methyl-N-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane methylamine, N-methyl-N-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl) N-(3-((2-((1-(1-cyclopropylpiperidin-4-yl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethane, N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane , N-(3-((2-((1-(1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-methyl-4-( 4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-methyl-6-N-morpholinylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine,N-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-(2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl) N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(tri- N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutyl ...3-((2-((2-ethyl-4-(4-methylpiperazin -methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentylaminoamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclopropanemethylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine,N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-piperan-4-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin- 4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-piperazin-4-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl) -N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl) N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluoro-N-methylcyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutylamine,N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylpentafenamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-methylamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-methylamide, N-(3-((2-((2-ethyl -4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-piperan-4-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-piperazin-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-carboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octyl) alkyl-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine,N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-methylamine, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-( (5-Chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-carboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl) N-(3-((2-((2-bromo-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)- 2-Bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-bromo-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane,N-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane Methamidoamine, N-(3-((2-((2-chloro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methamidoamine, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methamidoamine, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methamidoamine, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino) N-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-(2-() (2-Ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-N-methylcyclobutanemethane, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanemethane,N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl) 3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)azabicyclobutane-1-methylamine, N-(3-((5-bromo-2-((2- Ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidone-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)amino)propyl)-2,2-dimethylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine,N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin- 4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-methylamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4- N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)N-methylcyclobutane-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-piperan-4-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane- 3-Methylamine, N-(3-((2-((1-(2-((dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine,N-(3-((2-((1-(2-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)propyl)oxetane-3-carboxamide, 1-methyl -N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((1-(2-((dimethylamino)ethyl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine Amine, N,1-dimethyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((1-(2-((dimethylamino)ethyl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-methylamine, N,1-dimethyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amine N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrimidin-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine,N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-carboxamide, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl) N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-3-methylamine, N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-methyl-N-(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)oxetane-3-carboxamide, 1-methyl-N-(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)oxetane-3-carboxamide, N,1-dimethyl-N-(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)azacyclobutane-3-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxacyclobutane-3-carboxamide,N-(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-methylazabicyclobutane-3-methylamine, N-(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)cyclobutane-methylamine, N-(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)cyclobutane-3-methylamine, N-(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)cyclobutane-3-methylamine -((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-methylazabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-3-methylamine, N-(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)cyclobutane-methylamine, N-(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)cyclobutane-methylamine, N-(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)oxetane-3-methylamine, N-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazabicyclobutane-3-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentaspirinamine, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentaspirinamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pentaspirinamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pentaspirinamine,3,3-Difluoro-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-carboxamide, 3,3-difluoro-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-carboxamide, 3,3-difluoro-N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)cyclobutane-1-carboxamide -yl)amino)propyl)cyclobutane-1-methylamine, 3,3-difluoro-N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-methylamine, N-( 3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) (amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carbamate, N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl) N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-(5-) Methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane,N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-2-(4-methylpiperidin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-2-(4-methylpiperidin-1-yl)oxazol-5-yl ...oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-3-((2-((5-methyl-2-(4-methylpiperidin-1-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl)oxazol-5-yl) N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino) propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazolyl-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine,N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, 3,3-difluoro-N-(3-((2-(() 5-Methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-methylamine, 1-methyl-N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine Alkyl-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3- Methamidinium, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methamidinium, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methamidinium, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methamidinium,1-Methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazin-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl) 5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-5 ... -Methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N ...propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol- -methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)oxacyclobutane-3-carboxamide, 1-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)azacyclobutane-3-carboxamide, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)cyclobutanecarboxamide,N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)oxetane-3-methylamine, 1-methyl-N ... ]Octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine 1,1-Dimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)urea, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl) 1,1,3-trimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)urea and their pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers. Treatment

[0185] The compounds described in this article can serve as autophagy inhibitors for the treatment of conditions in patients in need. For example, a condition could be a solid tumor, or even cancer.

[0186] Examples of cancers 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, cancers that have metastasized to bone, papillary thyroid carcinoma, non-small cell lung cancer, and colorectal cancer. Cancers treated using the methods described herein may be metastatic.

[0187] In some embodiments, the compounds described herein may 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.

[0188] In some embodiments, the assay of autophagy inhibition using the compounds described herein is performed by monitoring autophagic flux, for example by monitoring the inhibition of autophagy-mediated clearance of the mCherry / GFP-LC3 fusion protein. In some embodiments, the assay of autophagy inhibition using the compounds described herein is performed by monitoring the accumulation of autophagy proteins such as p62 or LC-3. In some embodiments, the assay of autophagy inhibition using the compounds described herein is performed by the clearance of reduced luciferase-labeled LC3 protein. In some embodiments, the assay of autophagy inhibition using the compounds described herein is performed by monitoring the reduction of autophagosomes, for example by measuring fluorescent spots with the autophagosome marker Cyto-ID.

[0189] In some embodiments, ULK kinase cell inhibition by the compounds described herein is measured by the inhibition of phosphorylation of ULK receptors, including ATG13, ATG14, Beclin 1, or STING, in tumor cells or non-tumor host tissues. In some embodiments, ULK kinase cell inhibition by the compounds described herein is measured in host tissues including immune cells.

[0190] In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by the inhibition of phosphorylation of ULK receptors, including ATG13, ATG14, Beclin 1, or STING, in tumor cells or non-tumor host tissues. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in host tissues including immune cells. In some embodiments, in vivo inhibition of autophagic flux by the compounds described herein can be used as a pharmacokinetic model for monitoring the kinetics and extent of such ULK inhibition. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in animals with pancreatic cancer. In some embodiments, in vivo inhibition of ULK kinase by the compounds described herein is determined in animals with lung cancer. In some embodiments, in vivo inhibition of ULK kinase is determined in animals with colorectal cancer. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of autophagic flux in tumor cells or non-tumor host tissues by monitoring inhibition of autophagosome formation or by the accumulation of autophagy proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is determined in host tissues including immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacokinetic model for monitoring the kinetics and extent of such ULK inhibition.

[0191] In some embodiments, the inhibitory activities of the compounds described herein on autophagy and antitumor activity were evaluated in xenograft studies using human RAS mutant cell lines in immunocompromised mice, such as SCID or nude mice. In some embodiments, the inhibitory activities of the compounds described herein on autophagy and antitumor activity were evaluated in xenograft studies using tumor xenografts (PDX) derived from human RAS mutant patients in immunocompromised mice, such as SCID or nude mice. In some embodiments, xenograft studies included the evaluation of the compounds described herein in pancreatic cancer models. In some embodiments, the inhibitory activities of the compounds described herein on autophagy and antitumor activity were evaluated in genetically engineered murine models (GEMs) of mutant RAS cancer. In some embodiments, the autophagy inhibition and antitumor activity of the compounds described herein were evaluated in mouse GEM genotype orthotopic pancreatic cancer models called the following: KPC models (LSL-KrasG12D / +, LSL-Trp53R172H / +, Pdx-1-Cre) or variations of the KPC model.

[0192] In some embodiments, the compounds described herein will be evaluated in combination with MEK inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with RAF inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with ERK inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with direct RAS G12C inhibitors in xenograft or GEM cancer models.

[0193] In some embodiments, the autophagy inhibition and antitumor activity of the compounds described herein are evaluated in immunomodulatory mouse cancer models used to assess the immunomodulatory components targeting the mechanism of action of ULK inhibitors. In some embodiments, the immunomodulatory mouse model is a mouse GEM genotype orthotopic pancreatic cancer model referred to as a KPC model (LSL-KrasG12D / +, LSL-Trp53R172H / +, Pdx-1-Cre) or a variation 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.

[0194] In some embodiments, the immunomodulatory component suppressed by ULK is an enhanced innate immune response. In some embodiments, the immunomodulatory component suppressed by ULK is an enhanced acquired immune response. In some embodiments, the immunomodulatory component suppressed by ULK is the enhanced activity of antigen-presenting cells. In some embodiments, the immunomodulatory component suppressed by ULK is the enhanced antitumor activity of bone marrow cells, including macrophages. In some embodiments, the immunomodulatory component suppressed by ULK is the enhanced antitumor activity of natural killer cells. In some embodiments, the immunomodulatory component suppressed by ULK is the enhanced activity of effector T cells, including cytotoxic T cells.

[0195] In embodiments, this document provides a method for treating the condition described herein, comprising: administering a therapeutically effective amount of the compound described herein to a patient in need, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phosphorylated ATG13 antibody ELISA assay to detect, for example, inhibition of ULK kinase activity based on the amount of phosphorylated ATG13 in the sample. In some embodiments, the intended method comprises, as appropriate, 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 amount of phosphorylated ATG13 in the sample obtained before administration with the amount of phosphorylated ATG13 in the sample obtained during or after the administration process. In some embodiments, the phosphorylated ATG13 is p-S318ATG13.

[0196] In embodiments, this document provides a method for treating the condition described herein, comprising: administering a therapeutically effective amount of the compound described herein to a patient in need, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a 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 intended method comprises, as appropriate, contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phosphorylated ATG14 antibody ELISA assay before administration of 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 process. In some embodiments, phosphorylated ATG14 is p-ATG14 Ser29.

[0197] In embodiments, this document provides a method for treating the condition described herein, comprising: administering a therapeutically effective amount of the compound described herein to a patient in need, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect, for example, inhibition of ULK kinase activity based on the p62 content in the sample. In some embodiments, the method is intended to include, as appropriate, contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay before administering the compound, and comparing the p62 content in the sample obtained before administration with the p62 content in the sample obtained during or after the administration process.

[0198] In embodiments, this document provides a method for treating the condition described herein, comprising: administering a therapeutically effective amount of the compound described herein to a patient in need, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay to detect, for example, inhibition of ULK kinase activity based on the amount of pBeclin in the sample. In some embodiments, the method is intended to include, as appropriate, 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 pBeclin content in the sample obtained before administration with the pBeclin content in the sample obtained during or after the administration process.

[0199] The compounds described herein can be administered to patients (animals and humans) requiring such treatment at doses that provide optimal therapeutic efficacy. It should be understood that the dosage required for any particular application will vary from patient to patient, not only with the specific compound or composition chosen, but also with the route of administration, the nature of the condition being treated, the patient's age and condition, any concurrent medications or special diet followed by the patient, and other factors that a practitioner familiar with this technique will be aware of. The appropriate dosage is ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds described herein can be administered orally, subcutaneously, topically, non-enterally, by inhalation spray, or rectally in the form of formulations containing known, non-toxic, and pharmaceutically acceptable carriers, adjuvants, and mediators in dose units. Non-enteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0200] Treatment may be continued for as long or as short a period of time as needed. The composition may be administered, for example, once to four or more times daily. Appropriate treatment periods may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinite. Treatment may be terminated when the desired outcome is achieved. Combination therapy

[0201] For example, compounds of Formula I as defined herein, as described herein, may be administered in combination with one or more additional therapeutic agents to treat conditions described herein, such as cancer. For instance, this disclosure provides a pharmaceutical composition comprising, for example, 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 may be achieved by administering two or more therapeutic agents, each of which is separately formulated and administered. For example, a compound of Formula I as defined herein and additional therapeutic agents may be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a Formula I compound as a therapeutic agent and one or more additional therapeutic agents, such as a MAPKAP pathway inhibitor or a chemotherapeutic agent. For example, a Formula I compound as defined herein and additional therapeutic agents can be administered in a single formulation. Combination therapy also encompasses other combinations. Although two or more agents in a combination therapy can be administered simultaneously, it is not necessary. For example, the administration of the first agent (or combination of agents) may be minutes, hours, days, or weeks earlier than the administration of the second agent (or combination of agents). Therefore, two or more medications can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks or several weeks. In some cases, even longer time intervals are possible. Although in most cases it is expected that two or more medications used in combination therapy are present in the patient's body simultaneously, this is not necessary.

[0202] Combination therapy may also include two or more administrations of one or more of the drugs used in different sequences of component drugs. For example, if drug X and drug Y are used together, they may be administered one or more times in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0203] In some embodiments, one or more additional therapeutic agents, which may be administered in combination with the compounds provided herein, may be MAPKAP pathway inhibitors. Such MAPKAP pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.

[0204] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binitinib, and their pharmaceutically acceptable salts. Exemplary ERK inhibitors include, but are not limited to, uritinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and their pharmaceutically acceptable salts. Exemplary RAF inhibitors include, but are not limited to, LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and their pharmaceutically acceptable salts. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, and their pharmaceutically acceptable salts.

[0205] The compounds described herein can be administered in combination with other known therapeutic agents used to treat cancer. These other therapeutic agents include radiation therapy, anti-microtubule 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 therapies, cancer vaccines, and CAR-T cell therapy.

[0206] In some embodiments, additional therapeutic agents may be, but are not limited to, the following chemotherapeutic agents: anti-microtubule agents (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspensions including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or levodopa), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents, or DNA topoisomerase inhibitors. Agents (including anthracycline, such as cranberry, polyethylene glycol liposome cranberry, daunorubicin, idarubicin, mitoxantrone, or epirubicin; camptothecin, such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytosine nucleoside, gemcitabine, and methotrexate).

[0207] In some other embodiments, the additional therapeutic agent may be, but is not limited to, the following kinase inhibitors: erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, and temsirolimus. us), abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, Loxo 292. Larotrectinib and quizartinib; including but not limited to the following anti-estrogens: tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; including but not limited to the following anti-androgens: abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate. acetate); including but not limited to the following steroid drugs: prednisone and dexamethasone; including but not limited to the following PARP inhibitors: neraparib, olaparib, talazoparib, and rucaparib; including but not limited to the following topoisomerase I inhibitors: irinotecan, camptothecin, ezeticosine, and toponotecan; including but not limited to the following topoisomerase II inhibitors: anthracycline, etoposide, etoposide phosphate, and mitoxantrone;Including but not limited to the following histone deacetylase (HDAC) inhibitors: vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; including but not limited to the following DNA methylation inhibitors: DZNep and 5-aza-2'-deoxycytidine; including but not limited to the following proteasome inhibitors: bortezomib and carfilzomib; thalidomide; lenalidomide; pomalidomide; including but not limited to the following biological reagents: trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, and panitumumab. The following are included: anti-PD-1 agents: pembrolizumab, nivolumab, pidilizumab, and cemiplimab; anti-PD-L1 agents: atezolizumab, avelumab, durvalumab, and BMS-936559; anti-angiogenic agents: bevacizumab and aflibercept; and antibody-drug conjugates (ADCs): DM1, DM4, MMAE, MMAF, or camptothecin loadings; brentuximab / vitolamine. Vedotin and trastuzumab emtansine; radiation therapy; therapeutic vaccines including, but not limited to, sipuleucel-T.

[0208] In some embodiments, the additional therapeutic agent may be, but is not limited to, the following immunomodulators: anti-PD-1 or anti-PDL-1 therapeutic agents, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab; anti-TIM3 (anti-HAVcr2) therapeutic agents, including but not limited to TSR-022 or MBG453; anti-LAG3 therapeutic agents, including but not limited to relatlimab, LAG525, or TSR-033; and anti-4-1BB. (Anti-CD37, anti-TNFRSF9) drugs; CD40 agonist therapeutic agents, including but not limited to SGN-40, CP-870, CP-893 or RO7009789; anti-CD47 therapeutic agents, including but not limited to Hu5F9-G4; anti-CD20 therapeutic agents; anti-CD38 therapeutic agents; STING agonists, including but not limited to ADU-S100, MK-1454, ASA404 or acetamiprid; anthracyclines, including but not limited to cranberry or mitoxantrone; hypomethylating agents, including but not limited to azacytosine nucleoside or decitabine; other immunomodulatory therapeutic agents, including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, polidomide, presbyron or dexamethasone.

[0209] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs including goserelin and leuprolide. In some embodiments, the additional therapeutic agent is selected from the group consisting of: everolimus, trabectedin, abraxacin, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatinib, Nilotinib, Decaptinib, Panitumumab, Amarabicin, Ogovomumab, Lep-etu, Noratrilate, Azd2171, Batabulin, Atumtunab, Zhamumab, Atikaline, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Teximumab, Ipilimumab, Cothamseed Oil, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitrapezide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Amethionone, LY 317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Cranberry, Irinotecan, Lipid Cranberry, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0 325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-sideoxy-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole,DES (dextrin), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methanesulfonylpiperidinylmethyl)-indolyl]-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr- ...) t)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O4-(C2H4O2)x where x=1 to 2.4] acetate, goserele acetate, leuprolide acetate, triptorelin dihydroxynaphthyl acetate, medroxyprogesterone acetate, hydroxyprogesterone hexanoate, megestrol acetate, rhinoxifene, bicalutamide, halothamidine, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canenatinib, ABX-EGF antibody, erbitux, EKB-569, PK I-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, analoxime, valproic acid, nystatin A, FK-228, SU11248, sorafenib, KRN951, gluten, acridine, anagrelide, L-aspartate aminotransferase, BCG vaccine, bleomycin, buserelline (in), Busulfan, Carboplatin, Carchloromustine, Chlorbutazone, Cisplatin, Cladribine, Clodronate, Cyproterone Acid, Cytarabine, Dacarbazine, Actinomycin D, Donomycin, Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Flumethasone, Flutamide, Gemcitabine, Gleevec, Hydroxyurea, Idamycin, Ifosfamide, Imatinib, Leuprorelin, Levamisole, Lomustine, Nitrogen Mustard, Melphalan, 6-Mercaptopurine, Mesna, Metformin, Mitomycin Mitotane, Mitoxantrone, Nilutamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Pucofam, Porphyrom, Procarbazine, Raltitrexed, Rituximab, Streptozotocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Retinoic Acid, Vincristine, 13-cis-retinoic Acid, Phenylamidone Mustard, Uracil Mustard, Estramide, Hexamethylmelamine, Fluorouracil, 5-Deoxyurocil, Cytosine Arabinoside, 6-Mercaptopurine, Deoxymyotrophic Acid, Calcitriol, Valorarubicin, Photomycin, Vincristine, VinorelbineTopotecan, Razoxin, Marimastat, COL-3, Squalane, BMS-275291, Squalamine, Endothelial Somatostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Traloxifen, Iodoxifen, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denisuka Interleukin, Gefitin Nitroglycerin, bortezomib, irinotecan, toponotecan, cranberry, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), erbitux, cetyl alcohol polyoxyethylene ether free paclitaxel, epothilone B, BMS-247550, BMS-310705, traloxifen, 4-hydroxytamoxifen, piperacillin, ERA-923, azoxifen, fulvestrant, azithromycin, lasoxifene, edoxifene, SE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Tamsulosin, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wolman penicillin, ZM336372, L-779,450, PEG-filgrastim, Dabepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zygomaticosporin Prednisone, Cetuximab, Granulocyte-Macrophage Community-Stimulating Factor, Histamine Relin, Pegylated Interferon Alpha-2a, Interferon Alpha-2a, Pegylated Interferon Alpha-2b, Interferon Alpha-2b, Azacitidine, PEG-L Aspartame, Lenalidomide, Gefitinib, Hydrocortisone, Interleukin-11, Dexrazoxan, Alemazumab, All-trans Retinoic Acid, Ketoconazole, Interleukin-2, Medroxyprogesterone acetate, Immunoglobulin, Nitrogen Mustard, Methylprednisolone, Ibrimumab (Taizetan) Tiuxetan), androgens, decitabine, hexamethylmelamine, bexarotene, tosimomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, lipodycin, Edwina-aspartate, strontium-89, caspoxetine, netupiritine, NK-1 receptor antagonists, palonosetron, aspirin, diphenhydramine, acetal, metoclopramide, lorazepam, alprazolam, haloperidol, haloperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron.Ondansetron, dolasetron, tropisetron, spruitosis, erythropoietin, epoetin afa and dabepotin afa, ipramab, vemurafenib, and mixtures thereof. Pharmaceutical compositions and kits

[0210] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with a pharmaceutically acceptable carrier. Specifically, this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated with one or more pharmaceutically acceptable carriers. Such formulations include those suitable for oral, rectal, topical, buccal, non-intestinal (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but in any given case, the most suitable form of administration will depend on the severity and extent of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0211] Exemplary pharmaceutical compositions may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing one or more of the compounds described herein as active ingredients, blended with organic or inorganic carriers or excipients suitable for external, enteral, or non-enteral administration. The active ingredient may be compounded with a non-toxic, pharmaceutically acceptable carrier, for example, commonly used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or symptoms of a disease.

[0212] For the preparation of solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, such as a known tablet-making ingredient (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or colloid), and other pharmaceutical diluents such as water, to form a solid preformed composition containing a homogeneous mixture of the compounds provided herein or their non-toxic, pharmaceutically acceptable salts. When such preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, making the composition readily reproducible into equivalent dosage forms, such as tablets, pills, and capsules.

[0213] In oral administration to solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules and the like), the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) preservatives. (3) Wetting agents, such as glycerin; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blocking agents, such as paraffin; (6) Absorption promoters, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Adsorbents, 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 composition may also contain buffers. Similar solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or galactose and high molecular weight polyethylene glycol and the like.

[0214] Tablets can be prepared by compression or molding, as appropriate, together with one or more adjuncts. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the compositions of the present invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, may be scored or coated and shelled, as appropriate, such as enteric coatings and other coatings well known in pharmaceutical compounding techniques.

[0215] Compositions for inhalation or inhalation include solutions and suspensions, as well as 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 compositions of this invention, liquid dosage forms may contain inert diluents commonly used in this art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranyl ethanol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0216] In addition to the compositions of the present invention, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragali, and mixtures thereof.

[0217] The preparations for transrectal or transvaginal administration can be presented in suppository form, which can be prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers, such excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature, and thus will melt and release the active agent in the body cavity.

[0218] Dosage forms for transdermal administration of the compositions of the present invention include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0219] In addition to the compositions of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragali, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0220] 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 thereof. Sprays may further contain conventional propellants such as chlorofluorocarbons and unsubstituted volatile hydrocarbons such as butane and propane.

[0221] The compositions and compounds of this invention can alternatively be administered via aerosols. This is accomplished by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic sprayers can be used because they minimize the exposure of the agent to shear, which can degrade the compounds contained in the compositions of this invention. Typically, aqueous aerosols are prepared by co-forming an aqueous solution or suspension of the compositions of this invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific requirements of the compositions of this invention, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol); harmless proteins, such as serum albumin; sorbitol esters; oleic acid; lecithin; amino acids, such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0222] The pharmaceutical compositions of the present invention, applicable to non-enteral administration, comprise the compositions 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 just before use. These sterile powders may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0223] 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 the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. Appropriate flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0224] In another embodiment, enteric pharmaceutical formulations are provided, comprising the disclosed compounds and enteric-coated materials, and pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the jejunum approximately 6.5, and the terminal ileum approximately 7.5.

[0225] Therefore, the enteric material is insoluble up to, for example, 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. Examples of enteric-coated materials include cellulose acetate phthalate (CAP); hydroxypropyl methyl cellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methyl cellulose acetate succinate (HPMCAS); cellulose benzotriglyceride; hydroxypropyl methyl cellulose succinate; cellulose acetate succinate; cellulose hexahydrophthalic acid; cellulose propionate; cellulose maleate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methyl methacrylate and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate and methacrylate; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins such as corn gluten, 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 above 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 will benefit from this invention will recognize that it is not exhaustive and that other enteric-coated materials exist that satisfy the objectives described herein.

[0226] Advantageously, this article provides kits for use by consumers, for example, those needing cancer treatment. Such kits include suitable dosage forms, such as those described above; and instructions describing methods of using such dosage forms to mediate, reduce, or prevent inflammation. The instructions will guide consumers or medical personnel to administer the dosage form according to dosing patterns known to those skilled in the art. Such kits can advantageously be packaged and sold as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and similar dosage forms). Blister packs generally consist of a sheet of relatively rigid material covered with a foil of preferably transparent plastic material. During the packaging process, grooves are formed in the plastic foil. The grooves are the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the sheet of relatively rigid material is sealed on the side of the foil opposite to the direction in which the groove was formed, relative to the plastic foil. Therefore, the tablets or capsules are sealed in a groove between the plastic foil and the sheet. Preferably, the strength of the sheet allows for manual pressure to be applied to the groove, thereby creating an opening in the sheet at the groove placement point to remove the tablets or capsules from the blister pack. Subsequently, the tablets or capsules can be removed through this opening.

[0227] The kit may need to provide memory aids, such as numbering adjacent to the tablets or capsules, where the number corresponds to the number of days in the regimen to be taken of those specified tablets or capsules. Another example of such memory aids is a calendar printed on a card, such as "Week 1, Monday, Tuesday... etc... Week 2, Monday, Tuesday... etc." Other variations of memory aids are obvious. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a specified date. Furthermore, 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. [Example]

[0228] The compounds described herein can be prepared in various ways based on the teachings contained herein and the synthetic procedures known in this technique. In the description of the synthetic methods described below, it should be understood that, unless otherwise indicated, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) can be selected as standard conditions for that reaction. Those skilled in organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactants. Substituents incompatible with the reaction conditions will be obvious to those skilled in this technique, and therefore, alternative methods are indicated. The starting materials in the examples are commercially available or can be readily prepared from known materials using standard methods.

[0229] The following abbreviations are used in this disclosure and have the following definitions: "ADP" is adenosine diphosphate, "Boc" is tert-butyl carbonate, "CDI" is carbonyl diimidazole, "conc." is concentration, "Cs2CO3" is cesium carbonate, "CuI" is copper iodide (I), and "DBU" is 1,8-diazabicyclo[5.4].[0] Undecyl-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-dimethylmethamide, "dppf" is 1,1'-bis(diphenylphosphino)ferrocene, "DMEM" is Dulbecco's Modified Eagle Medium. Media), DMSO is dimethyl sulfoxide, DPPA is diphenylphosphine 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 one or more hours, HBTU is (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, H2 is hydrogen gas, HCl is hydrochloric acid, Hex is hexane, H2O is water, HOBt is hydroxybenzotriazole. "IC50" is the half-maximum inhibition concentration; "K2CO3" is potassium carbonate; "K3PO4" is potassium phosphate; "LiMHDS" is lithium bis(trimethylsilyl)acetonitrile; "MeCN" is acetonitrile; "MeOH" is methanol; "Me4tBuXPhos" is di-tertiary 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 one or more minutes; "MS" is mass spectrometry; "MTBE" is methyl tertiary 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-bromobutyldiamide, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd / C" is palladium / carbon, "Pd2(dba)3" is triphenylmethyleneacetone dipalladium(O), "Pd(OAc)2" is palladium(II) acetate, "Pd(PPh3)4" is tetrakis(triphenylphosphine)palladium(O), "prep-HPLC" is preparative high performance liquid chromatography, "PyBOP" is benzotriazol-1-yl-oxytripyrrolidone phosphonium hexafluorophosphate, "RT" is room temperature, also known as "ambient temperature", which should be understood as the range of normal laboratory temperature between 15-25°C, "satd"."T3P" represents saturation, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS" represents trimethylsilyl alkyl, "Tris" represents tris(hydroxymethyl)aminomethane, "Xantphos" represents 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan, "X-phos" represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and "ZnCl2" represents zinc chloride. [General Chemical Methods] [ ]

[0230] The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the following procedures, including intermediate preparation and preparation of accompanying examples. [Synthesis Process] [ ] [process] [1]

[0231] Procedure 1 explains amines [D] [-] [I] [-] [i] [、] [D] [-] [I] [-] [ii] [and] [D] [-] [I] [-] [iii] is prepared illustratively. It involves treatment with an amine R4-H (which can be aliphatic or heterocyclic) in the presence of a base (e.g., Cs₂CO₃ or K₂CO₃). [A] [-] [I] Obtain the compound [B] [-] [I]. Commercially available [products / methods] were used in the presence of a palladium catalyst (Suzuki coupling) or sage coupling reaction. Ester / Further treatment with acid / trifluoroborate, where R2a is Br [B] [-] [I] Obtain the compound [C] [-] [I]. Intermediate [C] [-] [I] Amines can be selectively converted to amines under mild reducing conditions, such as the reaction of zinc or iron metals with ammonium chloride. [D] [-] [I] [-] [i], where R2b is alkenyl, alkynyl, or cycloalkyl. Intermediate [C] [-] [I] can be completely reduced to [I] by palladium-catalyzed hydrogenation. [D] [-] [I] [-] [iii]. R2a is an intermediate of Cl, Br, alkyl, CN, or alkoxy groups. [B] [-] [I] It can be reduced to [a certain state] under mild reducing conditions, such as the reaction of zinc or iron with ammonium chloride. [D] [-] [I] [-] [ii].

[0232] In process 1, examples of X include N and CH, examples of Y include N, CH and CF, wherein neither X nor Y is N, examples of R2 include alkyl and cycloalkyl, and examples of R4 include N-linked alkyl and N-linked heterocyclic groups, wherein suitable substituents are exemplified by the following intermediates. [process] [2]

[0233] Process 2 explains amines [D] [-] [II] [-] [i] [、] [D] [-] [II] [-] [ii] [and] [D] [-] [II] [-] [iii] Example preparation. Under reducing amination conditions (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of a catalytic amount of acetic acid, in a polar solvent such as MeOH) [A] [-] [II] The reaction of (commercially available starting material) with amine R4-H yields the compound. [B] [-] [II]. Commercially available [products / methods] were used in the presence of a palladium catalyst (Suzuki coupling) or sage coupling reaction. Ester / Further treatment with acid / trifluoroborate, where R2a is Br [B] [-] [I] [I] Obtain the compound [C] [-] [II]. Intermediate substances [C] [-] [II] Amines can be selectively converted to amines under mild reducing conditions, such as the reaction of zinc or iron metals with ammonium chloride. [D] [-] [II] [-] [i], where R2b is alkenyl, alkynyl, or cycloalkyl. Intermediate [C] [-] [II] Can be completely reduced to by palladium-catalyzed hydrogenation. [D] [-] [II] [-] [iii]. R2a is an intermediate of Cl, Br, alkyl, CN, or alkoxy groups. [B] [-] [II] It can be reduced to [a specific substance] under mild reducing conditions, such as the reaction of zinc or iron with ammonium chloride. [D] [-] [II] [-] [ii].

[0234] In process 2, examples of X include N and CH, examples of Y include N, CH and CF, wherein neither X nor Y is N, examples of R2 include alkyl and cycloalkyl, and examples of R4 include N-linked alkyl and N-linked heterocyclic groups, wherein suitable substituents are exemplified by the following intermediates. [process] [3]

[0235] Process 3 explains amines [D] [-] [III] [-] [i] [、] [D] [-] [III] [-] [ii] and [D] [-] [III] [-] [iii] is an illustrative preparation, wherein L is -CH2-CH2-. Reduction with a reducing agent such as DIBAL. [A] [-] [III] [-] [i] Obtain aldehyde [A] [-] [III] [-] [ii]. Another preparation [A] [-] [III] [-] [ii] The method is to... [A] [-] [III] [-] [i] Reduction to the corresponding alcohol, followed by mild oxidative conditions, such as using MnO2. This is carried out under reductive amination conditions (e.g., sodium cyanoborohydride or sodium triethoxyborohydride, in the presence of a catalytic amount of acetic acid, in a polar solvent such as MeOH). [A] [-] [III] [-] [ii] Reaction with amine R4-H yields the compound [B] [-] [III]. Another preparation [B] [-] [III] The method is to... [A] [-] [III] [-] [I] is reduced to ethanol, and then the ethanol is converted to sulfonate. [A] [-] [III] [-] [iii]. In the presence of a base (such as triethylamine, betaine, or cesium carbonate), [A] [-] [III] [-] [iii] The reaction with amine R4-H yields [B] [-] [III]. Commercially available [products / methods] were used in the presence of a palladium catalyst (Suzuki coupling) or sage coupling reaction. Ester / Further treatment with acid / trifluoroborate, where R2a is Br [B] [-] [III] Obtain the compound [C] [-] [III]. Intermediate substances [C] [-] [III] Amines can be selectively converted to amines under mild reducing conditions, such as the reaction of zinc or iron metals with ammonium chloride. [D] [-] [III] [-] [iii], where R2b is alkenyl, alkynyl, or cycloalkyl. Intermediate [C] [-] [III] Can be completely reduced to by palladium-catalyzed hydrogenation. [D] [-] [III] [-] [ii]. Where R2a is an intermediate of Cl, Br, alkyl, CN, or alkoxy. [B] [-] [III] It can be reduced to [a specific substance] under mild reducing conditions, such as the reaction of zinc or iron with ammonium chloride. [D] [-] [III] [-] [i].

[0236] In process 3, examples of X include N and CH, examples of Y include N, CH and CF, wherein neither X nor Y is N, examples of R include methyl and ethyl, examples of R2 include alkyl and cycloalkyl, examples of R4 include N-linked alkyl and N-linked heterocyclic groups having substituents selected as appropriate, as illustrated in the table of intermediates below, and examples of LG include methanesulfonates and toluenesulfonates. [, , ] [ ] [process] [4]

[0237] Process 4 explains amines [D] [-] Exemplary preparation of [IV], wherein L is a direct bond -CH2- or -CH2-CH2-. In the presence of a catalytic amount of DMAP (if necessary), using an amide coupling agent (e.g., CDI, DCC, EDC, HOBt, HBTU, PyBOP, or T3P). [A] [-] [III] [-] [i] Reacts with various amines to give acetylamine. [B] [-] [IV] Commercially available [products] can be used in the presence of palladium catalyst (Suzuki coupling) or sage coupling reaction. Ester / Further treatment with acid / trifluoroborate, where R2a is Br [B] [-] [IV] Obtain the compound [C] [-] [IV]. Intermediate [C] [-] [IV] Amines can be selectively converted to amines under mild reducing conditions, such as the reaction of zinc or iron metals with ammonium chloride. [D] [-] [IV] [-] [i], where R2b is alkenyl, alkynyl, or cycloalkyl. Intermediate [C] [-] [IV] can be completely reduced to [IV] by palladium-catalyzed hydrogenation. [D] [-] [IV] [-] [iii]. R2a is an intermediate of Cl, Br, alkyl, CN, or alkoxy groups. [B] [-] [IV] It can be reduced to [a specific substance] under mild reducing conditions, such as the reaction of zinc or iron with ammonium chloride. [D] [-] [IV] [-] [ii].

[0238] In process 4, instances of X include N and CH, instances of Y include N, CH and CF, where neither X nor Y is N, instances of R include methyl and ethyl, instances of R2 include alkyl and cycloalkyl, and instances of R4 include -(CH2)mC(O)-B and -(CH2)m-C(O)-N(R5)R6, where m is 0, 1 or 2. [, , ] [ ] [process] [5]

[0239] Process 5 explains amines [D] [-] [V] is an example of preparation. [B] [-] [V] in the presence of a palladium catalyst (Suzuki coupling) and Ester / The reaction of acid / trifluoroborate yields the compound. [C] [-] [V]. Many Ester / The acid / trifluoroborate is commercially available, and those not commercially available can be readily prepared from the corresponding carboxylic acid (see process 21). Intermediate [C] [-] [V] can be converted into amines under standard reduction conditions, such as palladium-catalyzed hydrogenation or under mild reduction conditions involving zinc metal and ammonium chloride. [D] [-] [V].

[0240] In process 5, examples of X include N and CH, examples of Y include N, CH and CF, examples of R2 include alkyl and cycloalkyl, and examples of R4 include C-linked heterocyclic groups and heterocyclic groups, wherein suitable substituents are exemplified by the following intermediates. [process] [6]

[0241] Process 6 instructions come from [C] [-] [VI] [-] [i] of [D] [-] [VI] Exemplary preparation, wherein in [C] [-] [VI] [-] In [i], R4 contains a nitrogen protecting group, such as a Boc group. [C] [-] [VI] [-] [i] The protection can be removed under acidic conditions to provide an amine salt. In the presence of a catalytic amount of acetic acid, the salt is further treated with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in a polar solvent such as MeOH (reductive amination conditions) to obtain... [C] [-] [VI]. The intermediate can be reduced under standard reduction conditions, such as by palladium-catalyzed hydrogenation or by mild reduction conditions involving zinc metal and ammonium chloride. [C] [-] [VI] Converted to aniline [D] [-] [VI]

[0242] In process 6, examples of X include N and CH, examples of Y include N, CH and CF, wherein neither X nor Y is N, examples of PG include Boc protecting groups, examples of R2 include alkyl and cycloalkyl groups, examples of R4 include heterocyclic groups, examples of R6 include alkyl and cycloalkyl groups, wherein suitable substituents are exemplified by the following intermediates. [process] [7]

[0243] In some embodiments, universal pyrazolamide [D] [-] [VII] [ -] [i] or [D] [-] [VII] [-] [ii] is prepared by the two methods shown in process 7. Examples of R4-L linkage 7-1 or 7-2 are shown in this process. One method involves using commercially available [product / method] in the presence of a base (e.g., potassium carbonate, cesium carbonate, or sodium hydride) and a polar aprotic solvent (dimethylformamide, dimethylformamide, tetrahydrofuran, or similar solvents) at a temperature between ambient temperature and 150°C. [7] [-] [1] Alkylation [B] [-] [VII] (easily obtained by those skilled in this technique), nitro-pyrazole is obtained. [C] [-] [VII] [ -] [i] and / or [C] [-] [VII] [-] [ii]. [D] [-] [VII] [-] [i] or [D] [-] [VII] [-] [ii] The alternative preparation involves [B] [-] [VII] and commercially available [7] [-] [2] The photoelectrophoresis reaction yields nitro-pyrazole. [C] [-] [VII] [-] [i]and [C] [-] [VII] [-] [ii]. Those familiar with this technique should understand that when produced as a mixture, [C] [-] [VII] [-] [i]and [C] [-] [VII] [-] [ii] This is achieved through purification, crystallization, or chromatography using SFC. Finally, nitro-pyrazole is hydrogenated 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. [C] [-] [VII] [-] [i]and [C] [-] [VII] [-] [ii] Obtain pyrazole-amine [D] [-] [VII] [-] [i]and [D] [-] [VII] [-] [ii].

[0244] In process 7, examples of LG include Cl and Br, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, examples of R4 include heterocyclic groups having substituents suitable for selection as indicated by the following intermediates, C(O)NR6R9 and NR6R9, wherein each of R6 and R9 may be H or alkyl independently, and examples of L include -(CH2)m-, wherein m may be 0, 1, 2 or 3, and when m is 0, R4 is C connected to pyrazole, when m is 1, R4 is C connected to L, and when m is 2 or 3, R4 is N connected or C connected to L. [process] [8]

[0245] Universal pyrazole-amines substituted with a single R2 (i.e., where R2 is not hydrogen) [D] [-] [VIII] [-] [i]and [D] [-] [VIII] [-] [ii] The additional embodiments are prepared as described in process 8. To make ketone-esters... [A] [-] [VIII] [-] [i] Reacts with N,N-dimethylformamide dimethyl acetal or triethyl orthoformate / acetic anhydride to give [A] [-] [VIII] [-] [ii] (where LG is the appropriate detaching group required in the continuous cyclization / pyrazole formation reaction). In the presence of acid, [A] [-] [VIII] [-] [ii] with hydrazine

[10] [-] [1] (Those familiar with this technique can easily obtain) the reaction, mainly obtaining [B] [-] [VIII] [-] [i] or its location isomer [B] [-] [VIII] [-] [ii]. The site chemistry of cyclization is controlled under conditions (such as temperature and solvent) familiar to those skilled in the art. Used for synthesis [B] [-] [VIII] [ -] [i] (where R2 is not hydrogen) includes the following conditions: LG is OEt, in a protic solvent (such as ethanol), at low temperature (-10°C to RT), and in the presence of an acid. Synthesis [B] [-] [VIII] [-] [ii] The conditions include, where LG is NMe2, in a protic solvent (such as ethanol), under reflux, in the presence of an acid. Then, the ester is subjected to standard conditions known to those skilled in the art. [B] [-] [VIII] [-] [i] or [B] [-] [VIII] [-] [ii] Converted to the corresponding acid [C] [-] [VIII] [-] [i] or [C] [-] [VIII] [-] [ii]. By means of Curtius rearrangement... [C] [-] [VIII] [-] [i] or [C] [-] [VIII] [-] [ii] convert to the corresponding amine [D] [-] [VIII] [-] [i] or [D] [-] [VIII] [-] [ii].

[0246] In process 8, examples of LG include OMe, OEt, and N(CH3)2; examples of R2 include alkyl and cycloalkyl groups, wherein the alkyl and cycloalkyl groups may be fluorinated as appropriate; examples of R4 include heterocyclic groups having substituents suitable for selection as indicated by the following intermediates and NR6R9, wherein each of R6 and R9 may be an alkyl group independently; examples of L include -(CH2)m-, wherein m may be 0, 1, 2, or 3, and when m is 0, R4 is C-linked to pyrazole; when m is 1, R4 is C-linked to L; and when m is 2 or 3, R4 is N-linked or C-linked to L. [process] [9]

[0247] Similar to process 8, process 9 describes the amine. [D] [-] General preparation of [IX]. Pyrazol ester [B] [-] [IX] is obtained by using hydrazine 10-1 (easily obtained by those familiar with this technique) and intermediates. [A] [-] The reaction [IX] is used for preparation. In some embodiments, R2 and R3 are partially and independently varied, such that R3 is the same as or different from R2. The ester is prepared using standard conditions known to those skilled in the art. [B] [-] [IX] is converted to the corresponding acid. [C] [-] [IX]. Acid [C] [-] [IX] Converted to amines under standard Curtiss rearrangement conditions known to those skilled in the art. [D] [-] [IX].

[0248] In process 9, examples of R2 and R3 may independently include alkyl and cycloalkyl groups, wherein the alkyl and cycloalkyl groups may be fluorinated as appropriate; examples of R4 include heterocyclic groups having substituents suitable for selection as indicated by the following intermediates and NR6R9, wherein each of R6 and R9 may independently be an alkyl group; examples of L include -(CH2)m-, wherein m may be 0, 1, 2 or 3, and when m is 0, R4 is C-linked to pyrazole; when m is 1, R4 is C-linked to L; and when m is 2 or 3, R4 is N-linked or C-linked to L. [process]

[10] [ ] [ ]

[0249] In some embodiments, non-commercially available hydrazine 10-1 can be readily prepared by the two methods shown in process 10. One method involves making an amine

[10] [-] [2] Diazotization, followed by reduction using conditions familiar to those skilled in the art, such as by treatment with Sn(II)Cl2 in the presence of a proton source. Alternatively, hydrazine...

[10] [-] [1] The corresponding N-tert-butoxycarbonylhydrazine can be removed by acid catalysis of the tert-butoxycarbonyl group.

[10] [-] [3] Obtained. Those skilled in the art will recognize that, in some embodiments, carbamates are used.

[10] [-] [3] To hydrazine

[10] [-] The conversion of [1] also occurs in situ within the reaction sequence. Therefore, hydrazine is involved in this process.

[10] [-] [1] Carbamates are typically used in all processes in the presence of acid.

[10] [-] [3] All are hydrazine

[10] [-] [1] Substitute. N-tert-butoxycarbonylhydrazine

[10] [-] [3] Commercially available aldehydes or ketones can be used.

[10] [-] [4] It is prepared by reducing and amination of tributyl hydrazide carboxylate.

[0250] In process 10, examples of R4 include heterocyclic groups having substituents suitable for selection as exemplified by the following intermediates and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(C(R7)2)m-, wherein an example of R7 is H, and wherein m may be 0, 1, 2 or 3, and when m is 0, R4 is C-linked to nitrogen, when m is 1, R4 is C-linked to L, and when m is 2 or 3, R4 is N-linked or C-linked to L. [, , ] [ ] [process]

[11]

[0251] In some embodiments, universal pyrazolamide [D] [-] [VII] [-] [i]and [D] [-] [VII] [-] [ii] is prepared by the procedure shown in step 11. This procedure demonstrates the R4-L connection.

[11] [-] An example of [1]. Using...

[11] [-] [1] Alkylation [B] [-] [VII] (Nitropyrazole can be easily obtained by those skilled in this technique) [B] [-] [VII] [-] [i]and [B] [-] [VII] [-] A mixture of [ii] and these two isomers. [B] [-] [VII] [-] [i]and [B] [-] [VII] [-] [ii] Separation is achieved through SFC purification, crystallization, or chromatography. Various isomers [B] [-] [VII] [-] [i] or [B] [-] [VII] [-] [ii] Activated with MsCl or TsCl, respectively, to obtain [B] [-] [VII] [-] [iii] or [B] [-] [VII] [-] [iv]. The OMs or OTs were replaced with amine R4-H to obtain... [C] [-] [VII] [-] [i] or [C] [-] [VII] [-] [ii]. Finally, nitro-pyrazole is hydrogenated 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. [C] [-] [VII] [-] [i] or [C] [-] [VII] [-] [ii] Obtain pyrazole-amine [D] [-] [VII] [-] [i] or [D] [-] [VII] [-] [ii].

[0252] In process 11, examples of LG include Cl and Br, examples of R include methanesulfonate and toluenesulfonate, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, examples of R4 include heterocyclic groups having substituents as shown in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(CH2)m, wherein m is 2 or 3, and R4 is N-linked. [process]

[12]

[0253] Process 12 explains the general amine [D] [-] [X] [-] [i]and [D] [-] [X] [-] [ii] Synthesis. Therefore, in the presence of ammonium hydroxide, a commercially available aldehyde and glyoxal are condensed to yield an R2-substituted imidazole. [A] [-] [X]. This process demonstrates an example of R4-L connection 7-1 or 7-2. Nitroimidazole is nitrated under conditions known to those skilled in the art (e.g., nitric acid / concentrated sulfuric acid at temperatures ranging from 0°C to 100°C). [A] [-] [X], yielding nitroimidazole [B] [-] [X] [-] [i]. By alkylation ( [7] [-] [1]) or photoelectrophoresis ( [7] [-] [2]) will [B] [-] [X] [-] [i] transformed into [C] [-] [X] [-] [i]and [C] [-] [X] [-] [ii] mixtures. In some embodiments, substituted nitro-imidazolium [C] [-] [X] [-] [i]and [C] [-] [X] [-] [ii] can be obtained from [A] [-] Alkylation of [X] ( [7] [-] [1]) or photoelectrophoresis ( [7] [-] [2]) Obtain, get [B] [-] [X] [-] [ii]. Then make [B] [-] [X] [-] [ii] Nitrification, yielding [C] [-] [X] [-] [i]and [C] [-] [X] [-] [ii]. These two site-specific isomers [C] [-] [X] [-] [i]and [C] [-] [X] [-] [ii] They can be separated by SFC purification, crystallization, or chromatography. Each nitroimidazole is 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. [C] [-] [X] [-] [i]and [C] [-] [X] [-] [ii], respectively, the corresponding imidazoles were obtained. [D] [-] [X] [-] [i]and [D] [-] [X] [-] [ii].

[0254] In process 12, examples of LG in reagent 7-1 include Cl and Br, examples of R2 include alkyl and cycloalkyl groups, wherein the alkyl and cycloalkyl groups may be fluorinated as appropriate, examples of R4 include heterocyclic groups having substituents suitable for selection as illustrated in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, examples of L include -(CH2)m-, wherein m may be 2 or 3, and L is N connected to an imidazole ring. [process]

[13] [ ] [ ]

[0255] As illustrated in process 13, in some embodiments, substituted thiazolids [D] [-] [XI] may be derived from thiazoles with appropriate substitution. [A] [-] [XI] (easily obtained by those skilled in this technique) is used for preparation. This method is described in WO2006072436, the contents of which are hereby incorporated in their entirety. Fuming nitric acid or nitric acid containing sulfuric acid is used to nitrate bromothiazole. [A] [-] [XI] Bronitrothiazole was obtained [B] [-] [XI]. Various amine R4-H substitutions can be performed in the presence of TEA or K2CO3 under conditions familiar to those skilled in this technique (such as Buchwald, Ullmann, or nucleophilic aromatic substitution reactions). [B] [-] The bromine functional group on [XI] yields... [C] [-] [XI], where R4 is N-connected. Using [B] [-] [XI] with commercially available or synthetic products The Suzuki reaction of esters T (including but not limited to other boron salts) (see Procedure 21) provides [C] [-] [XI], where R4 is C-connected. Finally, hydrogenation is carried out 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. [C] [-] [XI], the corresponding thiazolidinediones were obtained. [D] [-] [XI].

[0256] In process 13, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, and examples of R4 include heterocyclic groups having substituents as shown in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be alkyl independently. [, , ] [ ] [process]

[14]

[0257] As illustrated in process 14, in some embodiments, substituted thiazolids [D] [-] [XII] can be prepared from a suitably substituted thiazole A-XI (easily obtained by those skilled in the art). This method has been described in WO2009158373, WO2016135163 and WO2011075515, the contents of which are hereby incorporated by reference in their entirety. Bromonitrothiazole A-XI is nitrated with fuming nitric acid or nitric acid containing sulfuric acid to obtain bromonitrothiazole B-XI. [B] [-] The bromine functional group on [XI] can be used with conditions such as carbonylation (C-XII-ia), zinc-mediated coupling, etc. [C] [-] [XII] [-] [ib]), Sonogashira, or Heck coupling reactions, as are familiar to those skilled in this technique, involve the substitution of various linker (L) synthons, followed by appropriate reduction, to obtain CC-linked [links]. [C] [-] [XII] [-] [ic]. This can be... [C] [-] [XII] [-] [ia]、 [C] [-] [XII] [-] [ib] and [C] [-] [XII] [-] [ic] is reduced to a primary alcohol, followed by methanesulfonation or toluenesulfonation to form [C] [-] [XII] [-] [ii]. Nucleophilic substitution with different nucleophilic reagents R4-H [C] [-] [XII] [-] [ii], obtained [C] [-] [XII] [-] [iii] Finally, reduction is carried out 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. [C] [-] [XII] [-] [iii], the corresponding thiazolidinediones were obtained. [D] [-] [XII].

[0258] In process 14, examples of LG include OT and OM, examples of R include methyl and ethyl, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, examples of R4 include heterocyclic groups having substituents suitable for selection as illustrated in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(CH2)m-, wherein m may be 1, 2 or 3. [process]

[15] [ ]

[0259] In a similar reaction sequence as shown in process 15, bromothiazole [A] [-] [XIII] (Easily obtained by those skilled in this technique) Thiazole-amine [D] [-] [XIII](Science of Synthesis, 627, 2002).

[0260] In process 15, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen or CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, and examples of R4 include heterocyclic groups having substituents as shown in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be alkyl independently. [, , ] [ ] [process]

[16]

[0261] As illustrated in process 16, in some embodiments, substituted thiazolids [D] [-] [XIV] can be derived from appropriately substituted thiazoles. [A] [-] [XIII] (easily obtained by those skilled in this technique) is used for preparation. This method has been described in WO2009158373, WO2016135163 and WO2011075515, the contents of which are hereby incorporated in their entirety. Fuming nitric acid or nitric acid containing sulfuric acid is used to nitrate bromothiazole. [A] [-] [XIII] yielded bromonitothiazole [B] [-] [XIII]. [B] [-] The bromine functional group on [XIII] can be used with methods such as carbonylation (C-). [XIV] [-] [ia]), Root Bank (Zinc-mediated coupling conditions) [C] [-] [XIV] [-] [ib]), Sonogashira, or Heck coupling reactions, as are familiar to those skilled in this technique, involve the substitution of various R4 groups followed by reduction to obtain CC-linked [rib] groups. [C] [-] [XIV] [-] [ic]. This can be... [C] [-] [XIV] [-] [ia]、 [C] [-] [XIV] [-] [ib] and [C] [-] [XIV] [-] [ic] is reduced to a primary alcohol, followed by methanesulfonation or toluenesulfonation to form [C] [-] [XIV] [-] [ii]. Nucleophilic substitution with different nucleophilic reagents R4-H [C] [-] [XIV] [-] [ii], obtained [C] [-] [XIV] [-] [iii] Finally, reduction is carried out in the presence of a hydrogen catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride. [C] [-] [XIV] [-] [iii] Obtain the corresponding thiazole-amine [D] [-] [XIV].

[0262] In process 16, examples of LG include OT and OM, examples of R include methyl and ethyl, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be fluorinated as appropriate, examples of R4 include heterocyclic groups having substituents suitable for selection as illustrated in the table of intermediates below and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(CH2)m-, wherein m may be 1, 2 or 3. [process]

[17]

[0263] Process 17 is described as reported in WO2014078378 regarding the substituted oxazole. [D] [-] The synthesis of [XV] is hereby incorporated in its entirety by quotation. This leads to the synthesis of various acid chlorides. [A] [-] [XV] [-] [i] and R2-substituted aminoalkyl nitrile

[17] [-] [1] (Those familiar with this technique can easily obtain) the reaction, and get [A] [-] [XV] [-] [ii]. Under acidic conditions such as acetic acid, sulfuric acid, or hydrochloric acid, [A] [-] [XV] [-] [ii] Converted to oxazolamide [D] [-] [XV].

[0264] In process 17, examples of R2 include alkyl, cycloalkyl, and alkoxy groups, wherein the alkyl, cycloalkyl, or alkoxy group may be fluorinated as appropriate, and examples of R4 include heterocyclic groups having substituents as illustrated in the table of intermediates below, which may be selected as appropriate, and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(CH2)m-, wherein m may be 0, 1, 2, or 3. [process]

[18]

[0265] As shown in process 18, some substituted oxazoles can be derived from carboxylic acid esters substituted with 2-diazo-3-sideoxy groups, as reported in Synlett, 1996, 1171. [A] [-] [XVI] preparation, the contents of which are hereby incorporated in their entirety by reference. Under Rh-catalyzed coupling conditions, primary amides were used.

[18] [-] [1] (This technique is readily available to those skilled in it) Treatment of diazonium esters [A] [-] After [XVI], acetylamine was obtained. [B] [-] [XVI]. The intermediate is dehydrated under cyclization dehydration conditions using a dehydrating agent (e.g., POCl3, T3P, or Burgess reagent). [B] [-] [XVI] yields oxazolyl ester [C] [-] [XVI] [-] [i]. Hydrolyzed oxazole ester [C] [-] [XVI] [-] [i], to obtain carboxylic acid [C] [-] [XVI] [-] [iI], under the Curtiss rearrangement, sodium azide or DPPA is used to convert it to oxazolamide. [D] [-] [XVI].

[0266] In process 18, examples of R2 include alkyl, cycloalkyl, and alkoxy groups, wherein the alkyl, cycloalkyl, or alkoxy group may be fluorinated as appropriate, and examples of R4 include heterocyclic groups having substituents as illustrated in the table of intermediates below, which may be selected as appropriate, and NR6R9, wherein each of R6 and R9 may be an alkyl group independently, and examples of L include -(CH2)m-, wherein m may be 0, 1, 2, or 3. [process]

[19]

[0267] As shown in process 19, in other embodiments, oxazole-amine [D] [-] [XVII] can be made from 2-halooxazole as described in WO2012033195. [C] [-] [XVII] [-] [i] Preparation, the contents of which are hereby incorporated by reference. Under Buchwald coupling conditions [C] [-] [XVII] [-] [i] Reaction with various amines R4-H yields 2-aminoalkyl-substituted oxazoles. [C] [-] [XVII] [-] [ii], where R4 is N-bonded. [C] [-] [XVII] [-] [i] with commercially available or synthesized products esters The Suzuki reaction of [T] (including but not limited to other boron salts) (see process 21) is used for [C] [-] [I] [-]

[21] , where R4 is C-linked. Hydrolyzed oxazole ester [C] [-] [XVII] [-] [i] The carboxylic acid is obtained, which is then converted to oxazolamide using sodium azide or DPPA under the Curtiss rearrangement. [D] [-] [XVII].

[0268] In process 19, examples of R2 include alkyl, cycloalkyl, or alkoxy groups, wherein the alkyl, cycloalkyl, or alkoxy group may be fluorinated as appropriate, and examples of R4 include heterocyclic groups having substituents as shown in the table of intermediates below, which may be selected as appropriate, and NR6R9, wherein each of R6 and R9 may be an alkyl group independently. [process]

[20]

[0269] In some embodiments, general triazoles [D] [-] [XVIII] [-] [i]and [D] [-] [XVIII] [-] [ii] This is prepared using the method shown in process 20. This process demonstrates the R4-L connection. [7] [-] [1] or [7] [-] [2] Example. Triazole [B] [-] [XVIII] was achieved by using the procedures described in Asian J. of Chem, 2014, 26, 4744 and Hanning Cailliao, 2008, 16, 49, and aldehydes.

[20] [-] [1] (This is readily available to those skilled in the art) The reaction is derived from dinitro esters [A] [-] [XVIII] [-] [i] Preparation, the contents of which are hereby incorporated in their entirety. Alternatively, [B] [-] [XVIII] can be nitrated [A] [-] [XVIII] [-] [ii] is prepared by alkylation. [7] [-] [1]) or photoelectrophoresis ( [7] [-] [2]) will [B] [-] [XVIII] transformed into [C] [-] [XVIII] [-] [i]and [C] [-] [XVIII] [-] [ii] A mixture of these two site-specific isomers. [C] [-] [XVIII] [-] [i]and [C] [-] [XVIII] [-] [ii] Nitrotriazole can be separated by SFC purification, crystallization, or chromatography. Nitrotriazole can be reduced in the presence of hydrogenation catalysts such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride. [C] [-] [I] [-]

[22] or [C] [-] [I] [-]

[23] , respectively obtained the corresponding triazoles [D] [-] [XVIII] [-] [i]and [D] [-] [XVIII] [-] [ii].

[0270] In process 20, examples of R2 include alkyl, cycloalkyl, alkoxy, halogen, or CN, wherein the alkyl, cycloalkyl, or alkoxy may be fluorinated as appropriate; examples of R4 include heterocyclic groups having substituents as illustrated in the table of intermediates below, which may be selected as appropriate, and NR6R9, wherein each of R6 and R9 may be an alkyl group independently; and examples of L include -(CH2)m-, wherein m is 2 or 3. [process] [twenty one ]

[0271] Process 21 Explanation: Non-commercially available acid / esters General preparation of [T]. These compounds can be readily prepared from substituted carboxylic acids. The carboxylic acid can be activated by 2-hydroxyisoindoline-1,3-dione in the presence of a coupling agent (e.g., DCI or Et3N / HATU) to give Q. Intermediate [Q] Transformation into [B2pin2Me]Li complex nickel-catalyzed decarboxylation boronization esters [T], which is premixed with methyllithium and B2pin2 (Science, 2107, 356, 1045 and JACS, 2016, 138, 2174), is hereby incorporated in its entirety by reference.

[0272] In process 21, examples of R4 include alkyl, cycloalkyl, and heterocyclic groups having suitable, as-yet-chosen substituents as illustrated in the table of intermediates below, and examples of L include -(CH2)m-, where m can be 0, 1, 2, or 3, and when m is 0, R4 is C-linked to... For esters, when m is 1, C in the R4 system is connected to L, and when m is 2 or 3, N in the R4 system is connected or C is connected to L. [process] [twenty two ]

[0273] Process 19 Explanation [L] [-] [I] [-] [1] and [L] [-] [I] [-] [2] General preparation. Commercially available 2,4-dichloro-5-iodopyrimidine is reacted with TMSCHF2 in a solvent such as NMP or DMF in the presence of CuI and CsF to produce difluoromethylpyrimidine. [L] [-] [II] [-] [1](US20150284341, the contents of which are hereby incorporated in their entirety). Difluoromethylpyrimidine [L] [-] [II] [-] [1] It can be converted into meththiopyrimidine by treatment with diethyl ether containing sodium thiomethoxide and zinc chloride at a temperature below 10°C. [L] [-] [I] [-] [1](WO2012110773, the contents of which are hereby incorporated in full). Trifluoromethylpyrimidine [L] [-] [I] [-] [2] can be with [L] [-] [I] [-] [1] A similar method was used with commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine [L] [-] [II] [-] [2] Preparation. [ ] [process] [twenty three ]

[0274] In process 23, R1 can be a cycloalkyl sulfonylurimidine. [L] [-] [III] (t=2) general preparation. In the presence of a palladium catalyst... Ester / Acid / Trifluoro Salt treatment of commercially available 5-bromo-2-chloro-6-(methylthio)pyrimidine (Suzuki coupling) yields R1-substituted thiopyrimidine. [L] [-] [III](t=0). Examples of R1 in this process include cycloalkyl groups such as cyclopropyl groups. The intermediate thiopyrimidine is oxidized, for example by mCPBA. [L] [-] [III] (t=0) is converted to sulfadiazine [L] [-] [III](t=2). [process] [twenty four ]

[0275] Process 24 Explanation [H] [-] [I] General preparation. In the presence of a base (Et3N or DIEA), in DCM using a commercially available acetylated chloride ( [F] [-] [I]) Handling commercially available products [E] [-] [I] Obtain acetylamine [G] [-] [I]. Many acetylated chlorides ( [F] [-] [I]) are commercially available, and in the presence of a base (Et3N or DIEA), are not commercially available products that readily possess the corresponding carboxylic acid of SOCl2. [F] [-] [I] [-] [1] Preparation. It can be removed after exposure to acids such as HCl or TFA. [G] [-] [I] Boc protecting group. In process 24, examples of RL may include alkyl and cycloalkyl (e.g., cyclobutyl). [process]

[25] [ ] [ ]

[0276] Process 25 Explanation [H] [-] [II] General preparation method. Compound [G] [-] [II] It can be achieved by making amines [E] [-] [II] Compared with commercially available isocyanates [F] [-] [II] The reaction is used to prepare the product. Various isocyanates, both commercially available and non-commercially available, can be readily prepared from the corresponding carboxylic acid or amine (see Procedure 27). The product can be removed upon exposure to an acid, such as HCl or TFA. [G] [-] [II] Boc protecting group. In process 25, examples of R9 may include alkyl and cycloalkyl (e.g., cyclobutyl) and examples of R6 may include H and alkyl. [process]

[26]

[0277] Process 26 Explanation [H] [-] [III] General preparation. Compound [G] [-] [III] It can be achieved by making amines [E] [-] [III] with trichloroethyl 2,2,2-aminocarbamate [F] [-] [III] The 2,2,2-aminocarbamate trichloroethyl ester is prepared by reaction [III] from an amine and an acid (see process 27). It can be removed after exposure to an acid, such as HCl or TFA. [G] [-] [III] Boc protecting group. In process 26, examples of R9 may include alkyl and cycloalkyl (e.g., cyclobutyl) and examples of R6 may include H and alkyl. [process]

[27]

[0278] Process 27 explains isocyanates [F] [-] [II] and carbamates [F] [-] [III] General preparation. Non-commercial isocyanates. [F] [-] [II] It can be prepared from amines or carboxylic acids. The reaction of amines with phosgene or phosgene equivalents (such as diphosgene, triphosgene, or N,N'-dicarbonylimidazolium) provides isocyanates. [F] [-] [II]. Alternatively, isocyanates can be obtained directly from carboxylic acids via the Curtiss rearrangement. [F] [-] [II]: The acid is mixed with diphenyl azidophosphate in a solvent (such as 1,4-dioxane or dimethylformamide) in the presence of a base (such as triethylamine), and the temperature of the reactants is increased to approximately 80-120°C. Some carbamates... [F] [-] [III] It can also be prepared via the Curtiss rearrangement in the presence of a suitable ethanol, such as triethanol. Trichloroethyl carbamate [F] [-] [III] It can also be readily prepared from amine by acetyl chloroformate under standard conditions. [process]

[28]

[0279] Process 28 describes the key intermediates. [J] and General preparation of [K]. Key intermediates. [J] can be obtained by heating, as appropriate, in the presence of an organic base (e.g., triethylamine or DIEA). [H] (free base or salt) and thiopyrimidine [L] [-] [I] Preparation, obtaining the key intermediate. [J]. In a similar manner, key intermediates [K] can be obtained through and [L] [-] [II] or [L] [-] [III] The reaction is caused by [H] preparation. [process]

[29]

[0280] Process 29 describes the key intermediates. General preparation of [M]. Treatment with commercially available chloroiodopyridine under Buchwald-Hartwig coupling conditions (Cs₂CO₃, Xantphos, and Pd(OAc)₂). [H] is typically carried out in aprotic solvents (e.g., DME, DMF, DMSO, or NMP) at temperatures ranging from ambient to 140°C to obtain the key intermediate. [M]. [process]

[30]

[0281] Process 30 is explained from the formula that has been replaced by D. [I] [-] [1] General preparation of compounds. Formula [I] [-] [1] can be prepared from key intermediates [K] and [J] Implementation. [K] and formula The first nucleophilic substitution reaction of the [D] amine is typically carried out in a polar solvent at temperatures ranging from ambient to 150°C, and in some embodiments under microwave heating, and, depending on the circumstances, in the presence of an acid, such as 1,4-dioxane containing 4 N HCl, to obtain the formula... [I] [-] [1]. Compounds not available for commercial sale. [D] It can be readily prepared (see process 1-20). The alternative general synthetic system of formula I is prepared via a two-step process, first by oxidation using various oxidants such as mCPBA. [J](t=0) transforms into sub-junction [J](t=1). Rhodium reacts with amines via nucleophilic substitution reactions. [D] The reaction is typically carried out in a polar solvent at temperatures ranging from ambient to 150°C, and in some embodiments under microwave heating, and, depending on the circumstances, in the presence of an acid, such as 1,4-dioxane containing 4 N HCl or pTSA. The formula contains a nitrogen-protecting group such as a Boc group on R4. [I] [-] [1] It can be protected under acidic conditions to obtain formula [I] [-] [1](R4 contains a free amine or salt). In the presence of a catalytic amount of acetic acid, in a polar solvent such as MeOH (reductive amination conditions), the formula is further treated with sodium cyanoborohydride or sodium triethoxyborohydride and an aldehyde or ketone. [I] [-] [A](free base or salt) yields the formula [I] [-] [1], wherein R4 contains nitrogen substituted with an alkyl or cycloalkyl group. For acetylation and sulfonation, free amines (or salts) can be treated with commercially available acetylated chlorides or sulfonyl chlorides to obtain the formula... [I] [-] [1], wherein R4 contains a nitrogen substituted with acetyl or sulfonylurea. In process 30, ring A may be phenyl or pyridyl (e.g., X = ring containing Y) or 5-membered heteroaryl (e.g., X1-Y-X2 containing a ring). [process]

[31]

[0282] Process 31 Explanation [I] [-] [2] General preparation of compounds. Formula [I] [-] [2] can be prepared by means of [D] and The Buchwald-Hartwig coupling reaction between [M] is achieved. Many amines not commercially available... [D] can be easily prepared (see process 1-12). In the case of nitrogen-protecting groups containing groups such as the Boc group... [I] [-] [2] After deprotection, reductive alkylation, acetylation, and sulfonation can be performed in a manner similar to that shown in process 30 to obtain the formula... [I] [-] [2]. In process 31, ring A may be phenyl or pyridyl (e.g., X = ring containing Y) or 5-membered heteroaryl (e.g., X1-Y-X2 containing ring).

[0283] The following compounds were prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: [Preparation of intermediates] [.] [ ]

[0284] The following compounds were prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: [General Method] [A] [:] [Aromatic nucleophilic substitution] [:] [Intermediate substance] [A1] [:]1-(3-bromo-4-nitrophenyl)-4-methylpiperazine

[0285] A mixture of 2-bromo-4-fluoro-1-nitrobenzene (50 g, 227 mmol) and 1-methylpiperazine (24 g, 250 mmol) in DMF (400 mL) was treated with K₂CO₃ (63 g, 455 mmol) at room temperature, and the reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with ice water (500 mL) and the precipitated solid was filtered off. The solid was further wet-milled with Et₂O and n-pentane to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (58 g, 85% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): d 7.98 (d, J = 9.4 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 2.2 and 9.4 Hz, 1H), 3.42 (m, 4H), 2.40 (m, 4H), 2.19 (s, 3H); LC-MS (ESI) m / z: 299.0 (M+H+). [General Method] [B] [:] Deprotection and reductive amination: [Intermediate substance] [A2] [:]3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0286] 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was treated with 1,4-dioxane containing 4 N HCl (16 mL, 62 mmol). A solution of [A13] (2.57 g, 6.2 mmol) in MeOH (30 mL) was prepared and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under vacuum to give 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (2.17 g, 100% yield) as a white solid. The material was used without further purification. A suspension of 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (1.92 g, 5.5 mmol) in DCE (25 mL) was treated with DIEA (2.9 mL, 17 mmol) and formaldehyde (1.2 mL, 17 mmol). The yellow suspension turned into a clear orange solution. The reaction mixture was stirred at room temperature for 10 minutes and then acetic acid (0.63 mL, 11 mmol) was added. The orange solution turned into a yellow suspension, which was stirred for 20 minutes. Sodium triethoxyborohydride (2.33 g, 11 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with an aqueous solution of NaHCO3 (50 mL) and extracted with DCM (3 × 50 mL). The combined organic compounds were dried over anhydrous Na2SO4, filtered, and concentrated to give a brown solid. The brown solid was purified by silica gel column chromatography (0 to 15% MeOH / DCM) to give 1.71 g, 95% yield, of 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 9.4 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.89 (dd, J = 9.5 and 2.7 Hz, 1H), 3.54 (d, J = 11.6 Hz, 2H), 3.22 (brs, 2H), 2.99-3.04 (m, 2H), 2.22 (s, 3H), 1.92-1.95 (m, 2H), 1.52-1.56 (m, 2H); LC-MS (ESI) m / z: 326.0 (M+H+). [General Method] [C] [:] [alkylation] [:] [Intermediate substance] [A3] [:]1-(2-Fluoroethyl)-4-(3-Methyl-4-nitrophenyl)piperazine

[0287] 1-(3-methyl-4-nitrophenyl)piperazine hydrochloride was treated with 1-fluoro-2-iodoethane (2.0 mL, 2.6 mmol). A mixture of the deprotected Boc product of [A4] (1.5 g, 0.58 mmol) and K2CO3 (4.0 g, 2.9 mmol) in 1,4-dioxane (20 mL) [Note: the described material is unstable - some solids are present in the orange liquid] was tightly sealed and heated to 100°C for 24 hours. The mixture was cooled to room temperature and the solids (K2CO3) were removed by filtration. The mixture was washed with DCM and the filtrate was concentrated to dryness to give a yellow oily 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine (1.52 g, 98% yield), which solidified into an amber solid upon standing. 1H NMR (400 MHz, DMSO-d6): d 7.97 (d, J = 9.6 Hz, 1H), 6.87-6.89 (m, 2H), 4.61 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 4.9 Hz, 1H), 3.41 (m, 4H), 2.69 (t, J = 4.9 Hz, 1H), 2.63 (t, J = 4.9 Hz, 1H), 2.54-2.56 (m, 7H); LC-MS (ESI) m / z: 268.2 (M+H+).

[0288] Use the general method AC described above to prepare the following intermediates listed in Table A. [surface] [A.] Example structure method Yield (%) 1H NMR (400 MHz, DMSO-d6): LC-MS (m / z: M+H+). A4 A 96 7.99 (d, J = 9.0 Hz, 1H), 6.86-6.88 (m, 2H), 3.43 (s, 8H), 2.54 (s, 3H), 1.41 (s, 9H)。 322.2 A5 A 90 7.97 (d, J = 9.6 Hz, 1H), 6.87 (m, 2H), 3.37 (brs, 4H), 2.62 (brs, 4H), 2.54 (s, 3H), 1.64 (m, 1H), 0.43 (m, 2H), 0.36 (m, 2H)。 262.3 A6 A 87 7.99 (d, J = 9.2 Hz, 1H), 6.58 (brs, 2H), 4.82 (s, 1H), 4.69 (s, 1H), 3.78 (m, 1H), 3.63 (m, 1H), 3.52 (m, 1H), 3.16 (d, J = 10 Hz, 1H), 2.54 (s, 3H), 1.91 (m, 2H)。 235.1 A7 A 54 7.95 - 7.98 (m, 1H), 6.72 - 6.74 (m, 2H), 3.73 (t, J = 6.0 Hz, 1H), 3.68 (t, J = 5.6 Hz, 1H), 3.58 - 3.62 (m, 2H), 3.54 (t, J = 6.0 Hz, 1H), 3.47 (t, J = 5.6 Hz, 1H), 3.26 (t, J = 5.2 Hz, 1H), 3.19 (t, J = 5.7 Hz, 1H), 2.54 (d, J = 3.3 Hz, 3H), 1.80 (t, J = 6.3Hz, 1H), 1.73 (s, 1H), 1.28 (s, 4H), 1.14 (s, 5H). 358.2 (M+Na+H+) A8 A 100 8.01 (d, J = 9.3 Hz, 1H), 7.24 (m, 1H), 7.01 (m, 1H), 3.44 (brs, 8H), 1.41 (s, 9H). 408.0 410.0 (M+Na+H+) (M+Na+3H+) A9 B 92 7.98 (d, J = 9.4 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.01 (dd, J = 9.4及2.7 Hz, 1H), 3.42 (t, J = 5.0 Hz, 4H), 2.44 (t, J = 5.0 Hz, 4H), 2.35 (q, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). A10 B 95 No NMR data 328.0 330.0 A11 A 58 8.02 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.0 and 2.0 Hz, 1H), 3.73 (m, 2H), 3.41 (m, 2H) 287.0 289.0 A12 A 53 8.0 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 6.99 (m, 1H), 4.02 (s, 2H), 3.72 (brs, 2H), 3.45 (d, J = 4.0, 2H), 2.90 (s, 3H). 313.0 A13 A 76 7.99 (d, J = 9.5 Hz, 1H), 7.19 (s, 1H), 6.95 - 6.97 (m, 1H), 4.16 - 4.23 (m, 2H), 3.72 (d, J = 12.1Hz, 2H), 2.99 (d, J = 12.1 Hz, 2H), 1.85 (brs, 2H), 1.67 (d, J = 7.5 Hz, 2H), 1.41 (s, 9H). A14 A 37 7.99 (d, J = 9.4 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 9.4 and 2.8 Hz, 1H), 4.57 (t, J = 4.2 Hz, 1H), 3.44 (dd, J = 12.9 and 5.6 Hz, 1H), 3.01 - 3.07 (m, 1H), 2.88 - 2.97 (m, 3H), 2.80 - 2.86 (m, 1H), 2.71 (dd, J = 13.3, 4.9 Hz, 1H), 2.51 (s, 1H), 1.85 - 1.92 (m, 1H), 1.69 - 1.75 (m, 1H) A15 A 87 8.02 (m, 1H), 7.33 (m, 1H), 3.26 (m, 4 H), 2.43 (m, 4 H), 2.20 (s, 3 H) 318.0 320.0 A16 A 20 8.03 (d, J = 9.2 Hz, 1H), 6.93 (s, 1H), 6.69 (d, J = 9.3 Hz, 1H), 3.72 (t, J = 8.5 Hz, 1H), 3.58 - 3.66 (m, 2H), 3.52 (t, J = 7.8 Hz, 1H), 3.41 - 3.46 (m, 1H), 2.35 - 2.42 (m, 1H), 2.23 - 2.30 (m, 1H) A17 A 76 8.03 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 9.3, 2.6 Hz, 1H), 3.70 - 3.73 (m, 1H), 3.58 - 3.66 (m, 2H), 3.53 (dt, J = 10.3 and 6.8 Hz, 1H), 3.41 - 3.46 (m, 1H), 2.36 - 2.41 (m, 1H), 2.23 - 2.30 (m, 1H). A18 A 77 7.97 (dd, J = 9.4 and 4.1Hz, 1H), 7.07 (s, 1H), 6.86 (d, J = 9.6 Hz, 1H), 3.47 - 3.76 (m, 6 H), 3.21 - 3.28 (m, 2H), 1.67 - 1.81 (m, 2H), 1.21 (d, J = 52.0 Hz, 9H). 422.2 424.2 A19 A 36 7.98 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 9.4, 2.8 Hz, 1H), 4.11 (d, J = 12.2 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H), 2.92 - 3.05 (m, 3H), 2.63 (t, J = 11.3 Hz, 1H), 2.15 (t, J = 11.3Hz, 1H), 2.0( q, J = 8.7 Hz, 1H), 1.91 - 2.00 (m, 1H), 1.80 - 1.86 (m, 1H), 1.64 - 1.73 (m, 2H), 1.30 - 1.40 (m, 1H). 326.0 328.0 A20 A 64 7.98 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 9.4, 2.8 Hz, 1H), 4.11 (d, J = 12.2 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H), 2.92-3.05 (m, 3H), 2.63 (t, J = 11.3 Hz, 1H), 2.15 (t, J = 11.3Hz, 1H), 2.06 (q, J = 8.7 Hz, 1H), 1.91-2.00 (m, 1H), 1.80-1.86 (m, 1H), 1.64-1.73 (m, 2H), 1.30- 1.40 (m, 1H)。 326.0 328.0 A21 A 86 7.97 (d, J = 9.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 3.40 (brs, 4H), 2.54 (s, 3H), 2.40 (brs, 4H), 2.20 (s, 3H)。 236.2 A22 A 41 8.00 (d, J = 9.1Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 9.1, 2.5 Hz, 1H), 4.05 (m,, 2H), 3.81 (dd, J = 9.1, 5.1Hz, 2H), 2.11 (s, 6 H)。 300.2 302.2 A23 B 44 7.99 (d, J = 9.4 Hz, 1H), 6.6 - 6.9 (brm, 2H), 4.59 (s, 1H), 3.49 (s, 1H), 3.34 (s, 2H), 2.81 (dd, J = 9.6 and 2.0 Hz, 1H), 2.42, (d, J = 9.7 Hz, 1H), 2.27 (s, 3H), 1.90 (d, J = 9.8 Hz, 1H), 1.75 (d, J = 9.8 Hz, 1H). 312.0 314.0 A24 A 90 8.86 (s, 1H), 6.83 (s, 1H), 3.68 (brs, 8H), 2.51 (s, 3H). 224.33 A25 A 99 8.84 (s, 1H), 6.83 (s, 1H), 3.71 (brs, 4H), 2.52 (s, 3H), 2.37 (brs, 4H), 2.20 (s, �H). 237.2 A26 A 83 8.84 (s, 1H), 6.79 (s, 1H), 3.71 (brs, 4H), 2.89 (q, 2H), 2.38 (brs, 4H), 2.21 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H). 251.2 A27 A 74 7.87 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 9.2 Hz, 1H), 6.53 (s, 1H), 3.90 (s, 3H), 3.43 (s, 4H), 2.41 (s, 4H), 2.21 (s, 3H), 252.1 A28 A 71 7.82 (d, J = 9.2 Hz, 1H), 6.51 (m, 2H), 4.82 (m, 1H), 3.92 (m, 4H), 2.40 (m, 4H), 2.21 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H). 280.1 A29 B 87 7.99 (d, J = 9.3 Hz, 1H), 6.60-6.91 (brm, 2H), 4.59 (s, 1H), 3.49 (s, 1H), 3.34 (s, 2H), 2.81 (dd, J = 9.6 and 2.0 Hz, 1H), 2.42, (d, J = 9.7 Hz, 1H), 2.27 (s, 3H), 1.90 (m, 1H), 1.75 (m, 1H). 312.0 314.0 [, , ] [ ] [intermediate] [A30] [:]1-(3-bromo-4-nitrophenyl)-4-methylpiperazinyl-2-one.

[0289] A mixture of (2-aminoethyl)(methyl)aminocarbamate tributyl ester (4.3 g, 24 mmol) and potassium carbonate (3.8 g, 27 mmol) in DMF (50 mL) was treated with 4-fluoro-2-bromo-1-nitrobenzene (5 g, 22 mmol) at room temperature under a nitrogen atmosphere and stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude substance was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (CV)) to give (2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)aminocarbamate tributyl ester) (5.6 g, 66% yield) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 9.0 Hz, 1H), 6.77 (S, 1H), 6.46 (d, J = 9.0 Hz, 1H), 3.54 (s, 2H), 3.31 (t, J = 6.0 Hz, 2H), 2.90 (s, 3H), 1.47 (s, 9H); LC-MS (ESI) m / z: 374.1 (M+H+).

[0290] A mixture of ((2-((3-bromo-4-nitrophenyl)-2-chloroacetamino)ethyl(methyl)carbamate tributyl ester (5.6 g, 15 mmol) and TEA (7.6 g, 75 mmol) in DCM (100 mL) was treated with chloroacetyl chloride (5.1 g, 45 mmol) at 0 °C under a N2 atmosphere and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic matter was evaporated under reduced pressure, and the crude matter was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (CV)) to give (2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetamino)ethyl(methyl)carbamate tributyl ester (5.6 g, 66% yield) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d6): δ 8.12 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 6.66 (d, J = 7.4 Hz, 1H), 4.24 (m, 2H), 3.82 (s, 2H), 3.18 (s, 2H), 2.70 (s, 3H), 1.41 (s, 9H); LC-MS (ESI) m / z: 374.1 (M+H+).

[0291] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.6 g, 12 mmol) in 1,4-dioxane containing 4 N HCl was treated at 0 °C under a N2 atmosphere with 1,4-dioxane (100 mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure and the crude substance was purified by crystallization in Et2O (100 mL) to give N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (4.79 g, 99% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (brs, 2H), 8.16 (m, 2H), 7.83 (d, J = 7.8 Hz, 1H), 4.20 (s, 2H), 3.98 (t, 2H), 3.20 (s, 2H), 2.56 (s, 3H), 1.41 (s, 9H); LC-MS (ESI) m / z: 374.1 (M+H+).

[0292] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.0 g, 12 mmol) in DMF (50 mL) was added to 60% mineral oil (1.1 g, 25 mmol) containing NaH at 0 °C under a N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and the solution was extracted with EtOAc (2 × 50 mL). The combined organic compounds were evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (CV)) to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazin-2-one (3.1 g, 76% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.0 (d, J = 9.4 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 2.3 and 9.3 Hz, 1H), 4.0 (s, 2H), 3.72 (t, J = 5.4 Hz, 2H), 3.45 (t, J = 5.4 Hz, 2H), 2.90 (s, 3H); LC-MS (ESI) m / z: 314.2 (M+H+). [Intermediate substance] [A31] [:]1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine:

[0293] A solution of (5-(4-methylpiperazin-1-yl)-2-nitrophenyl)methanol (1.0 g, 4.0 mmol) in DMF (30 mL) was cooled to 0 °C. Sodium hydride (0.80 g, 60% in minerals) was added fractionally, and the mixture was stirred under the same conditions. Iodomethane (1.7 g, 12 mmol) was added at 0 °C, and the mixture was slowly heated to room temperature and stirred for 2 hours. The reactants were diluted with EtOAc and carefully quenched with ice water. The mixture was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (hexane / EtOAc) to give 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine (0.76 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.03 (m, 1H), 7.08 (s, 1H), 6.96 (m, 1H), 4.76 (s, 2H), 3.45 (brs, 4H), 3.40 (s, 3H), 2.42 (brs, 4H), 2.22 (s, 3H); LC-MS (ESI) m / z: 266.2 (M+H+). [General Method] [D] [:] [Suzuki Coupling Reaction] [:] [Intermediate substance] [C1] [:]1-Methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazolium:

[0294] A suspension of 4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-1,3,2-dioxane (0.80 g, 3.0 mmol) and 4-bromo-1-methyl-1H-imidazolium (0.49 g, 3.0 mmol) in a mixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated with potassium carbonate (1.26 g, 9.1 mmol) and the suspension was stirred. The reaction mixture was degassed by bubbling argon for two minutes and treated with a Pd(dppf)Cl2·DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours. The reactants were diluted with water and extracted with DCM (4 × 25 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum to give a black oil. The black oil was purified using silica gel (0 to 15% MeOH / DCM, 15 column volumes (CV)) to give 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazolium (0.31 g, 47% yield). ¹H NMR (400 MHz, DMSO-d6): δ 8.02 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 3.70 (s, 3H), 2.57 (s, 3H); LC-MS (ESI) m / z: 218.2 (M+H+).

[0295] Use the general method D described above to prepare the intermediates listed in Table B. [surface] [B.] intermediate structure method Yield (%) ¹H NMR (400 MHz, DMSO-d⁶): δ LC-MS (m / z: (M+H+) B2 D 62 No NMR data 319.2 B3 D 64 No NMR data 233.2 B4 D 72 8.34 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.63 (m, 1H), 3.88 (s, 3H), 2.56 (s, 3H). 218.2 [General Method] [E] Alkylation and methanesulfonation: intermediate [C1] [:] 2-(3-methyl-4-nitro-1H-pyrazole-1-yl)ethyl methanesulfonic acid.

[0296] (A) A solution of 3-methyl-4-nitro-1H-pyrazole (15 g, 118 mmol) in acetonitrile (200 mL) was treated with 2-bromoethane-1-ol (16 g, 130 mmol) and potassium carbonate (48.8 g, 354 mmol). The reaction mixture was heated at 90 °C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by SFC to give 2-(3-methyl-4-nitro-1H-pyrazole-1-yl)ethane-1-ol. 1H 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: 172.1 (M+1).

[0297] (B) A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl-1-ol (5.0 g, 29 mmol) in DCM (50 mL) was treated with triethylamine (5.8 g, 58 mmol) followed by methanesulfonyl chloride (5.0 g, 44 mmol) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with chilled 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 give 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonic acid (6.0 g, 83% yield) as a grayish-white solid. 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: 250.2 (M+H+). [General Method] [F] [:] [Nucleophilic substitution reaction] [:] Example [C2]:N,N-Dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl-1-amine

[0298] 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonic acid was treated with potassium carbonate (3.8 g, 28 mmol) and THF containing 2N dimethylamine (60 mL, 12 mmol) at 10 °C under a N2 atmosphere. A solution of [C1] (5.0 g, 20 mmol) in anhydrous THF (70 mL). The reaction mixture was quenched with chilled 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 give N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl-1-amine (1.9 g, 48% yield). 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). );MS (ESI) m / z: 199.2 (M+H+). [General Method] [G] [:] [Photoperiodic Reaction] [:] intermediate [C3]: 1-Methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine.

[0299] Triphenylphosphine (154.7 g, 59 mmol) was added to a solution of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.4 mmol) and 1-methylpiperidin-4-ol (4.5 g, 39.4 mmol) in anhydrous THF (60 mL) under a nitrogen atmosphere, and the mixture was cooled to 0 °C. Diisopropyl azodicarbonate (12 mL, 59 mmol) was added dropwise to the mixture over a period of 30 minutes, with stirring continued at room temperature for 30 hours. THF was removed under reduced pressure, and then 30 mL of 3 N HCl aqueous solution was added. The resulting solution was washed with EtOAc (3 × 20 mL) and then alkalized with a saturated aqueous solution of potassium carbonate (until pH = 9). The solution was extracted with 10% methanol / DCM (3 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography using a silicone column (0 to 10% MeOH / DCM, 15 column volumes (CV)) to obtain a mixture of regioisomers. These two regioisomers were separated by SFC to obtain 1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (2.0 g, 23% yield) as a white solid. Another regioisomer, 1-methyl-4-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (1.4 g, 15% yield), was also obtained. 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 4.16 (m, 1H), 2.91 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 2.13 (m, 2H), 1.98 (m, 4H); MS (ESI) m / z: 225.4 (M+H+).

[0300] The intermediates listed in Table C were prepared using the general methods B, C, and EG described above. [surface] [C.] Instance number structure method Yield (%) 1H NMR (400 MHz, DMSO-d6): LC-MS m / z: (M+H+). C4 G 16 8.85 (s, 1H), 4.36 (m, 1H),4.02 (m, 2H), 2.87(m, 2H), 2.42 (s, 3H), 1.98 (m, 2H), 1.78 (m, 2H), 1.41 (s, 9H) 255.4 (M-56) C5 G & B 97 8.83 (s, 1H), 4.14 (m, 1H), 2.85 (m, 4H), 2.18 (s, 3H), 1.97 (m, 6H), 1.19 (t, J = 7.2 Hz, 3H)。 253.5 C6 G & B 93 8.82 (s, 1H), 4.11 (m, 1H), 3.04 (m, 2H), 2.42 (s, 3H), 2.20 (m, 2H), 1.98 (m, 6H), 0.83 (m, 1H), 0.46 (m, 2H), 0.07 (m, 2H) 265.5 C7 G & B 97 8.83 (s, 1H), 4.53 (m, 2H), 4.42 (m, 2H), 4.17 (m, 1H), 3.42 (t, J = 6.2 Hz, 1H), 2.77 (m, 2H), 2.42 (s, 3H), 2.02 (m, 2H), 1.93 (m, 4H) 267.2 C8 G & C 46 8.85 (s, 1H), 4.25 (m, 1H), 3.07 (m, 4H), 2.43 (s, 3H), 2.06 (m, 4H)。 228.4 C9 G & C 36 8.82 (s, 1H), 4.58 (m, 2H), 4.48 (m, 2H), 4.01 (m, 1H), 2.95 (m, 4H), 2. 67 (m, 2H), 2.61 (m, 2H), 2.45 (s, 3H), 257.2 C10 G 31 8.87 (s, 1H), 4.76 (m, 1H),4.27 (t, J = 8.4, 2H), 4.14 (m, 2H), 2.45 (s, 3H), 1.40 (s, 9H) 283.4 C11 G & B 58 8.92 (s, 1H), 4.97 (m, 1H), 3.63 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 2.44 (s, 3H), 2.28 (d, J = 6.8 Hz, 2H), 1.51 (m, 1H), 0.85 (d, J = 6.4 Hz, 6H)。 239.41 C12 G 36 8.86 (s, 1H), 4.96 (brs, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 3.46 (m, 1H), 3.40 (m, 1H), 2.42 (s, 3H), 2.29 (m, 2H), 1.39 (s, 9H)。 241.2 (M-56) C13 G 56 8.86 (s, 1H), 4.96 (brs, 1H), 3.70 (m, 1H), 3.57 (m, 1H), 3.47 (m, 1H), 3.45 (m, 1H), 2.42 (s, 3H), 2.32 (m, 2H), 1.39 (s, 9H)。 241.1 (M-56) C14 G & B 84 8.78 (s, 1H), 4.87 (m, 1H), 2.80 (m, 2H), 2.64 (m, 1H), 2.42 (m, 1H), 2.40 (s, 3H), 2.35 (m, 2H), 2.21 (s, 3H) 211.4 C15 G & B 85 8.79 (s, 1H), 4.85 (m, 1H), 2.90 (brs, 1H), 2.81 (brs, 2H), 2.56 (brs, 1H), 2.42 (s, 3H), 2.32 (brs, 1H), 2.11 (brs, 1H), 1.98 (m, 1H), 1.02 (d, J = 6.4 Hz, 6H) 239.4 C16 G 36 7.31 (s, 1H), 4.25-4.31 (m, 3H), 2.86 (t, J = 12.9 Hz, 2H), 2.34 (s, 3H), 2.13 (d, J = 12.7 Hz, 2H), 1.92 (m, 2H), 1.47 (s, 9H)。 333.2 (M+Na+H+) C17 G & B 98 7.95 (s, 1H), 4.18 (m, 1H), 2.83 (d, J = 11.3 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.00 (m, 4H), 1.86-1.94 (m, 2H)。 225.2 C18 G 26 8.85 (s, 1H), 4.37 (m, 1H), 4.03 (m, 2H), 2.85 (m, 4H), 2.00 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H), 1.18 (t, J = 7.4 Hz, 3H)。 369.4 (M-56) C19 G & B 95 8.83 (s, 1H), 4.14 (m, 1H), 2.85 (m, 4H), 2.18 (s, 3H), 1.97 (m, 6H), 1.19 (t, J = 7.2 Hz, 3H)。 239.3 C20 G & B 87 8.81 (s, 1H), 4.11 (m, 1H), 2.84 (m, 4H), 2.73 (m, 1H), 2.22 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.19 (m, 3H), 0.97 (d, J = 6.2 Hz, 6H)。 267.2 C21 G & C 39 8.27 (s, 1H), 4.14 (m, 1H), 2.85 (m, 4H), 1.98 (m, 6H), 1.19 (t, J= 7.6 Hz, 3H)。 242.4 C22 F 60 8.74 (s, 1H), 4.11 (t, J = 6.4, Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.50 (m, 4H), 2.41 (s, 3H), 0.86 (t, J = 6.8 Hz, 6H) 227.2 C23 F 24 8.78 (s, 1H), 4.20 (t, J = 6.32 Hz, 2H), 3.52 (t, J = 4.50 Hz, 4H), 2.70 (t, J = 6.28 Hz, 2H), 2.41 (s, 3H), 2.40 (m, 4H)。 241.5 C24 F 26 8.79 (s, 1H), 4.12 (t, J = 7.08 Hz, 2H), 3.54 (t, J = 4.48 Hz, 4H), 2.41 (s, 3H), 2.29 (m, 4H), 2.24 (m, 2H), 1.93 (t, J = 6.88 Hz, 2H)。 255.4 C25 F 73 8.79 (s, 1H), 4.19 (t, J = 5.6 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.45 (m, 4H), 2.41 (s, 3H), 1.65 (m, 4H)。 225.2 C26 F 80 8.78 (s, 1H), 4.15 (t, J = 6.8, Hz, 2H), 3.82 (m, 4H),2.52 (m, 2H), 2.42 (m, 2H), 1.95 (s, 3H),1.65 (m, 4H)。 239.2 C27 F 85 8.75 (s, 1H), 4.18 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.35 (m, 4H), 1.44 (m, 4H), 1.35 (m, 2H)。 239.4 C28 F 40 8.77 (s, 1H), 4.10 (t, J = 6.8 Hz, 2H), 2.41 (s, 3H), 2.25 (brs, 4H), 2.19 (t, J = 6.8 Hz, 2H), 1.93 (m, 2H), 1.46(m, 4H), 1.31(brs, 2H). 253.4 [Preparation Example] [C29] [:] [ ]

[0301] A solution of 5-methyl-4-nitro-1H-pyrazole (2.0 g, 16 mmol) in DMF (15 mL) was treated fractionally with sodium hydride (0.94 g, 24 mmol) at 0 °C under Ar conditions for 15 minutes. The mixture was stirred at room temperature for 2 hours, followed by the addition of methyl 2-bromo-2-methylpropionate (4.3 g, 24 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (2 × 80 mL). The combined organic matter was washed with water (80 mL) and 10% LiCl aqueous solution (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography to give methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazole-1-yl)propionate (2.9 g, 81% yield) as a white solid. 1H NMR (500 MHz, DMSO-d 6): 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+).

[0302] 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 a solution of lithium hydroxide hydrate (0.54 g, 13 mmol) in water (10 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with water (60 mL), and acidified with 1N HCl aqueous solution until the pH was about 4. The resulting suspension was filtered, washed with water (2 × 10 mL), and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate (2.2 g, 81% yield) as a white solid. LC-MS m / z: 214.2 (M+H+).

[0303] A suspension of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionic acid (2.3 g, 11 mmol) in DCM (30 mL) was treated with one drop of DMF followed by ethylenediamine (2.8 mL, 32 mmol). The suspension was stirred at room temperature for 3 hours, and then the solution was concentrated to a clear state. The residue was dissolved in THF (30 mL) and the solution was slowly added to NH4OH solution (10 mL / water (40 mL)). The suspension was stirred at room temperature for 1 hour, and then concentrated. The suspension was diluted with water (50 mL) (approximately 10 mL), and the solid was filtered, washed with water, and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionic acid (2.1 g, 92% yield). LC-MS m / z: 213.2 (M+H+). [General Method] [H] [:] [Suzuki Coupling Reaction] [:] [ ] [Intermediate substance] [D1] [:]1-(3-Cyclopropyl-4-nitrophenyl)-4-methylpiperazine. [ ]

[0304] 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine was treated with K3PO4 (43 g, 200 mmol). [A21], 20 g, 67 mmol) and cyclopropyl A mixture of acid (8.6 g, 100 mmol) in toluene: H₂O (9:1) (200 mL) was prepared, and the reaction mixture was purged with nitrogen for 20 min. Tricyclohexylphosphine (3.7 g, 13 mmol) and Pd(OAc)₂ (2.2 g, 10 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0 to 80% EtOAc / hexane, 15 column volumes (CV)) to give 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, 69% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 9.3 Hz, 1H), 6.85 (dd, J = 2.4 and 9.4 Hz 1H), 6.55 (s, 1H), 3.36 (m, 4H), 2.45 (m, 1H), 2.40 (m, 4H), 2.20 (s, 3H), 0.94 (m, 2H), 0.75 (m, 2H); LC-MS (ESI) m / z: 261.3 (M+H+). [Intermediate substance] [D12] [:]1-Methyl-4-(4-nitro-3-vinylphenyl)piperazine. [ ]

[0305] 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine was treated with K2CO3 (42 g, 301 mmol) at room temperature. A mixture of [A21] (30 g, 100 mmol) and potassium trifluorovinylborate (20 g, 150 mmol) in DMSO (210 mL) was prepared, and the reaction mixture was purged with nitrogen for 15 min. PdCl2 (dppf) (3.7 g, 5.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with cold water (300 mL), and the solution was extracted with EtOAc (3 × 250 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 80% EtOAc / hexane, 10 column volumes (CV)) to give 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (20 g, 81% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J = 9.2 Hz, 1H), 7.21 (m, 1H), 6.98 (m, 2H), 5.77 (t, J = 17.2 Hz, 1H), 5.41 (d, J = 11.2 Hz, 1H), 3.44 (t, J = 4.8 Hz, 4H), 2.42 (t, J = 4.8 Hz, 4H), 2.21 (s, 3H); LC-MS (ESI) m / z: 247.3 (M+H+). [ ]

[0306] Using the general method H described above, prepare the intermediates listed in Table D below. [surface] [D.] Example structure Yield (%) ¹H NMR (400 MHz, DMSO-d⁶): δ LC-MS (m / z: (M+H+)). D2 43 7.90 (d, J = 9.3 Hz, 1H), 6.84 (dd, J = 9.3 and 2.7 Hz, 1H), 6.53 (d, J = 2.7 Hz, 1H), 3.36-3.45 (m, 8H), 2.44-2.47 (m, 1H), 1.41 (s, 9H), 0.93-0.97 (m, 2H), 0.73-0.76 (m, 2H). No MS data D3 91 No NMR data 276.2 D4 62 7.83 (d, J = 5.9 Hz, 1H), 6.63 (d, J = 5.9 Hz, 1H), 3.21 (s, 4H), 2.43 (s, 4H), 2.35-2.40 (m, 1H), 2.20 (s, 3H), 0.96 (m, 2H), 0.74 (m, 2H). 280.2 D5 53 7.91 (d, J = 9.2 Hz, 1H), 6.84 (m, 1H), 6.49 (m, 1H), 3.98 (s, 2H), 3.68 (m, 2H), 3.45 (m, 2H), 2.9 (s, 3H), 2.47 (s, 1H), 0.94 (m, 2H), 0.78 (m, 2H). 276.1 D6 78 7.91 (d, J = 9.2 Hz, 1H), 6.84 (m, 1H), 6.49 (m, 1H), 3.98 (s, 2H), 3.68 (m, 2H), 3.45 (m, 2H), 2.8 (s, 3H), 2.47 (s, 1H), 0.94 (m, 2H), 0.78 (m, 2H) 276.1 D7 44 7.91 (d, J = 9.3 Hz, 1H), 6.66 (dd, J = 2.6 and 9.4 Hz 1H), 6.32 (d, J = 2.4 Hz, 1H), 3.59 (m, 2H), 3.53 (m, 2H), 3.28 (m, 1H), 2.58 (m, 2H), 2.44 (m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 0.95 (dd, J = 1.6 and 8.4 Hz, 2H), 0.73 (m, 2 H). 276.1 D8 93 7.90 (d, J = 9.3 Hz, 1H), 6.86 (dd, J = 9.3 and 2.6 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.30-3.33 (m, 4H), 2.46-2.48 (m, 1H), 0.93-0.96 (m, 2H), 0.73-0.76 (m, 2H). No LC-MS data D9 58 7.89 (d, J = 8.5 Hz, 1H), 6.87 (m, 1H), 6.55 (d, J = 2.6 Hz, 1H), 3.99 (m, 2H), 2.97 - 3.04 (m, 2H), 2.88 (m, 1H), 2.55 (m, 1H), 2.45 - 2.47 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.80 - 1.85 (m, 1H), 1.63 - 1.74 (m, 2H), 1.35 (m, 1H), 0.92 - 0.96 (m, 2H), 0.72 - 0.75 (m, 2H). 288.2 D10 64 7.91 (d, J = 9.2 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.55 (s, 1H), 3.48 (s, 1H), 2.80 (d, J = 9.5 Hz, 1H), 2.53 (m, 1 H), 2.41 (d, J = 9.8 Hz, 1H), 2.27 (s, 3H), 1.89 (d, J = 9.3 Hz, 1H), 1.73 (d, J = 9.7 Hz, 1H), 0.94 (m, 2H), 0.71 (m, 2H). 274.2<00�3254> D11 <🔢003256> 78 7.90 (d, J = 9.0 Hz, 1H), 6.28 (dd, J = 9.1及2.4 Hz, 1H), 6.01 (s, 1H), 4.01 (t, J = 7.8 Hz, 2H), 🆕3.75 (dd, J = 8.6及5.2 Hz, 2H), 3.12 (m, 1H), 2.10 (s, 6 H), 0.95 (m, 2H), 0.8 (m, 2H). 262.2 D13 87 It should be noted that there seems to be an error in the original text where "3.75 (dd, J = 8.6及5.2 Hz, 2H)" was misformatted in the Chinese input. It has been corrected in the translation for better readability. Also, the "🔢" and "🆕" are just used to mark the position of the corrected content in the translation for your reference.7.98 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 17.2 and 10.9 Hz, 1H), 6.95-6.97 (m, 2H), 5.79 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.46 (s, 8H), 1.41 (s, 9H). 356.2 (M+Na+H+). D14 77 No NMR data 262.2 D15 96 No NMR data 276.2 D16 90 7.98 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 17.3, 10.9 Hz, 1H), 7.00 (m 1H), 6.98 (s, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.72 (t, J = 4.8 Hz, 4H), 3.41 (t, J = 4.8 Hz, 4H). 235.2 D17 81 8.01 (d, J = 9.1 Hz, 1H), 7.25 (dd, J = 17.3 and 10.9 Hz, 1H), 6.62-6.65 (m, 2H), 5.78 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 3.73-3.77 (m, 1H), 3.46-3.70 (m, 4H), 2.35-2.43 (m, 1H), 2.24-2.31 (m, 1H). No data D18 72 8.01 (d, J = 9.1 Hz, 1H), 7.25 (dd, J = 17.3 and 10.9 Hz, 1H), 6.62 - 6.65 (m, 2H), 5.78 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 3.73 - 3.77 (m, 1H), 3.46 - 3.70 (m, 4H), 2.35 - 2.43 (m, 1H), 2.24 - 2.31 (m, 1H). No data D19 32 7.99 (d, J = 9.2 Hz, 1H), 7.24 (m, 1H), 6.96 (m, 2H), 5.86 (d, J = 18.12 Hz, 1H), 5.44 (d, J = 11.92 Hz, 1H), 4.05 (s, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.47 (t, J = 5.4 Hz, 2H), 2.91 (s, 3H). 262.2 D20 42 7.99 (d, J = 9.2 Hz, 1H), 7.22 (m, 1H), 6.96 (m, 2H), 5.85 (m, 1H), 5.44 (d, J = 11.0 Hz, 1H), 4.04 (s, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.92 (s, 3H). 262.3 D21 87 7.96 (d, J = 9.3 Hz, 1H), 7.23 (dd, J = 17.2 and 10.9 Hz, 1H), 6.81-6.86 (m, 2H), 5.76 (d, J = 17.2 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 11.4 Hz, 2H), 3.21-3.25 (brs, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.23 (s, 3H), 1.94-1.96 (m, 2H), 1.54-1.58 (m, 2H). 274.2 D22 56 No data 260.2 D23 95 7.96 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 17.2 and 10.9 Hz, 1H), 7.00 (dd, J = 9.4 and 2.9 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 5.79 (dd, J = 17.2 and 1.2 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 4.15 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 12.6 Hz, 1H), 2.91-3.06 (m, 3H), 2.62 (t, J = 11.2 Hz, 1H), 2.18 (td, J = 11.2 and 3.2 Hz). Hz, 1H), 2.06 (q, J = 8.6 Hz, 1H), 1.98 (m, 1H), 1.84 (m, 1H), 1.63-1.76 (m, 2H), 1.34-1.42 (m, 1H). 274.2 D24 100 7.96 (d, J = 9.2 Hz, 1H), 7.21 (dd, J = 17.2 and 10.8 Hz, 1H), 7.00 (dd, J = 9.4 and 2.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 5.79 (dd, J = 17.2 and 1.2 Hz, 1H), 5.41 (dd, J = 11.0 and 1.2 Hz, 1H), 4.15 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 12.6 Hz, 1H), 3.06 (d, J = 11.2 Hz, 1H), 2.92 - 3.03 (m, 2H), 2.62 (t, J = 11.2 Hz, 1H), 2.17 (td, J = 11.2 and 3.2 Hz, 1H), 2.06 (q, J = 8.6 Hz, 1H), 1.95 - 2.01 (m, 1H), 1.81 - 1.87 (m, 1H), 1.63 - 1.74 (m, 2H), 1.37 (m, 1H). 274.2 D25 79 7.90 (d, J = 13.6 Hz, 1H), 7.06 - 7.15 (m, 2H), 5.83 (d, J = 17.2 Hz, 1H), 5.47 (d, J = 11.0 Hz, 1H), 3.28 (m, 4H), 2.45 (m, 4H), 2.22 (s, 3H). 266.2 D26 75 7.98 (d, J = 9.4 Hz, 1H), 7.27 (m, 1H), 6.80 (dd, J = 2.8 and 9.2 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 5.70 (d, J = 18.4 Hz, 1H), 5.39 (d, J = 11.2 Hz, 1H), 3.66 (m, 2H), 3.59 (m, 2H), 2.63 (m, 2H), 2.45 (m, 2H) 2.25 (s, 3H), 1.89 (m, 2H). 262.2 D27 92 7.98 (d, J = 9.4 Hz, 1H), 7.26 (dd, J = 17.2 and 10.9 Hz, 1H), 6.84 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 9.2 Hz, 1H), 5.75 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.52 - 3.81 (m, 6H), 3.23 - 3.31 (m, 2H), 1.72 - 1.90 (m, 2H), 1.22 (d, J = 55.8 Hz, 9H). No MS data D28 57 7.93 (d, J = 9.2 Hz, 1H), 6.95 (dd, J = 2.6, and 9.2 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 5.07 (s, 1H), 4.83 (s, 1H), 3.40 (brs, 4H), 2.41 (brs, 4H), 2.21 (s, 3H), 1.82 (s, 3H). 262.3 D29 88 7.93 (d, J = 9.2 Hz, 1H), 6.94 (m, 1H), 6.69 (d, J = 2.0 Hz, 1H), 5.07 (s, 1H), 4.83 (s, 1H), 3.40 (m, 4H), 2.45 (m, 4H), 2.35 (q, J = 6.8 Hz, 2H), 1.98 (s, 3H), 1.02 (t, J = 6.8 Hz, 3H). 276.3 D30 92 7.90 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 5.71 (s, 1H), 3.37 (m, 4H), 2.41 (m, 8H), 2.20 (s, 3H), 1.95 (m, 2H) 289.2 D31 91 7.97 (d, J = 9.2 Hz, 1H), 7.24 (dd, J = 17.2 and 10.8 Hz, 1H), 6.61 (m, 2H), 5.73 (d, J = 17.2 Hz, 1H), 5.38 (d, J = 11.0 Hz, 1H), 4.60 (s, 1H), 3.49 (s, 1H), 3.31 (s, 2H), 2.82 (dd, J = 9.6 and 2.0 Hz, 1H), 2.43-2.45 (m, 1H), 2.28 (s, 3H), 1.71-1.90 (m, 2H). 260.2 [General Method] [I] [:] [Restore] [(] [A] [)] [intermediate] [E1] [:]2-Cyclopropyl-4-(4-methylpiperazin-1-yl)aniline. [ ]

[0307] 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine was treated with NH4Cl (73 g, 14 mmol) at 0 °C. A solution of [D1] (12 g, 46 mmol) was prepared in MeOH (60 mL), and the reaction mixture was stirred at 0 °C for 10 minutes. Zinc powder (30 g, 459 mmol) was slowly added to the reaction mixture in an ice-water bath (internal temperature increased to 20 °C). After stirring for 15 minutes, the reaction mixture was warmed to room temperature and vigorously stirred at room temperature for 16 hours. The mixture was filtered through a diatomaceous earth mat® and washed with THF (500 mL). The filtrate was concentrated under reduced pressure to give 10 g (95%) of 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline as a dark brown, viscous solid. 1H NMR (400 MHz, DMSO-d6): δ 6.52 (m, 2H), 6.43 (d, J = 2.0 Hz, 1H), 4.52 (brs, 2H), 2.88 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H), 1.65 (m, 1H), 0.813 (m, 2H), 0.47 (m, 2H); LC-MS (ESI) m / z: 213.2 (M+H+). [(] [B] [)] [Intermediate substance] [E11] [:]2-Ethyl-4-(4-methylpiperazinyl-1-yl)aniline.

[0308] 1-Methyl-4-(4-nitro-3-vinylphenyl)piperazine was treated with Pd / C (20 g, 10% w / w, 50% moisture) under a nitrogen atmosphere. A solution of [D12] (20 g, 81 mmol) was prepared in EtOAc (200 mL), and the mixture was subsequently stirred at room temperature for 3 hours under hydrogen pressure. After general treatment, 2-ethyl-4-(4-methylpiperazin-1-yl)aniline (16 g, 90% yield) was obtained as a brown viscous solid. ¹H NMR (400 MHz, DMSO-d6): δ 6.61 (s, 1H), 6.52 (m, 2H), 4.25 (brs, 2H), 2.89 (t, J = 4.4 Hz, 4H), 2.41 (m, 6H), 2.19 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H); LC-MS (ESI) m / z: 219.3 (M+H+).

[0309] The intermediates listed in Table E were prepared using the general methods I(A) and I(B) described above. [surface] [E.] Example structure method Yield (%) 1H NMR (400 MHz, DMSO-d6): MS m / z: (M+H+). E2 I(A) 76 6.56 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.45 (s, 1H), 4.53 (s, 2H), 3.39 (s, 4H), 2.80 (s, 4H), 1.63 (s, 1H), 1.39 (s, 9H), 0.80 (d, J = 8.0 Hz, 2H), 0.47 (d, J = 5.2 Hz, 2H). No MS data E3 I(A) 100 6.51-6.56 (m, 2H), 6.43 (s, 1H), 4.49 (s, 2H), 3.67 (t, J = 4.6 Hz, 4H), 2.85 (t, J = 4.5 Hz, 4H), 1.62-1.68 (m, 1H), 0.79-0.82 (m, 2H), 0.45-0.48 (m, 2H) 219.2 E4 I(A) 100 6.49 (d, J = 5.1 Hz, 1H), 6.38 (d, J = 5.1 Hz, 1H), 4.85 (s, 2H), 2.80 (s, 4H), 2.40 (s, 4H), 2.18 (s, 3H), 0.80 (d, 2H), 0.44 (d, 2H) 250.2 E5 I(A) 96 6.56 (m, 2H), 6.46 (s, 1H), 4.56 (s, 2H), 3.48 (s, 2H), 3.32 (s, 2H), 3.18 (s, 2H), 2.85 (s, 3H), 1.65 (m, 1H), 0.83 (m, 2H), 0.50 (m, 2H)。 246.1 E6 I(A) 70 6.55 (m, 2H), 6.46 (s, 1H), 4.55 (brs, 2H), 3.48 (s, 2H), 3.32 (s, 2H), 3.17 (s, 2H), 2.85 (s, 3H), 1.65 (s, 1H), 0.82 (m, 2H), 0.50 (m, 2H)。 246.2 E7 I(A) 74 6.63 (m, 1H), 6.46 (m, 1H), 6.27 (s, 1H), 3.54 (brm, 2H), 3.32 (m, 6H) 3.16 (m, 2H), 2.82 (s, 3H), 2.11 (brs, 2H), 1.70 (s, 1H), 0.84 (brs, 2H), 0.51 (brs, 2H). 246.2 E8 I(A) 100 6.57 (m, 2H), 6.44 (m, 1H), 4.48 (brs, 2H), 3.40 (m, 1H), 3.26 (m, 1H), 2.96 (m, 2H), 2.56 (m, 1 H), 2.18 - 2.26 (m, 2H), 2.04 (m, 2H), 1.62 - 1.80 (m, 4H), 1.32 (m, 1H), 0.81 (m, 2H), 0.45 (m, 2 H). 258.2 E9 I(A) 91 6.51 (d, J = 8.6 Hz, 1H), 6.24 (s, 1H), 6.08 (s, 1H), 4.19 (s, 1H), 3.63 (s, 1H), 3.31 (s, 2H), 3.05 - 3.05 (m, 1H), 2.80 (brs, 2H), 2.39 (s, 3H), 1.91 (s, 1H), 1.81 (s, 1H), 1.66 (brs, 1H), 0.81 (m, 2H), 0.46 (m, 2H) 244.2 E10 I(A) 100 No NMR data 232.2 E12 I(B) 92 6.50 (d, J = 8.0 Hz, 1H), 6.29 (brs, 1H), 6.24 (d, J = 7.6 Hz, 1H), 4.50 (s, 1H), 4.31 (s, 1H), 4.11 (brs, 2H), 3.64 (brs, 2H), 3.39 (m, 1H), 2.79 (d, J = 8.8 Hz, 1H), 2.01 (s, 3H), 1.85 (m, 1H), 1.74 (m, 1H). 205.1 E13 I(B) 72 6.48 (d, J = 8.4Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.35 (m, 1H), 4.07 (brs, 2H), 3.33-3.48 (m, 4H), 3.00-3.31 (m, 2H), 2.52-2.71 (m, 1H), 2.00 (s, 3H), 1.43-1.80 (m, 3H), 1.26- 1.39 (m, 9H). 306.2 E14 I(B) 82 6.48 (d, J = 8.4 Hz, 1H), 6.34-6.38 (m, 2H), 4.06 (brs, 2H), 2.51-2.72 (m, 4H), 2.39 (q, J = 7.5 Hz, 2H), 1.77-1.83 (m, 3H), 1.59 (m, 4H), 1.37 (s, 2H), 1.32-1.35 (m, 3H), 1.23-1.25 (m, 2H), 1.07-1.13 (m, 2H), 0.82 (dt, J = 15.1 and 7.5Hz, 2H). The 1H NMR spectrum was split into two isomers. Therefore, protons were used. 320.2 E15 I(B) 97 6.58 (brs, 1H), 6.52 (m, 2H), 4.34 (brs, 2H), 2.88 (m, 4H), 2.49 (m, 4H), 2.19 (s, 3H), 2.01 (s, 3H). 206.1 E16 I(B) 100 6.58 (s, 1H), 6.48 - 6.53 (m, 2H), 4.59 (t, J = 4.9 Hz, 1H), 4.50 (t, J = 4.9 Hz, 1H), 4.35 (brs, 2H), 2.89 (t, J = 4.7 Hz, 4H), 2.67 (t, J = 4.7 Hz, 1H), 2.61 (t, J = 4.8 Hz, 1H), 2.55 (t, J = 4.7 Hz, 4H), 2.01 (s, 3H). 238.2 E17 I(B) 44 6.58 (s, 1H), 6.49 (m, 2H), 4.33 (brs, 2H), 2.84 (brs, 4H), 2.63 (brs, 4H), 2.01 (s, 3H), 1.62 (m, 1H), 0.42 (m, 2H), 0.31 (m, 2H). 232.3 E18 I(B) 99 No NMR data 292.2 E19 I(B) 92 6.49 (m, 2H), 6.27 (dd, J = 2.0 and 8.0 Hz, 1H), 4.19 (brs, 2H), 3.73 (s, 3H), 2.93 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H). 222.1 E20 I(B) 100 6.52 (d, J = 8.4 Hz, 1H), 6.46 (m, 1H), 6.28 (m, 1H), 4.46 (m, 1H), 4.25 (brs, 2H), 2.91 (m, 4H), 2.41 (m, 4H), 2.13 (s, 3H), 1.17 (d, J = 8.4 Hz, 6H) 250.3 E21 I(B) 100 6.63 (m, 1H), 6.53 (m, 2H), 4.39 (brs, 2H), 3.41 (brs, 4H), 2.83 (brs, 4H), 2.30 (q, 2H), 1.40 (s, 9H), 1.09 (t, J = 7.44 Hz, 3H). 306.2 E22 I(B) 92 6.63 (s, 1H), 6.52 (s, 2H), 4.47 (brs, 2H), 2.91 (m, 5H), 2.42 (brs, 4H), 2.19 (s, 3H), 1.12 (d, J = 6.8 Hz, 6H). 234.2 E23 I(B) [[ID=�6]] 93 6.63 (s, 1H), 6.51 (m, 2H), 4.37 (brs, 2 H), 2.92 (m, 5H), 2.47 (m, 4H), 2.33 (q, J=7.2 Hz, 2H), 1.12 (d, J=6.8 Hz, 6H), 1.01 (t, J = 7.2 Hz, 3H). 248.3 E24 I(B) 100 No NMR data 207.2 E25 I(B) 98 6.52 (d, J = 8.5 Hz, 1H), 6.26-6.30 (m, 2 H), 4.16 (s, 2 H), 3.24-3.45 (m, 4 H), 3.10-3.14 (m, 1H), 2.41 (q, J = 7.8 Hz, 2 H), 2.28-2.32 (m, 1H), 2.13-2.17 (m, 1H), 1.10 (t, J = 7.6 Hz, 3 H). 216.2 E26 I(B) 95 6.52 (d, J = 8.5 Hz, 1H), 6.26-6.30 (m, 2 H), 4.16 (s, 2 H), 3.24-3.45 (m, 4 H), 3.10-3.14 (m, 1H), 2.41 (q, J = 7.8 Hz, 2 H), 2.28-2.32 (m, 1H), 2.13-2.17 (m, 1H), 1.10 (t, J = 7.6 Hz, 3 H). 216.2 E27 I(B) 91 No NMR data 238.2 E28 I(B) 87 6.49 (brs, 1H), 6.40 (m, 2H), 3.48 (m, 6H), 2.57 (m, 2H), 2.45 (m, 4H) 2.30 (s, 3H), 1.85 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H). 233.2 E29 I(B) 100 No NMR data 246.2 E30 I(B) 97 6.45-6.50 (m, 3 H), 4.28 (br s, 2 H), 3.94 (s, 1H), 2.88-2.94 (m, 2 H), 2.78-2.83 (m, 1H), 2.75 (t, J = 7.5 Hz, 3 H), 2.60-2.64 (m, 1H), 2.44-2.46 (m, 1H), 2.39 (q, J = 7.5 Hz, 2 H), 1.55-1.59 (m, 2 H), 1.09 (t, J = 7.5 Hz, 3 H). 232.2 E31 I(B) 85 No NMR data 246.2 E32 I(B) 100 No NMR data 246.2 E33 I(B) 76 6.66 (m, 2H), 6.51 (s, 1H), 4.57 (brs, 2H), 2.96 (m, 4H), 2.89 (m, 8H), 2.43 (s, 3H), 2.20 (m, 3H), 1.90 (m, 2H) 260.3 E34 I(B) 88 6.90 (s, 1H), 6.77 (m, 1H), 6.50 (s, 1H), 4.75 (brs, 2H), 3.98 (s, 2H), 2.82 (s, 4H), 2.16 (m, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.81 (m, 1H), 1.32 (m, 3H) 234.2 E35 I(B) 77 6.89 (s, 1H), 6.78 (m, 1H), 6.52(s, 1H), 4.93 (brs, 2H), 3.39 (s, 2H), 2.86 (s, 4H), 2.16 (m, 2H), 1.98 (m, 1H), 1.89 (m, 1H), 1.80 (m, 1H), 1.35 (m, 3H) 234.2 E36 I(B) 77 No data 232.2 E37 I(B) 90 7.56 (s, 1H), 6.48 (s, 1H), 4.33 (brs, 2H), 3.21 (brs, 4H), 2.41 (q, 2H), 2.37 (brs, 4H), 2.19 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H)。 221.1 E38 I(B) 92 7.57 (s, 1H), 6.53 (s, 1H), 4.37 (brs, 2H), 3.67 (brs, 4H), 3.16 (brs, 4H), 2.05 (s, 3H)。 194.2 E39 I(B) 96 7.55 (s, 1H), 6.52 (s, 1H), 4.33 (brs, 2H), 3.33 (brs, 4H), 2.31 (brs, 4H), 2.19 (s, 3H), 2.02 (s, 3H)。 207.2 E40 I(B) 100 6.74 (brm, 1H), 6.71 (m, 1H), 6.49 (d, J = 7.4 Hz, 1H), 4.57 (brs, 2H), 4.00 (brm, 2H), 2.73 (brm, 2H), 2.33 (m, 1H), 1.99 (s, 3H), 1.83 (m, 2H), 1.38 (s, 9H), 1.32 (m, 2H)。 313.2 (M+Na+H+). E41 I(B) 100 6.99 (brm, 1H), 6.95 (m, 1H), 6.54 (d, J = 7.4 Hz, 1H), 5.85 (brm, 1H), 4.82 (brs, 2H), 3.92 (brm, 2H), 3.16 (s, 3H), 2.96 (brm, 2H), 2.54 (m, 2H), 2.38 (m, 2H), 2.03 (s, 3H)。 185.2 E42 I(B) 93 7.84 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.76 (brs, 2H), 3.80 (s, 3H), 2.02 (s, 3H)。 188.4 E43 I(B) 93 7.51 (s, 1H), 7.32 (s, 1H), 7.26 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 4.78 (brs, 2H), 3.64 (s, 3H), 2.07 (s, 3H)。 264.2 E44 I(B) 94 7.01 (s, 1H), 4.03 (m, 1H), 3.97 (brs, 2H), 3.85 (m, 2H), 2.83 (brs, 2H), 1.99 (s, 3H), 1.97 (m, 2H), 1.64 (m, 2H), 1.40 (s, 9H)。 281.5 E45 I(B) 75 6.97 (s, 1H), 4.02 (brs, 2H), 3.85 (m, 1H), 3.86 (m, 2H), 2.88 (m, 2H), 2.25 (s, 3H), 2.12 (m, 2H), 1.99 (s, 3H), 1.85 (m, 2H)。 195.1 E46 I(B) 94 6.96 (s, 1H), 3.76-3.82 (m, 1H), 3.55 (brs, 2H), 2.89 (m, 2H), 2.32 (m, 2H), 1.93-1.97 (m, 5H), 1.86 (m, 2H), 1.74-1.77 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H)。 209.2 E47 I(B) 85 7.01 (s, 1H), 3.79 (m, 1H), 3.53 (brs, 2H), 2.80 (m, 2H), 2.71 (m, 1H), 2.18 (m, 2H), 1.97 (s, 3H), 1.88 (m, 2H), 1.74 (m, 2H), 0.96 (d, J= 6.4 Hz, 6H)。 223.1 E48 I(B) 98 6.97 (s, 1H), 4.02 (brs, 2H), 3.77 (m, 1H), 3.01 (m, 2H), 2.19 (m, 2H), 1.97 (s, 3H), 1.80 (m, 2H), 1.31 (m, 4H), 0.83 (m, 1H), 0.46 (m, 2H), 0.06 (m, 2H) 235.5 E49 I(B) 95 6.98 (s, 1H), 4.53 (t, J= 6.4 Hz, 2H), 4.42 (t, J= 6.0 Hz, 2H), 3.85 (m, 1H), 3.74 (brs, 2H), 3.40 (m, 1H), 2.73 (m, 2H), 1.98 (s, 3H), 1.85 (m, 6H) 237.2 E50 I(B) 84 6.95 (s, 1H), 3.81 (m, 1H), 3.75 (brs, 2H), 2.78 (m, 2H), 2.39 (m, 2H), 1.96 (s, 3H), 1.75 (m, 4H)。 198.4 E51 I(B) 72 6.97 (s, 1H), 4.58 (m, 2H), 4.48 (m, 2H), 3.81 (m, 1H), 3.55 (brs, 2H), 2.96 (m, 4H), 2.67 (m, 2H), 2.60 (m, 2H), 1.97 (s, 3H)。 227.2 E52 I(B) 92 7.04 (s, 1H), 4.88 (m, 1H), 4.16 (t, J= 8.0 Hz, 2H), 4.00 (brs, 2H), 3.71 (brs, 2H), 2.02 (s, 3H), 1.39 (s, 9H) 253.23 E53 I(B) 93 6.97 (s, 1H), 4.65 (m, 1H), 4.05 (brs, 2H), 3.42 (m, 2H), 2.16 (m, 2H), 1.98 (s, 3H), 1.39 (s, 9H), 1.35 (m, 2H)。 267.4 E54 I(B) 89 6.97 (s, 1H), 4.64 (m, 1H), 3.63 (brs, 2H), 3.59 (m, 2H), 3.39 (m, 2H), 2.16 (m, 2H), 1.98 (s, 3H), 1.39 (s, 9H) 267.2 E55 I(B) 88 6.99 (s, 1H), 4.58 (m, 1H), 3.62 (brs, 2H), 2.67 (m, 2H), 2.56 (m, 1H), 2.41 (m, 1H), 2.24 (s, 3H), 1.97 (s, 3H), 1.91 (m, 1H), 1.20 (m, 1H)。 181.1 E56 I(B) 85 7.01 (s, 1H), 4.54 (t, J = 7.6 Hz, 1H), 3.74 (brs, 2H), 2.84 (m, 1H), 2.74 (m, 1H), 2.69 (m, 1H), 2.58 (m, 1H), 2.37 (m, 1H), 2.19 (m, 1H), 1.98 (s, 3H), 1.94 (m, 1H), 1.01 (t, J = 5.6 Hz, 6H)。 209.5 E57 I(B) 92 7.35 (s, 1H), 4.14 (m, 1H), 4.01 (brs, 2H), 2.75 (brs, 2H), 2.45 (m, 2H), 2.12 (m, 2H), 1.99 (m, 2H), 1.75 (m, 2H), 1.40 (s, 9H), 1.17 (t, J = 7.4 Hz, 3H)。 295.3 E58 I(B) 88 6.95 (s, 1H), 4.25 (m, 1H), 4.09 (brs, 2H), 3.50 (m, 2H), 3.38 (m, 2H), 2.79 (m, 2H), , 2.16 (s, 3H), 1.80 (m, 4H), 1.06 (t, J= 7.8 Hz, 3H 209.2 E59 I(B) 94 6.96 (s, 1H), 3.78 (m, 1H), 3.52 (brs, 2H), 2.82 (m, 2H), 2.71 (m, 1H), 2.20 (m, 2H), 1.96 (s, 3H), 1.92 (m, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 0.96 (d, J= 6.8 Hz, 6H) 237.2 E60 I(B) 63 6.96 (s, 1H), 3.78 (m, 1H), 3.67 (brs, 2H), 2.78 (m, 2H), 2.39 (m, 2H), 1.93 (m, 2H), 1.84 (m, 4H), 1.06 (t, J= 7.8 Hz, 3H) 212.4 E61 I(B) 94 6.95 (s, 1H), 4.01 (brs, 2H), 3.89 (t, J = 6.4 Hz, 2H), 4.01 (brs, 2H), 3.56 (m, 2H), 2.13 (s, 6H), 1.96 (s, 3H)。 169.2 E62 I(B) 88 6.95 (s, 1H), 4.11 (m, 2H), 3.87 (t, J = 6.8 Hz, 2H), 3.51 (brs, 2H), 2.44 (m, 4H), 1.95 (s, 3H), 0.91 (t, J = 6.8 Hz, 6H)。 197.3 E63 I(B) 91 6.96 (s, 1H), 3.93 (t, J= 6.8 Hz, 2H), 3.54 (m, 6H), 2.57 (t, J= 6.8 Hz, 2H), 2.36 (brs, 4H), 1.96 (s, 3H) 211.1 E64 I(B) 83 6.92 (s, 1H), 3.84 (t, J= 7.6 Hz, 2H), 3.55 (m, 6H), 2.49 (brs, 1H), 2.29 (m, 4H), 2.17 (t, J= 6.8 Hz, 2H), 1.77 (m, 2H), 1.35 (s, 2H) 225.2 E65 I(B) 99 6.95 (s, 1H), 4.03 (brs, 2H), 3.92 (t, J = 7.2, Hz, 2H), 2.68 (t, J = 6.8 Hz, 2H), 2.41 (m, 4H), 1.96 (s, 3H), 1.64 (m, 4H). 195.1 E66 I(B) 88 6.93 (s, 1H), 4.01 (t, J = 6.8 Hz, 2H), 3.82 (t, J = 6.8 Hz, 2H), 2.37 (m, 4H), 2.22 (m, 2H), 1.97 (s, 3H), 1.75 (m, 4H). 209.2 E67 I(B) 79 6.95 (s, 1H), 3.91 (t, J = 6.8 Hz, 2H), 3.64 (brs, 2H), 2.52 (t, J = 6.4 Hz, 2H), 2.33 (m, 4H), 1.96 (s, 3H), 1.44 (m, 4H), 1.35 (m, 2H). 209.5 E68 I(B) 90 6.91 (s, 1H), 3.82 (t, J = 6.8 Hz, 2H), 3.55 (brs, 2H), 2.32 (m, 4H), 2.13 (m, 2H), 1.97 (s, 3H), 1.77 (m, 2H), 1.46 (m, 4H), 1.35 (brs, 2H). 223.5 E69 I(B) 99 No NMR 183.2 [Coupling Methods] [J] [(] [A] [)] [and] [Boc] [Deprotection of functional groups] [:] [ ] [Intermediate substance] [F1] [:]N-(3-aminopropyl)cyclobutanemethylamine hydrochloride. [ ] [ ]

[0310] A solution of (3-aminopropyl)aminocarbamate tributyl ester (5.0 g, 29 mmol) in EtOAc (100 mL) was treated with saturated NaHCO3 (100 mL) aqueous solution, and the two-phase mixture was treated dropwise with cyclobutane carbonyl chloride (3.6 mL, 32 mmol) while stirring at room temperature for 18 hours. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic matter was dried over anhydrous Na2SO4 and concentrated to give (3-(cyclobutanemethamino)propyl)aminocarbamate tributyl ester (5.6 g, 76% yield) as a white solid. 1H NMR (DMSO-d 6, 500 MHz): δ7.57 (s, 1H), 6.73 (s, 1H), 2.85-3.00 (m, 5H), 2.04-2.12 (m, 2H), 1.97 (m, 2H), 1.86 (m, 1H), 1.69-1.76 (m, 1H), 1.47 (m, 1H), 1.36 (s, 9H); MS (ESI) m / z: 279.2 (M+H+).

[0311] A solution of tert-butyl 3-(cyclobutanemethylamino)propyl)aminocarbamate (5.6 g, 0.022 mol) in 100 mL MeOH was treated dropwise with 27 mL (0.11 mol) of 1,4-dioxane containing 4 N HCl while stirring at room temperature for 3 hours. The solution was concentrated to dryness, then resuspended in MeOH and concentrated again (this process was repeated twice) to give N-(3-aminopropyl)cyclobutanemethylaminohydrochloride (4.7 g, 100% yield) as a white solid. 1H NMR (DMSO-d 6, 500 MHz): δ 7.96 (brs, 3H), 7.87 (brm, 1H), 3.09 (m, 2H), 2.96 (m, 1H), 2.74 (m, 2H), 2.13 (m, 2H), 1.5-2.0 (m, 6H); MS (ESI) m / z: 140.2 (M+H+). [Coupling Methods] [J] [(] [B] [)] [and] [Boc] [Deprotection of functional groups] [:] [ ] [Intermediate substance] [F2] [:]N-(3-aminopropyl)-3,3-difluoro-N-methylcyclobutane-1-methamide TFA salt. [ ]

[0312] A solution of 3,3-difluorocyclobutane-1-carboxylic acid (0.27 g, 2.0 mmol) and DIEA (1.6 mL, 9.0 mmol) in DCM (5 mL) was treated with HOBt (0.52 g, 2.7 mmol), followed by EDC (0.52 g, 2.7 mmol), and stirred at room temperature for 5 minutes. A solution of (3-(methylamino)propyl)aminocarboxylic acid tributyl ester (0.34 g, 1.8 mmol) in DCM (5 mL) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was quenched with brine (30 mL) and extracted with DCM (3 × 25 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude compound was purified by silica gel column chromatography (0 to 10% MeOH / DCM, 15 column volumes (CV)) to give tributyl 3-(3,3-difluoro-N-methylcyclobutane-1-methamido)propyl)aminoformate (0.54 g, 98% yield), which was dissolved in DCM (6 mL) and subsequently treated with TFA (0.18 mL). The solution was stirred at room temperature for 3 h and then concentrated to give N-(3-aminopropyl)-3,3-difluoro-N-methylcyclobutane-1-methamido) TFA salt (100% yield).

[0313] The intermediates listed in Table F were prepared using the general method J described above. [surface] [F.] Example intermediate method Yield (%) NMR 1H NMR (DMSO-d 6, 500 MHz) LC-MS (m / z: M+H+) F2 J(A) 86 7.71 (m, 3H), 7.45 (m, 1H), 3.10 (m, 2H), 3.01 (m, 2H), 2.51 (m, 2H), 1.08 (s, 9H). 159.4 F3 J(A) 86 8.05 (brs, 1H), 7.92 (brs, 2H), 3.10 - 3.3 (m, 3H), 2.84 (s, 3H), 2.61 (m, 2H), 2.0 - 2.15 (m, 4H), 1.87 (m, 1H), 1.67 (m, 3H). 171.2 F4 J(A) 8.05 (brs, 1H), 7.91 (brs, 2H), 3.10 - 3.3 (m, 5H), 2.67 (m, 2H), 2.0 - 2.2 (m, 4H), 1.85 (m, 1H), 1.67 (m, 3H), 1.07 (t, J = 7.0 Hz, 3H). 168.2 F5 J(A) 7.94 (brs, 3H), 4.90 (brs, 1H), 3.61 - 3.69 (m, 1H), 3.30 (t, J = 6.9 Hz, 2H), 2.69 (m, 2H), 2.58 (m, 1H), 2.06 - 2.18 (m, 4H), 1.85 - 1.97 (m, 1H), 1.71 - 1.77 (m, 3H), 0.80 (m, 2H), 0.67 (m, 2H). 197.2 F6 J(A) 85 No NMR 157.2 F7 J(A) 86 No NMR 173.2 [Example] [L1] [:]2-Chloro-5-cyclopropyl-4-(methanesulfonyl)pyrimidine.

[0314] 5-Bromo-2-chloro-6-(methylthio)pyrimidine (25.0 g, 105 mmol) and cyclopropyl pyrimidine were treated with K3PO4 (66.7 g, 315 mmol) A suspension of acid (13.7 g, 158 mmol) in toluene:H₂O (9:1) (650 mL) was prepared. The reaction mixture was purged with nitrogen for 20 min, followed by the addition of tricyclohexylphosphine (5.9 g, 21 mmol) and Pd(OAc)₂ (2.35 g, 10.50 mmol). 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 silicone column chromatography (0% to 10% EtOAc / hexane) to give 14.0 g (66% yield) of 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (s, 1H), 2.58 (s, 3H), 1.67 (m, 1H), 1.03 (m, 2H), 0.67 (m, 2H); MS (ESI) m / z: 201.0 (M+H+).

[0315] A solution of 2-chloro-5-cyclopropyl-6-(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 heated to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated aqueous NaHCO3 solution (2 × 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-chloro-5-cyclopropyl-6-(methylsulfony)pyrimidine (3.6 g, 86% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 2.89 (s, 3H), 2.16 (m, 1H), 1.16 (m, 2H), 0.93 (m, 2H); MS (ESI) m / z: 217.0 (M+H+). [Example] [L2] [:]4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine.

[0316] A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 g, 0.46 mol) in 2 L of ether 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 thiomethoxide (49 g, 0.94 mol) was added at 0 °C, and the reaction mixture was heated to room temperature and stirred for 48 h. The reaction mixture was quenched with 2 N HCl in an ice-water bath, followed by extraction with Et2O (3 × 500 mL). The combined organic extracts were washed with water (500 mL) at 35 °C, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 100 g (95% yield) of 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s 1H), 2.62 (s 3H). [General Method] [K] [:] [Substitution reaction] [:] [ ] intermediate [K20]:N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine

[0317] 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine ( [L2], 0.50 g, 2.1 mmol) in DMF (10 mL) solution cooled to 0 °C, was reacted with N-(3-aminopropyl)cyclobutylmethylamine HCl salt ( [F1] (0.50 g, 2.4 mmol) and DIEA (1.1 mL, 6.4 mmol) were suspended in DMF (10 mL) and slowly heated to room temperature while stirring for 18 hours. The mixture was concentrated to dryness and the residue was purified by silicone column chromatography (15 to 40% EtOAc / hexane, 20 column volumes (CV)) to give N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine (0.52 g, 70% yield) as a white solid. MS (ESI) m / z: 349.2 (M+H+).

[0318] Using the general method K described above, prepare the intermediates listed in Table G below. [, , ] [ ] [surface] [G.] Instance number intermediate Yield (%) NMR 1H NMR (DMSO-d 6, 500 MHz) LC-MS (m / z: M+H+) K1 52 7.69 (s, 2H), 7.45 (brs, 1H), 3.37 (m, 2H), 3.09 (m, 2H), 2.97 (m, 1H), 2.10 (m, 2H), 2.00 (m, 2H), 1.88 (m, 1H), 1.73 (m, 1H), 1.64 (m, 2H), 1.52 (m, 1H), 0.89 (m, 2H), 0.54 (m, 2H). 309.2 K2 72 No NMR data 323.2 K3 83 7.69 (d, J = 6.6 Hz, 1H), 7.46-7.52 (m, 1H), 3.13-3.40 (m, 7H), 2.03-2.18 (m, 3H), 1.66-1.95 (m, 5H), 1.48-1.56 (m, 1H), 1.02 (m, 3H), 0.89 (m, 2H), 0.56 (m, 2H)。 337.2 K4 87 7.68 (s, 1H), 7.39-7.48 (m, 1H), 3.53 (t, J = 7.4 Hz, 1H), 3.27-3.43 (m, 3H), 2.82-3.12 (m, 3H), 1.83-1.92 (m, 2H), 1.69 (m, 1H), 1.48 (m, 1H), 0.86 (m, 2H), 0.70 (d, J = 6.3 Hz, 2H), 0.67 (m, 1H), 0.61 (m, 1H), 0.53 (m, 2H)。 309.2 K5 60 7.69 (s, 1H), 7.43-7.47 (m, 1H), 3.27-3.41 (m, 4H), 2.70-3.00 (m, 4H), 1.67-1.87 (m, 2H), 1.51 (m, 1H), 0.91-1.00 (m, 6H), 0.89 (m, 2H), 0.54(m, 2H)。 311.2 K6 93 7.69 (s, 1H), 7.46-7.51 (m, 1H), 3.32-3.38 (m, 4H), 2.98 (s, 3H), 1.72-1.78 (m, 2H), 1.47-1.52 (m, 1H), 1.17 (s, 9H), 0.86-0.90 (m, 2H), 0.53-0.56 (m, 2H). 325.2 K7 92 No NMR data 359.2 K8 56 8.14 (s, 1H), 7.90 (t, J = 5.7 Hz, 1H), 7.65 (t, J = 5.7 Hz, 1H), 3.34 (q, J = 6.5 Hz, 2H), 3.05 (q, J = 6.4 Hz, 2H), 2.96 (p, J = 8.4 Hz, 1H), 2.06-2.14 (m, 2H), 1.99 (m, 2H), 1.81-1.90 (m, 1H), 1.73 (m, 1H), 1.63 (m, 2H). 303.2 K9 81 8.05 (s, 1H), 7.26 (brs, 1H), 3.46 (m, 4H), 3.31 (m, 1H), 3.02 (s, 3H), 2.32 (m, 2H), 2.19 (m, 2H), 1.97 (m, 1H), 1.80 (m, 1H), 1.68 (m, 2H). 317.2 K10 90 No NMR data 303.2 K11 71 8.23 (s, 1H), 7.73 (brs, 1H), 7.67 (brs, 1H), 3.33 (m, 2H), 3.05 (m, 2H), 2.10 (m, 2H), 2.01 (m, 3H), 1.90 (m, 1H), 1.73 (m, 1H), 1.62 (m, 2H). 347. K12 63 8.18 (s, 1H), 5.99 (brs, 1H), 3.67 (t, J = 6.8 Hz, 2H), 3.34 (s, 3H), 3.26 (m, 2H), 3.06 (m, 1H), 2.31 (m, 2H), 2.15 (m, 2H), 1.97 (m, 1H), 1.95 (m, 3H). 361.2 363.2 K13 8.23 (s, 1H), 7.68 (m, 1H), 3.34 (m, 4H), 3.02 (s, 3H), 2.86 (m, 1H), 1.64 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H). 349.2 359.2 K14 82 No NMR 363.2 365.2 K15 80 No NMR 347.0 349.0 K16 58 8.31 (s, 1H), 7.67 (brs, 1H), 7.39 (t, J = 5.2 Hz, 1H), 3.34 (m, 2H), 3.04 (m, 2H), 2.95 (m, 1H), 2.11 (m, 2H), 2.01 (m, 2H), 1.87 (m, 1H), 1.74 (m, 1H), 1.60 (t, J = 6.6 Hz, 2H). 395.2 K17 100 No NMR 363.2 K18 33 8.25 (s, 1H), 7.49 (brs, 2H), 3.42 (m, 2H), 3.07 (m, 2H), 2.47 (s, 3H), 1.65 (t, J = 6.64 Hz, 2H), 1.08 (s, 9H). 351.3 K19 36 8.24 (s, 1H), 7.77 (t, J = 5.2 Hz, 1H), 7.53 (t, J = 4.8 Hz, 1H) 3.42 (m, 2H), 3.05 (m, 2H), 2.50 (m, 1H),...

Claims

1. A method for preparing a compound of formula I-1 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof: Formula I-1 Wherein: The A group is selected from the following groups: phenyl, pyridyl, and 5-membered heteroaryl; the R1 group is selected from the following groups: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorine groups as appropriate; the R2 group is selected from the following groups: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, and C1-C5 alkoxy-C2-C5 alkyl, wherein each of the C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy may be substituted by one, two, or three independently occurring fluorine or cyano groups as appropriate; R3 is selected from the group consisting of: H, halogens, C1-C6 alkyl and C1-C6 alkoxy groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may be substituted with one or more independently occurring fluorines as appropriate; R4 is selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p-NR6R9, C(O)-NR6R9, 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, as appropriate, another ring nitrogen or oxygen, wherein B may be substituted with R7 on one or more usable carbons and may be substituted with R9 on usable nitrogen as appropriate; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, as appropriate, another ring nitrogen or oxygen, wherein D may be substituted with R7 on one or more usable carbons and may be substituted with R9 on usable nitrogen as appropriate; R7 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently occurring fluorines, or two R7s may be attached to the atoms to which they are attached to form a side oxygen group; R6 covered by formula I-1 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines, as appropriate; The R6 group covered by R4 or V is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted by one or more independently occurring fluorines;The R9 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; and the R5 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R10 is independently selected from the following groups of components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently appearing fluorines, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL series is selected from the following groups of components: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12, wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be substituted by one, two or three independently appearing fluorines, depending on the situation; U is N or CR13; V series is selected from the following groups of components: oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R11 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R12 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R13 is selected from H and C1-C3 alkyl; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate, or two R34s are connected to the carbon atom to form a C3-C6 cycloalkyl; L is -(C(R10)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 constraints are: when m is 0, R4-system C is connected to ring A; when m is 1, R4-system C is connected to L; and when m is 2 or 3, R4-system N is connected or C is connected to L; and other constraints are: when r is 0 and q is 1, then U is not CR13 and V is not O; and when r or q is 1, then U is not N and V is not O or NR6; The method comprises: reacting a compound of formula K or J (t=1): with a compound of formula D: where t is 1.

2. The method of claim 1, comprising reacting a compound of formula K or J (t=1) with a compound of formula D: i) for the compound of formula K, the method comprising reacting in a polar solvent at a temperature ranging from ambient to 150°C, under microwave heating as appropriate, and in the presence of 1,4-dioxane containing an acid of 4 N HCl as appropriate; or ii) for the compound of formula J (t=1), the method comprising reacting in a polar solvent at a temperature ranging from ambient to 150°C, under microwave heating as appropriate, and in the presence of an acid, wherein the acid is 1,4-dioxane or 4 N HCl in pTSA.

3. The method of claim 1, wherein when formula I-1 further comprises a nitrogen protecting group on R4, the method further comprises protecting the nitrogen protecting group under acidic conditions to obtain the compound of formula I-1, the method further comprising, where appropriate: i) reacting the compound of formula I-1 with sodium cyanoborohydride or sodium triethoxyborohydride and an aldehyde or ketone in a polar solvent of MeOH in the presence of a catalytic amount of acetic acid to obtain the compound of formula I-1, wherein R4 contains a nitrogen substituted with an alkyl or cycloalkyl group; or ii) reacting the compound of formula I-1 with an acetochlor or sulfonyl chloride to obtain the compound of formula I-1, wherein R4 contains a nitrogen substituted with an acetochlor or sulfonyl group.

4. The method of claim 1 further comprises: reacting a compound of formula H, wherein n, R6 and RL are as defined in formula I-1, with a compound of formula L-II or L-III to obtain a compound of formula K, wherein R1 of formula L-II is chlorine, bromine or iodine, and R1 of formula L-III is alkyl, branched alkyl or cycloalkyl.

5. The method of claim 1 further comprises: reacting a compound of formula J with an oxidizing agent, wherein the oxidizing agent is mCPBA, to obtain a compound of formula J (t=1), and further comprising reacting a compound of formula H, wherein n, R6 and RL are as defined in formula I-1, with a compound of formula L-1 to obtain a compound of formula J, wherein R1 of formula L-1 is CHF2 or CF3.

6. A method for preparing a compound of formula I-2 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof: Formula I-2, wherein: The A group is selected from the following groups: phenyl, pyridyl, and 5-membered heteroaryl; the R1 group is selected from the following groups: halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein the C1-C5 alkyl and C3-C5 cycloalkyl may be substituted by one, two, or three independently occurring fluorine groups as appropriate; the R2 group is selected from the following groups: halogen, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, and C1-C5 alkoxy-C2-C5 alkyl, wherein each of the C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy may be substituted by one, two, or three independently occurring fluorine or cyano groups as appropriate; R3 is selected from the group consisting of: H, halogens, C1-C6 alkyl and C1-C6 alkoxy groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may be substituted with one or more independently occurring fluorines as appropriate; R4 is selected from the group consisting of: B, D, NR6R9, NR6-(C(R10)2)p-NR6R9, C(O)-NR6R9, 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, as appropriate, another ring nitrogen or oxygen, wherein B may be substituted with R7 on one or more usable carbons and may be substituted with R9 on usable nitrogen as appropriate; D is selected from C-linked heterocyclic groups and heteroaryl groups having at least one nitrogen and, as appropriate, another ring nitrogen or oxygen, wherein D may be substituted with R7 on one or more usable carbons and may be substituted with R9 on usable nitrogen as appropriate; R7, each time it appears, is independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R10)2)h-NR6R9, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may be substituted with one or more independently appearing fluorines, or two R7s may be attached to the atoms to which they are attached to form a side oxygen group; The R6 system covered by formula I-2 is selected from the group consisting of: H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently appearing fluorines, depending on the situation; The R6 group covered by R4 or V is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted by one or more independently occurring fluorines;The R9 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R5, SO2R5, a C-linked heterocyclic group having at least one nitrogen and, where appropriate, another cyclic nitrogen or oxygen, and a heteroaryl group, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; and the R5 group is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclic groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl may, where appropriate, be substituted with one or more independently occurring fluorine groups; R10 is independently selected from the following groups of components each time it appears: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently appearing fluorines, or two R10s may be attached to their attached carbons to form a C3-C5 cycloalkyl; RL series is selected from the following groups of components: C1-C6 alkyl and C3-C6 cycloalkyl, NR11R12, wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be substituted by one, two or three independently appearing fluorines, depending on the situation; U is N or CR13; V series is selected from the following groups of components: oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R11 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R12 is selected from the group consisting of H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate; R13 is selected from H and C1-C3 alkyl; R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted with one or more independently occurring fluorines as appropriate, or two R34s are connected to the carbon atom to form a C3-C6 cycloalkyl; L is -(C(R10)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 constraints are that when m is 0, R4-system C is connected to ring A; when m is 1, R4-system C is connected to L; and when m is 2 or 3, R4-system N is connected or C is connected to L; and other constraints are that when r is 0 and q is 1, then U is not CR13 and V is not O; and when r or q is 1, then U is not N and V is not O or NR6; The method comprises: reacting a compound of formula M with a compound of formula D.

7. The method of claim 6, wherein when formula I-2 further comprises a nitrogen protecting group on R4, the method further comprises protecting the nitrogen protecting group under acidic conditions to obtain the compound of formula I-2, the method further comprising, where appropriate: i) reacting the compound of formula I-2 with sodium cyanoborohydride or sodium triethoxyborohydride and an aldehyde or ketone in a polar solvent of MeOH in the presence of a catalytic amount of acetic acid to obtain the compound of formula I-2, wherein R4 contains a nitrogen substituted with an alkyl or cycloalkyl group; or ii) reacting the compound of formula I-2 with an acetochlor or sulfonyl chloride to obtain the compound of formula I-2, wherein R4 contains a nitrogen substituted with an acetochlor or sulfonyl group.

8. The method of claim 6 further comprises: reacting a compound of formula H with a compound of the following formula to obtain a compound of formula M: wherein n, R1, R6 and RL are as defined in formula I-2.

9. The method of any one of claims 1 to 8, wherein the compound of formula D is of formula DIi, formula DI-ii, formula DI-iii, formula D-II-i, formula D-II-ii, formula D-II-iii, formula D-III-i, formula D-III-ii, formula D-III-iii, formula D-IV-i, formula D-IV-ii, formula D-IV-iii, formula DV, formula D-VI, formula D-VII-i, formula D-VII-ii, formula D-VIII-i, formula D-VIII-ii, formula D-IX, formula DXi, formula DX-ii, formula D-XI, formula D-XII, formula D-XIII, formula D-XIV, formula DX, formula D-XVI, formula D-XVII, formula D-XVIII-i, or formula D-XVII-ii, wherein X is selected from N and CH, and Y is selected from N, CH and CF, wherein X and Y are not both N; L, R2, and R4 are defined as in Formula I-1 or Formula I-2; R2b is alkenyl, alkynyl, or cycloalkyl; and R2a is chlorine, bromine, alkyl, CN, or alkoxy; the limitation is that R4 of Formula D-VI contains nitrogen substituted with R6.

10. As in request item 1 or 6, where R4 is B.

11. As in request 10, wherein R4 is selected from the group consisting of: where u is 1 or 2.

12. As in request item 11, wherein R4 is selected from the group consisting of: .

13. As in request item 12, wherein R4 is selected from the group consisting of: .

14. As in request item 12, wherein R4 is selected from the group consisting of: .

15. As in request item 1 or 6, where R4 is D.

16. As in request item 15, wherein R4 is selected from the group consisting of: .

17. As in request item 16, wherein R4 is selected from the group consisting of: .

18. As in request item 1 or 6, where L is -(CH2)m.

19. As in request item 18, where m is 0.

20. As in request item 18, where m is 2.

21. As in request item 18, where m is 3.

22. The method of claim 1 or 6, wherein R1 is selected from the group consisting of halogens, C1-C5 alkyl groups and C3-C5 cycloalkyl groups, wherein the C1-C5 alkyl groups and C3-C5 cycloalkyl groups may be substituted with one, two or three independently occurring fluorines, as appropriate.

23. As in request item 1 or 6, where R1 is CF3.

24. As in request item 1 or 6, where R1 is CF2H.

25. The method of claim 1 or 6, wherein R1 is selected from the group consisting of chlorine, bromine and fluorine.

26. The method of claim 25, wherein R1 is bromine.

27. The method of claim 1 or 6, wherein R1 is cyclopropyl.

28. The method of claim 1 or 6, wherein R2 is selected from the group consisting of: C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl and C2-C5 alkynyl, wherein the C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl and C2-C5 alkynyl may be substituted by one, two or three independently occurring fluorines, as appropriate.

29. The method of claim 28, wherein R2 is selected from the group consisting of C1-2 alkyl and C3-4 cycloalkyl.

30. The method of claim 1 or 6, wherein the R6 system covered by formula I-1 or formula I-2 is selected from the group consisting of H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups may be substituted by one or more independently occurring fluorines, as appropriate.

31. The method of claim 1 or 6, wherein the RL group is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups, each of which may be substituted with one, two or three independently occurring fluorines as appropriate.

32. The method of request item 31, wherein RL is cyclobutyl.

33. The method of request item 30, where RL is NR11R12.

34. The method of claim 30, wherein RL is, wherein U is N or CR13; V is selected from the group consisting of oxygen, C(R34)2 and NR6; r is 0, 1 or 2; q is 1, 2 or 3; R13 is selected from H and C1-C3 alkyl; and R34 is independently selected from H, C1-C3 alkyl and C3-C5 cycloalkyl each time it appears, wherein the C1-C3 alkyl and C3-C5 cycloalkyl may be substituted by one or more independently appearing fluorines, or two R34s may be connected to the carbon to which they are attached to form a C3-C6 cycloalkyl.

35. As in request item 1 or 6, where n is 3.

36. The method of claim 1, wherein the compound of formula I-1 or a pharmaceutically acceptable salt thereof, enantiomer, stereoisomer, or tautomer is selected from the group consisting of: N-(3-((5-cyclopropyl-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amine N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentylamine, N-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino) )propyl)cyclobutanemethylamine, N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4- N-(3-((2-((1-(1-amino-2-methyl-1-sideoxypropyl-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-methoxy-4-(4-methylpiperazine- 1-(3-((2-((1-(2-cyanopropyl-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((4-methyl)) N-(3-((5-chloro-2-(((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-) -bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)N-methylcyclobutanemethylamine,N-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane methylamine, N-methyl-N-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane methylamine, N-methyl-N-(3-((2-(2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl) N-(3-((2-((1-(1-cyclopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemidine, N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-) -pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-( (1-(1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)) 5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine, 1,1-dimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)urea,N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine, and 1,1,3-trimethyl-3-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)urea, and their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers.

37. The method of claim 6, wherein the compound of formula I-2 or a pharmaceutically acceptable salt thereof, enantiomer, stereoisomer or tautomer is selected from the group consisting of: N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-6-N-morpholinylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl) N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1- N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentylamine,N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclopropane-3-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amine) N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-(3-((5-bromo) -2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-piperan-4-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl -4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethane, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethane, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethane,N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluoro-N-methylcyclobutane-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutylamine, N-(3-((2-((2-ethyl-4-(4-methyl)) Piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylpentafenamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-methylamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-methylamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin -4-yl)amino)propyl)-N-methyltetrahydro-2H-piperan-4-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-methylamine, N-(3-( (5-Bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-piperan-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-carboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-carboxamide,N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl) N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylaziridine-3-methylamine, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylaziridine-3-methylamine, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N, 1-Dimethylazacyclobutane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-methylamine, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2- ... -bromo-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane,N-(3-((2-((2-bromo-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2] [1] Octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((2-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane 、N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane-4-yl)-2-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-chloro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino) N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl))phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)) N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((4-(4-methylpiperazin-1-yl)) -2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine,N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)azacyclobutane-1-methylamine, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-1-methylamine, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazacyclobutane-1-methylamine, 3-(3-((2-((2-ethyl-4-) -(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethylazacyclobutane-1-methylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((1-(2-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl) N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethane,N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-methylamine, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)N-methylcyclobutanemethylamine, N-(3-(( 5-Chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutane carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-piperan-4-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-(( 1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3- ((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide,1-Methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((1-(2-((dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3- Methamidinium, N,1-dimethyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methamidinium, N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazacyclobutane-3-methamidinium, N,1-dimethyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amine N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-methylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-( 1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanemethylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanemethylamine, N -(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxacyclobutane-3-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazacyclobutane-3-carboxamide, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide,N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxacyclobutane-3-methylamine, ... -yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, 1-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N,1-dimethyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amine 3-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutane-3-methylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxacyclobutane-3-methylamine, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(8-methyl-8-) ... Azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazabicyclobutane-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)oxabicyclobutane-3-carboxamide,N-(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-methylazabicyclobutane-3-methylamine, N-(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)cyclobutanemethylamine, N-(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)oxetane-3-carboxymethylamine, N-(3-((5-chloro-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazabicyclomethylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutylamine, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)terpentine) acetylamine, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pentylamine, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) )amino)pyrimidin-4-yl)amino)propyl)pentafenamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pentafenamide, 3,3-difluoro-N-(3-((2-((3-methyl) 3,3-Difluoro-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-methylamine, 3,3-difluoro-N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-methylamine,3,3-Difluoro-N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)propyl)cyclobutane-1-carboxamide N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-methylamine, N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1) ,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane methylamine,N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-1-(1-methylpiperazin-4-yl)-1H- 1,2,3-Triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl) N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((5-methyl-2-(4-methylpiperidin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((5-methyl-2-(4-methylpiperidin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxetane-5-methylamine) N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-methylamine,3,3-Difluoro-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-methamide, 1-methyl-N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methamide, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin -4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino) propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazolyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane Alkyl-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, 1-methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azacyclobutane-3-methylamine, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazin-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethylamine,N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazolyl-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((4-methyl- 2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanemethane, N ...propyl)cyclobutanemethane, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol -methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)oxacyclobutane-3-carboxamide, 1-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)azacyclobutane-3-carboxamide, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-yl)amino)-5-(trifluoromethyl)pyridine-4-yl)amino)propyl)cyclobutane Methamidinium, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)oxetane-3-methamidinium, and 1-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)oxetane-3-methamidinium, and pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers thereof.