AMINOPYRIMIDINE AMIDE AUTOPHAGY INHIBITORS AND METHODS OF USE THEREOF - Patent application

Abstract

Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancer.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 62 / 862,469, filed June 17, 2019, U.S. Application No. 62 / 862,470, filed June 17, 2019, U.S. Application No. 62 / 911,739, filed October 7, 2019, and U.S. Application No. 62 / 911,740, filed October 7, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing [0001.1] This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on June 9, 2020, is named DCP-081WO_SL.txt and is 27,190 bytes in size. [Background technology]

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

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

[0005] Currently, the most widely used autophagy inhibitors are the well-known antimalarial drugs, chloroquine and hydroxychloroquine. These antimalarial drugs are thought to block autophagy by sequestering lysosomal compartments and increasing the pH of these lysosomes, thereby inactivating proteases that degrade and regenerate nutrients. These antimalarial drugs have multiple mechanisms of action beyond lysosomal inhibition and are known to induce retinopathy in patients. Therefore, there is a need for more targeted agents that selectively block autophagy without the toxicity of these antimalarial drugs. ULK1 kinase is an autophagy initiator protein and a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stresses, including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity through inhibition of mTORC1, and energy depletion activates ULK kinase activity through activation by the AMP-activated protein kinase AMPK. Importantly, kinase-free mutants of ULK kinases block the initiation of canonical autophagy, suggesting that small-molecule inhibitors of ULK kinase activity can block autophagy.

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

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

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

[0009] Mutations in the gene encoding the LRRK2 kinase are the cause of Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) and sporadic Parkinson's disease patients. The most common LRRK2 mutation in Parkinson's disease is the LRRK2 G2019S mutation. These LRRK2 mutations are gain-of-function mutations that cause overactivation of LRRK2 signaling. Autophagy is a process used by brain neurons to maintain health and homeostasis. Autophagy is a process by which cells identify, localize, and destroy aging organelles and structural elements within the cell. In particular, for proteins known to aggregate in neurons, autophagy eliminates such toxic protein aggregates to maintain neuronal health. LRRK2 activity suppresses autophagy, and the LRRK2 G2019S gain-of-function mutation further suppresses autophagy and is associated with aggressive forms of Parkinson's disease.

[0010] Increased LRRK2 kinase activity has also been 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 important in Dectin-1-mediated innate immune responses, such as NFkB pathway activation and increased TNF-alpha production in dendritic cells of Crohn's disease patients.

[0011]

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

[0012]

[0011] There is a need for new targeted therapies that inhibit autophagy and can be used in combination with MAPKAP pathway inhibitors, chemotherapeutic agents, and / or other targeted therapeutic agents. Summary of the Invention

[0013]

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

[0014] For example, the compounds provided herein have the following formula I:

[0015] [ka]

[0016] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is selected from the group consisting of phenyl and 5- or 6-membered or heteroaryl; W is CH or N; and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and optionally substituted on one or more available carbons by R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0017] [ka]

[0018] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when m is 0, R 4 is C-bonded to ring A, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0019] Also described herein is a compound represented by

[0020] [ka]

[0021] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein W is CH or N, X is CH or N, and Y is C(R 33 ) or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 33 is selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7 and R 9and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R10 each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0022] [ka]

[0023] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when X and Y are not both N, r is 0, and q is 1, then U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0024] In a further aspect, described herein is a compound of formula ID:

[0025] [ka]

[0026] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; wherein ring DD is selected from the group consisting of:

[0027] [ka]

[0028] W is CH or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and optionally substituted on one or more available carbons by R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0029] [ka]

[0030] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when m is 0, R 4 is C-bonded to the pyrazolyl ring, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it. DETAILED DESCRIPTION OF THE INVENTION

[0031]

[0016] The features and other details of the present disclosure will now be described in more detail.Specific terms employed in the specification, examples and appended claims are summarized here.These definitions should be read in light of the remainder of this disclosure as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0032] 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 of 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 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, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0033]

[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 of 2 to 6 or 3 to 4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0034]

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

[0035] As used herein, the term "alkoxyalkyl" refers to a straight-chain or branched alkyl group attached to an oxygen, which is attached to a second straight-chain or branched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups referred to herein as C1-C6 alkoxy-C1-C6 alkyl, where each alkyl group independently contains 1 to 6 carbon atoms. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

[0036]

[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 of 2 to 6 or 3 to 6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0037] As used herein, the term "cyano" refers to the radical --CN. As used herein, the term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3 to 6 or 4 to 6 carbons, referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0038] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to oxygen (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3 to 6 carbon atoms, referred to herein as C3-C6 cycloalkoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

[0039] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I. As used herein, the term "heteroaryl" refers to a monocyclic aromatic 5- or 6-membered ring system containing one or more heteroatoms, e.g., 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. When possible, the heteroaryl ring may be linked to an adjacent radical through a carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, or pyrimidine.

[0040] The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 4- to 10-membered ring structures, including monocyclic, bridged, or fused rings, which contain 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to adjacent radicals through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran.

[0041] As used herein, the term "lactam" refers to a cyclic amide of an aminocarboxylic acid having a 1-azacycloalkan-2-one structure, or an analog having unsaturation or a heteroatom replacing one or more carbon atoms of the ring. "Alpha-lactam" refers to a lactam consisting of a three-membered ring. "Beta-lactam" refers to a lactam consisting of a four-membered ring. "Gamma-lactam" refers to a lactam consisting of a five-membered ring. "Delta-lactam" refers to a lactam consisting of a six-membered ring. "Epsilon-lactam" refers to a lactam consisting of a seven-membered ring.

[0042] As used herein, the term "oxo" refers to the radical =O.

[0030] "Combination therapy" is a treatment that involves the administration of two or more therapeutic agents, eg, a compound of Formula I and a MAPKAP pathway inhibitor, to a patient in need of treatment.

[0043]

[0031] In this specification, the terms "disease," "disorder," and "condition" are used interchangeably.

[0032] "Individual," "patient," or "subject" are used interchangeably herein and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered to mammals such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0044] "MAPKAP pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996). The terms "MAPKAP pathway inhibitors" and "MAPKAP kinase inhibitors" are used interchangeably herein.

[0045] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0046]

[0035] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvent, dispersion medium, coating, isotonic and absorption delaying agent, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0047]

[0036] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0048]

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to the salt of an acidic or basic group that may be present in the compound used in the composition. The compounds contained in the present composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The compounds contained in the present composition that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. The compounds contained in the present composition that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0049] The compounds of the present disclosure may contain one or more chiral centers and therefore exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of substituents around the stereogenic carbon atom, although those of skill in the art will recognize that the structure may implicitly indicate a chiral center. The compounds described herein encompass various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, although those of skill in the art will recognize that the structure may implicitly indicate a chiral center.

[0050] As used herein, a "therapeutically effective amount" includes an amount of a subject compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in therapeutically effective amounts to treat disorders.

[0051]

[0040] As used herein, "treating" includes any effect of attenuating, reducing, modulating, or eliminating, for example, resulting in the improvement of a condition, disease, disorder, or the like.

[0052]

[0041] The present disclosure also encompasses isotopically labeled compounds that are identical to those enumerated herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P,35 S, 18 F, and 36 Cl, etc. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0053] Individual enantiomers and diastereomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by the preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures may also be resolved into their component enantiomers by well-known methods such as chiral-phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0054] compound In one aspect, the compounds provided herein have the following formula I:

[0055] [ka]

[0056] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is selected from the group consisting of phenyl and 5- or 6-membered or heteroaryl; W is CH or N; and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7and optionally substituted on one or more available carbons by R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0057] [ka]

[0058] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when m is 0, R 4 is C-bonded to ring A, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0059]

[0044] For example, also described herein is a compound represented by the following formula IA:

[0060] [ka]

[0061] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein W is CH or N, X is CH or N, and Y is C(R 33 ) or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 33 is selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12, and

[0062] [ka]

[0063] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when X and Y are not both N, r is 0, and q is 1, then U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0064] In some embodiments, W is N. In some embodiments, X is CH and Y is N. In some embodiments, X is CH and Y is C(R 33 )

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

[0066] [ka]

[0067] wherein u is 1, 2 or 3. In some embodiments, R 4 is selected from the group consisting of:

[0068] [ka]

[0069] In some embodiments, R 4 is selected from the group consisting of:

[0070] [ka]

[0071] In some embodiments, R 4 is selected from the group consisting of:

[0072] [ka]

[0073] In some embodiments, R 4 is D.

[0074] In some embodiments, R 4 is selected from the group consisting of:

[0075] [ka]

[0076] In some embodiments, L is —(CH 2 ) 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.

[0077] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0078] In some embodiments, R 2is selected from the group consisting of C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl, and C2-C5 alkynyl, wherein C1-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 2 is C 1-2 Alkyl and C 3-4 cycloalkyl.

[0079] In some embodiments, R 3 is selected from the group consisting of H, C1-C3 alkyl, and C 1- The C3 alkyl may be optionally substituted by one or more independent occurrences of fluorine.

[0080] In some embodiments, R L is selected from the group consisting of C1-C6 alkyl, and C3-C6 cycloalkyl, each of which is optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0081] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 is. In some embodiments, R L teeth,

[0082] [ka]

[0083] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0084] In some embodiments, n is 3. In some embodiments, L is —(CH 2 ) m .

[0085] [ka]

[0086] or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, or 4; and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of:

[0087] [ka]

[0088] R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0089] [ka]

[0090] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when both X and Y are not N, r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0091] In some embodiments, R1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted with 1, 2, or 3 independent occurrences of fluorine and C3-C5 cycloalkyl. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0092] In some embodiments, R 2 is selected from the group consisting of C-C cycloalkyl, C-C alkyl, and halogen. 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromo.

[0093] In some embodiments, R 3 is selected from the group consisting of H and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted by one or more independent occurrences of fluorine.

[0094] In some embodiments, R 4 is selected from the group consisting of:

[0095] [ka]

[0096] In some embodiments, R 4 is selected from the group consisting of:

[0097] [ka]

[0098] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine.

[0099] In some embodiments, R 7 is H. In some embodiments, R L is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0100] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 is. In some embodiments, R L teeth,

[0101] [ka]

[0102] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0103] In some embodiments, —N(R 3 )-C(O)-R L is selected from the group consisting of:

[0104] [ka]

[0105] In some embodiments, —N(R 3 )-C(O)-R L is selected from the group consisting of:

[0106] [ka]

[0107] In some embodiments, n is 3. In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0108] [ka]

[0109] In the formula, R 1each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0110] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0111] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0112] In some embodiments, R1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0113] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0114] [ka]

[0115] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0116] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

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

[0118] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0119] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0120] [ka]

[0121] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

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

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

[0124] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0125] In some embodiments, the compound is represented by the following formula IC:

[0126] [ka]

[0127] or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, or 4; and R 1is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of:

[0128] [ka]

[0129] R 9 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7combine with the atom to which they are attached to form oxo, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0130] [ka]

[0131] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when both X and Y are not N, r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0132] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, where C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted with 1, 2, or 3 independent occurrences of fluorine and C3-C5 cycloalkyl. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0133] In some embodiments, R 2 is selected from the group consisting of C-C cycloalkyl, C-C alkyl, and halogen. 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromo.

[0134] In some embodiments, R 3 is selected from the group consisting of H and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted by one or more independent occurrences of fluorine.

[0135] In some embodiments, R 4 is selected from the group consisting of:

[0136] [ka]

[0137] In some embodiments, R 4 is selected from the group consisting of:

[0138] [ka]

[0139] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine.

[0140] In some embodiments, R 7 is H. In some embodiments, R L is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0141] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 is. In some embodiments, R L teeth,

[0142] [ka]

[0143] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0144] In some embodiments, —N(R 3 )-C(O)-R L is selected from the group consisting of:

[0145] [ka]

[0146] In some embodiments, —N(R 3 )-C(O)-R L is selected from the group consisting of:

[0147] [ka]

[0148] [000100] In some embodiments, n is 3. [000101] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0149] [ka]

[0150] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0151] [000102] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0152] [000103] In some embodiments, R 1Each occurrence of is CF2H and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0153] [000104] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 each occurrence of is independently selected from H and C1-C3 alkyl, and R 34 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0154] [000105] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0155] [ka]

[0156] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0157] [000106] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0158] [000107] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0159] [000108] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0160] [000109] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0161] [ka]

[0162] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, and n is 3.

[0163] [000110] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0164] [000111] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3 each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0165] [000112] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence of is independently selected from C-C alkyl, C-C cycloalkyl, bromo, and chloro; 3each occurrence of is independently selected from the group consisting of H, and C-C alkyl; 9 is independently selected from H and C1-C3 alkyl, and n is 3.

[0166] [000113] Also described herein is a compound of formula ID:

[0167] [ka]

[0168] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein ring DD is selected from the group consisting of:

[0169] [ka]

[0170] W is CH or N, and R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN, where B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen and B is selected from R 7 and R 9 and D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and optionally substituted on one or more available carbons by R 9 may be optionally substituted on an available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C 2- C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10 each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbon to which they are attached to form a C3-C5 cycloalkyl, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0171] [ka]

[0172] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 11is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m -, h is 1, 2, or 3, m is 0, 1, 2, or 3, n is 2, 3, or 4, and p is 2 or 3, with the proviso that when m is 0, R 4 is C-bonded to the pyrazolyl ring, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0173] [000114] In some embodiments, W is N. In some embodiments, W is CH. [000115] In some embodiments, ring DD is selected from the group consisting of:

[0174] [ka]

[0175] [000116] In some embodiments, ring DD is selected from the group consisting of:

[0176] [ka]

[0177] [000117] In some embodiments, ring DD is:

[0178] [ka]

[0179] [000118] In some embodiments, R 4 is D. [000119] In some embodiments, R 4 is selected from the group consisting of:

[0180] [ka]

[0181] [000120] In some embodiments, R 4 is selected from the group consisting of:

[0182] [ka]

[0183] [000121] In some embodiments, R 4 is B. [000122] In some embodiments, R 4 is selected from the group consisting of:

[0184] [ka]

[0185] In the formula, u is 1 or 2. [000123] In some embodiments, R 4 is selected from the group consisting of:

[0186] [ka]

[0187] [000124] In some embodiments, R 4 is selected from the group consisting of:

[0188] [ka]

[0189] [000125] In some embodiments, L is -(CH) 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.

[0190] [000126] In some embodiments, R 4 is D and m is 0. In some embodiments, R 4 is D and m is 1. In some embodiments, R 4 is selected from D and B, and m is 2. In some embodiments, R 4 is selected from D and B, and m is 3.

[0191] [000127] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 1is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0192] [000128] In some embodiments, R 2 is selected from the group consisting of C3-C5 cycloalkyl, C1-C5 alkyl, halogen, cyano, C2-C5 alkenyl, and C2-C5 alkynyl, wherein the C1-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 2 is C 1-2 Alkyl and C 3-4 cycloalkyl. In some embodiments, R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine.

[0193] [000129] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 is. [000130] In some embodiments, R L teeth,

[0194] [ka]

[0195] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0196] [000131] In some embodiments, n is 3. [000132] In some embodiments, the compound is represented by the following formula IE:

[0197] [ka]

[0198] or a pharmaceutically acceptable salt thereof, wherein ring DD is selected from the group consisting of:

[0199] [ka]

[0200] n is 2, 3, or 4; R 1is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of:

[0201] [ka]

[0202] R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7combine with the atom to which they are attached to form oxo, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0203] [ka]

[0204] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m - and m is 0, 1, 2, or 3, with the proviso that when m is 0, R4 is C-bonded to the pyrazolyl ring, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0205] [000133] In some embodiments, ring DD is selected from the group consisting of:

[0206] [ka]

[0207] [000134] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0208] [000135] In some embodiments, R 2 is selected from the group consisting of C-C cycloalkyl, C-C alkyl, and halogen. 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromo.

[0209] [000136] In some embodiments, R 3 is selected from the group consisting of H and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted by one or more independent occurrences of fluorine.

[0210] [000137] In some embodiments, R 4 is D. [000138] In some embodiments, R 4 is selected from the group consisting of:

[0211] [ka]

[0212] [000139] In some embodiments, R 4 is selected from the group consisting of:

[0213] [ka]

[0214] [000140] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine.

[0215] [000141] In some embodiments, R7 is H. [000142] In some embodiments, R L is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0216] [000143] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 is. [000144] In some embodiments, R L teeth,

[0217] [ka]

[0218] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0219] [000145] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0220] [000146] In some embodiments, -N(R 3 )-C(O)-R L is selected from the group consisting of:

[0221] [ka]

[0222] [000147] In some embodiments, -N(R 3 )-C(O)-R L is selected from the group consisting of:

[0223] [ka]

[0224] [000148] In some embodiments, n is 3. [000149] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0225] [ka]

[0226] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl;6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 7 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0227] [000150] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0228] [000151] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 Each occurrence of is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IE.1 as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IE.2 and formula IE.3 as defined above.

[0229] [000152] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0230] [ka]

[0231] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0232] [000153] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0233] [000154] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IE.4 as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IE.5 and formula IE.6 as defined above.

[0234] [000155] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0235] [ka]

[0236] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0237] [000156] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0238] [000157] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0239] [000158] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IE.7, as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IE.8 and formula IE.9, as defined above.

[0240] [000159] In some embodiments, the compound has the formula IF:

[0241] [ka]

[0242] or a pharmaceutically acceptable salt thereof, wherein ring DD is selected from the group consisting of:

[0243] [ka]

[0244] n is 2, 3, or 4; R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of:

[0245] [ka]

[0246] R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, and R L represents C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 , and

[0247] [ka]

[0248] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is selected from the group consisting of N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, C-C alkyl and C-C cycloalkyl optionally substituted by one or more independent occurrences of fluorine, R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, and L is -(C(R 10 )2) m- and m is 0, 1, 2, or 3, with the proviso that when m is 0, R4 is C-bonded to the pyrazolyl ring, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0249] [000160] In some embodiments, ring DD is selected from the group consisting of:

[0250] [ka]

[0251] [000161] In some embodiments, R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. 1 is CF. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chloro, bromo, and fluoro. 1 is bromo. In some embodiments, R 1 is cyclopropyl.

[0252] [000162] In some embodiments, R 2 is selected from the group consisting of C-C cycloalkyl, C-C alkyl, and halogen. 2 is selected from the group consisting of C1-C2 alkyl, C3-C4 cycloalkyl, and bromo.

[0253] [000163] In some embodiments, R 3 is selected from the group consisting of H and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted by one or more independent occurrences of fluorine.

[0254] [000164] In some embodiments, R 4 is D. [000165] In some embodiments, R 4 is selected from the group consisting of:

[0255] [ka]

[0256] [000166] In some embodiments, R 4 is selected from the group consisting of:

[0257] [ka]

[0258] [000167] In some embodiments, each R 6 and R 9 is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine.

[0259] [000168] In some embodiments, R 7 is H. [000169] In some embodiments, R L is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine.

[0260] [000170] In some embodiments, R L is cyclobutyl. In some embodiments, R L is NR 11 R 12 In some embodiments, R L but,

[0261] [ka]

[0262] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 isn't it.

[0263] [000171] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0264] [000172] In some embodiments, -N(R 3 )-C(O)-R Lis selected from the group consisting of:

[0265] [ka]

[0266] [000173] In some embodiments, -N(R 3 )-C(O)-R L is selected from the group consisting of:

[0267] [ka]

[0268] [000174] In some embodiments, n is 3. [000175] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0269] [ka]

[0270] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 7is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0271] [000176] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0272] [000177] In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9each occurrence of is selected from H and C1-C3 alkyl, and R 34 Each occurrence of is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 7 is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and R 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IF.1, as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IF.2 and formula IF.3, as defined above.

[0273] [000178] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0274] [ka]

[0275] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0276] [000179] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0277] [000180] In some embodiments, R 1Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IF.4, as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IF.5 and formula IF.6, as defined above.

[0278] [000181] In some embodiments, the compound is represented by a formula selected from the group consisting of:

[0279] [ka]

[0280] In the formula, R 1 each occurrence of is independently selected from the group consisting of CF, CFH, bromo, chloro, or cyclopropyl; R 2 each occurrence of is independently selected from the group consisting of C-C alkyl, C-C cycloalkyl, and halogen; 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; 9 each occurrence of is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 34is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0281] [000182] In some embodiments, R 1 Each occurrence of is bromo and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3. In some embodiments, R 1 Each occurrence of is CF3 and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl; 9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C1-C3 alkyl, C3-C5 cycloalkyl, and n is 3.

[0282] [000183] In some embodiments, R 1 Each occurrence of is CF2H and R 2 each occurrence is independently selected from C-C alkyl and C-C cycloalkyl; R 3 is independently selected from the group consisting of H and C1-C2 alkyl; 6 is independently selected from the group consisting of H, C-C alkyl, and C-C cycloalkyl;9 each occurrence of is selected from H and C1-C3 alkyl, and R 34 is independently selected from H, C-C alkyl, C-C cycloalkyl, and n is 3. In some embodiments, the compound is represented by formula IF.7, as defined above. In some embodiments, the compound is represented by a formula selected from the group consisting of formula IF.8 and formula IF.9, as defined above.

[0283] [000184] Also described herein are compounds such as N-(3-((5-cyclopropyl-2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1 -yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((1-(2-cyanopropan-2-yl)- 3-Methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino )propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(piperidine- 4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-methyl-N-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide,N-methyl-N-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((1-(1-cyclopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide samide, N-(3-((2-((1-(1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-d3-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octane- 4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutyramide, N-(3-((2-((2-ethyl -4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclopropanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine -4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide cyclobutanecarboxamide, 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-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutyramide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylpivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino )propyl)-N-methyltetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-pyran-4-carboxamide N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, 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-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo)[2.2.1]heptan-2-yl)phenyl) N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3 -((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-bromo-2-( (2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-((1R,5S)- 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2- ((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide samide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide , N-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-( (2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidine-1-carboxamide, 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-dimethylazetidine-1-carboxamide, 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 N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)propyl)cyclobutanecarboxamide N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-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-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, 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-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-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)azetidine-3-carboxamide, N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, 1-Methyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 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)azetidine-3-carboxamide, N-(3-((2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine- 3-carboxamide, N,1-dimethyl-N-(3-((2-((3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, 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-methylazetidine-3-carboxamide, 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)cyclobutanecarboxamide, N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)propyl)cyclobutanecarboxamide 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-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)azetidine-3-carboxamide amide, 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)azetidine-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)cyclobutanecarboxamide, 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)oxetane-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-methylazeti 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)cyclobutanecarboxamide, 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)oxetane-3-carboxamide azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, 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)cyclobutanecarboxamide , 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-carboxamide, 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)-1-methylazetidine-3-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutyramide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl propyl)pivalamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)pivalamide, )amino)propyl)pivalamide, 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)pivalamide, 3,3-difluoro-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)propyl)pivalamide, 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)cyclobutane-1-carboxamide, 3,3-difluoro-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)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)propyl)cyclobutane-1-carboxamide, 3,3-difluoro-N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-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-methylpiperidine- 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-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, 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-carboxamide, 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)cyclobutanecarboxamide, 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)cyclobutanecarboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide oxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino) N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5 ... N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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)thiazol-4-yl)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-carboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3 -carboxamide, 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-carboxamide, 1-methyl-N-(3-((2-((5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)amino)propyl)cyclobutane-1-carboxamide 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)azetidine-3-carboxamide, 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)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((5-methyl- 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, 1-methyl-N-(3-((2-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)oxazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide thiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide 1-methyl-N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azetidine-3-carboxamide, N-(3-((2-((3-methyl-1- (8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyridin-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)pyridin-4-yl)amino)propyl)azetidine-3-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, 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)propyl)azetidine-1-carboxamide, 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, 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)azetidine-1-carboxamide, 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 pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

[0284] Treatment method [000185] The compounds described herein can act as an autophagy inhibitor, useful for treating disorders in patients who need treatment.Disorders can be, for example, tumors, for example solid tumors.Disorders can also be cancer.

[0285] [000186] Exemplary disorders also include gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, and colorectal cancer. The cancer treated by the methods described herein may be a metastatic cancer.

[0286] [000187] In some embodiments, the compounds described herein are useful for treating cancer caused by RAS mutations. In some embodiments, the cancer is caused by KRAS mutations. In some embodiments, the cancer has additional mutations in tumor suppressor proteins, including mutations in TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, these additional mutations occur in one or more of TP53, PTEN, CDN2A / INK4A, p16, or STAG2. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal.

[0287] [000188] In some embodiments, cellular inhibition of autophagy by a compound described herein is determined by monitoring autophagic flux, e.g., by monitoring inhibition of autophagy-mediated clearance of an mCherry / GFP-LC3 fusion protein. In some embodiments, cellular inhibition of autophagy by a compound described herein is determined by monitoring the accumulation of an autophagy protein, such as p62 or LC-3. In some embodiments, cellular inhibition of autophagy by a compound described herein is determined by a decrease in the clearance of luciferase-tagged LC3 protein. In some embodiments, cellular inhibition of autophagy by a compound described herein is determined by monitoring the decrease in cellular autophagosomes, e.g., by measuring fluorescent puncta using the autophagosome marker Cyto-ID.

[0288] [000189] In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, cellular inhibition of ULK kinase by the compounds described herein is determined in host tissues, including immune cells.

[0289] [000190] In some embodiments, in vivo inhibition of autophagy by compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates, including ATG13, ATG14, Beclin 1, or STING, in either tumor cells or non-tumor host tissues. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in host tissues, including immune cells. In some embodiments, in vivo inhibition of autophagic flux by compounds described herein can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in animals bearing pancreatic cancer. In some embodiments, in vivo inhibition of ULK kinase by compounds described herein is determined in animals bearing lung cancer. In some embodiments, in vivo inhibition of ULK kinase is determined in animals bearing colorectal cancer. In some embodiments, in vivo inhibition of autophagy by the compounds described herein is determined by inhibiting autophagic flux in tumor cells or non-tumor host tissues by monitoring the inhibition of autophagosome formation or the accumulation of autophagy proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is determined in host tissues containing immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition.

[0290] [000191] In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in xenograft studies utilizing human RAS mutant cell lines in immunodeficient mice, such as SCID or nude mice. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in xenograft studies utilizing human RAS mutant patient-derived tumor xenografts (PDX) in immunodeficient mice, such as SCID or nude mice. In some embodiments, xenograft studies include evaluation of compounds described herein in pancreatic cancer models. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in syngeneic genetically engineered mouse models (GEM) of mutant RAS cancer. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in the KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / + , Pdx-1-Cre) or a variant of the KPC model, known as the GEM syngeneic orthotopic pancreatic cancer model.

[0291] [000192] In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with MEK inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAF inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with ERK inhibitors. In some embodiments, the compounds described herein are evaluated in xenograft or GEM cancer models in combination with RAS G12C direct inhibitors.

[0292] [000193] In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in an immunocompetent mouse cancer model to assess the immunomodulatory component to the mechanism of action of ULK inhibitors. In some embodiments, the immunocompetent mouse model is the KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / + The mouse GEM syngeneic orthotopic pancreatic cancer model is known as a variant of the KPC model (Pdx-1-Cre, Pdx-1-Cre, or KPC model). In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a MEK inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a RAF inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with an ERK inhibitor. In some embodiments, the immunomodulatory properties of compounds described herein are evaluated in combination with a RAS G12C direct inhibitor.

[0293] [000194] In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced innate immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced adaptive immune response. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced activity of antigen-presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced anti-tumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is enhanced activity of effector T cells, including cytotoxic T cells.

[0294] [000195] In one embodiment, provided herein is a method of treating a disorder described herein, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the intended compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of phospho-ATG13 in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a phospho-ATG13 antibody ELISA assay prior to administration of the compound and comparing the level of phospho-ATG13 in the sample obtained before administration with the level of phospho-ATG13 in a sample obtained during or after the administration course. In some embodiments, the phospho-ATG13 is p-S318ATG13.

[0295] [000196] In one embodiment, provided herein is a method of treating a disorder described herein, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the intended compound), wherein detecting comprises contacting a sample (including but not limited to, tumor, blood, saliva, or tissue) obtained from the patient with a phospho-ATG14 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of phospho-ATG14 in the sample. In some embodiments, contemplated methods comprise optionally contacting a sample (including but not limited to, tumor, blood, saliva, or tissue) obtained from the patient before administration of the compound with a phospho-ATG14 antibody ELISA assay and comparing the level of phospho-ATG14 in the sample obtained before administration with the level of phospho-ATG14 in a sample obtained during or after the administration course. In some embodiments, the phospho-ATG14 is p-ATG14 Ser29.

[0296] [000197] In one embodiment, provided herein is a method of treating a disorder described herein, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., after the first week, two weeks, or month after administration of the intended compound), wherein detecting comprises contacting a sample obtained from the patient (including, but not limited to, tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of p62 in the sample. In some embodiments, contemplated methods include optionally contacting a sample (including, but not limited to, tumor, blood, saliva, or tissue) obtained from the patient before administration of the compound with a p62 antibody ELISA assay and comparing the level of p62 in the sample obtained before administration with the level of p62 in a sample obtained during or after the administration course.

[0297] [000198] In one embodiment, provided herein is a method of treating a disorder described herein, comprising administering a therapeutically effective amount of a compound described herein to a patient in need thereof and detecting engagement of the compound with a ULK kinase during or after the administration course (e.g., at a discrete time point, e.g., one week, two weeks, or the following month after the initial administration of the intended compound), wherein the detection comprises contacting a sample (including, but not limited to, tumor, blood, saliva, or tissue) obtained from the patient with a pBeclin antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of pBeclin in the sample. In some embodiments, contemplated methods include optionally contacting a sample (including, but not limited to, tumor, blood, saliva, or tissue) obtained from the patient before administration of the compound with a pBeclin antibody ELISA assay and comparing the level of pBeclin in the sample obtained before administration with the level of pBeclin in a sample obtained during or after the administration course.

[0298] [000199] The compounds provided herein can be administered to patients (animals and humans) in need of such treatment at dosages that will provide optimal pharmaceutical efficacy. It will be understood that the dosage required for any particular application will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concomitant medications or special diets the patient is subsequently following, and other factors that will be recognized by those skilled in the art, and that the appropriate dosage will ultimately be at the discretion of the attending physician. To treat the above-mentioned clinical conditions and diseases, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0299] [000200] Treatment can be continued for as long or as short a period as desired. The composition may be administered, for example, one to four times daily or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinitely. The treatment period can be terminated when the desired results are achieved.

[0300] Combination therapy [000201] The compounds described herein, e.g., compounds of Formula I as defined herein, can be administered in combination with one or more additional therapeutic agents to treat disorders described herein, such as cancer. For example, the present disclosure provides pharmaceutical compositions comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I as defined herein and one additional therapeutic agent are administered. In some embodiments, a compound of Formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, e.g., a pharmaceutical composition comprising a compound of Formula I as one therapeutic agent and one or more additional therapeutic agents, such as a MAPKAP pathway inhibitor or a chemotherapeutic agent. For example, the compound of Formula I defined herein and the additional therapeutic agent can be administered in a single preparation. Other combinations are also encompassed in combination therapy. Two or more drugs in combination therapy can be administered simultaneously, but this is not required. For example, the administration of a first drug (or combination of drugs) can precede the administration of a second drug (or combination of drugs) by minutes, hours, days, or weeks. Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or more weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessary, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0301] [000202] Combination therapy can also include two or more administrations of one or more of the agents used in the combination, with the component agents being administered in a different order. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, e.g., in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0302] [000203] In some embodiments, one or more additional therapeutic agents that can 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.

[0303] [000204] Exemplary MEK inhibitors include but are not limited to trametinib, selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts.Exemplary ERK inhibitors include but are not limited to ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and their pharmaceutically acceptable salts.Exemplary RAF inhibitors include but are not limited to LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and their pharmaceutically acceptable salts.Exemplary Ras inhibitors include but are not limited to AMG-510, MRTX849, and their pharmaceutically acceptable salts.

[0304] [000205] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiation therapy, antitubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, antiestrogens, antiandrogens, steroids, anti-EGFR drugs, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, antiangiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug conjugates (ADCs), immunotherapeutics including immunomodulators, targeted therapeutic agents, cancer vaccines, and CAR-T cell therapy.

[0305] [000206] In some embodiments, the additional therapeutic agent is selected from the group consisting of, but not limited to, an antitubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, an auristatin, or a maytansinoid), vinorelbine, a DNA alkylating agent (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), a DNA intercalating agent or a DNA topoisomerase inhibitor (including, e.g., an anthracycline such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin; a camptothecin such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine (5-azacytadine), The chemotherapeutic agents may include cyclosporine, gemcitabine, and methotrexate.

[0306] [000207] In some other embodiments, the additional therapeutic agent is erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, loxo292, larotrine, kinase inhibitors, including but not limited to quizartinib, antiestrogens, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane, antiandrogens, including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, steroids, including but not limited to prednisone and dexamethasone, neraparib, olaparib, talazoparib, and rucaparib PARP inhibitors including but not limited to ribamide; topoisomerase I inhibitors including but not limited to irinotecan, camptothecin, exatecan, and topotecan; topoisomerase II inhibitors including but not limited to anthracyclines, etoposide, etoposide phosphate, and mitoxantrone; histone deacetylase (HDAC) inhibitors including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat; DZNep and 5-aza-2'-deoxycytidine DNA methylation inhibitors, including but not limited to, bortezomib and carfilzomib, proteasome inhibitors, including but not limited to, thalidomide, lenalidomide, pomalidomide, biologic agents, including but not limited to, trastuzumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab, anti-PD-1, including pembrolizumab, nivolumab, pidilizumab, and cemiplimab, anti-PD-L1, including atezolizumab, avelumab, durvalumab, and BMS-936559,Anti-angiogenic drugs, including bevacizumab and aflibercept, and antibody-drug conjugates (ADCs) with payloads of DM1, DM4, MMAE, MMAF, or camptothecin, including brentuximab vedotin and trastuzumab emtansine, radiation therapy, and therapeutic vaccines, including, but not limited to, sipuleucel-T.

[0307] [000208] In some embodiments, the additional therapeutic agent is an anti-PD-1 or anti-PDL-1 therapeutic agent, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab; an anti-TIM3 (anti-HAVcr2) therapeutic agent, including but not limited to TSR-022 or MBG453; an anti-LAG3 therapeutic agent, including but not limited to leratolimab, LAG525, or TSR-033; a CD40 agonist therapeutic agent, including but not limited to anti-4-1BB (anti-CD37, anti-TNFRSF9), SGN-40, CP-870, 893, or RO7009789; an anti-CD40 agonist therapeutic agent, including but not limited to Hu5F9-G4; 47 therapeutic agent, anti-CD20 therapeutic agent, anti-CD38 therapeutic agent; immunomodulatory therapeutic agent including but not limited to STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazole, anthracyclines including but not limited to doxorubicin or mitoxantrone, hypomethylating agents including but not limited to azacitidine or decitabine; or other immunomodulatory therapeutic agents including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone.

[0308] [000209] 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 everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6, Azgly 10] acetate (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 O4-(C2H4O2) x(wherein x=1 to 2.4)], goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevac, hydroxyurea, idarubicin, ifosfamide, ibuprofen Matinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoid acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668 , EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and erbitux, cremophor-free paclitaxel, epithilone BB), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage Phage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone methicillin, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine dolamin, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, spegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0309] Pharmaceutical Compositions and Kits [000210] Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most appropriate form of administration in any particular case will depend on the degree and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral or subcutaneous administration.

[0310] [000211] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form containing one or more of the compounds described herein as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application.The active ingredient can be formulated with a conventional non-toxic pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.The active substance compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0311] [000212] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical carrier, such as conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of the compounds provided herein, or their non-toxic pharmaceutically acceptable salts. When these preformulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0312] [000213] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; and (5) solution retarding agents. (5) additives such as sorbitol, PEG-1, PEG-2, PEG-3, PEG-4, PEG-5, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-11, PEG-12, PEG-13, PEG-14, PEG-15, PEG-16, PEG-17, PEG-18, PEG-19, PEG-20, PEG-21, PEG-22, PEG-23, PEG-24, PEG-25, PEG-26, PEG-27, PEG-28, PEG-29, PEG-30, PEG-31, PEG-32, PEG-33, PEG-34, PEG-35, PEG-36, PEG-37, PEG-38, PEG-40, PEG-41, PEG-42, PEG-43, PEG-44, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49, PEG-49, PEG-49, PEG-49, PEG-48, PEG-49, PEG-49, PEG-49, PEG-49, PEG-49, PEG-49, PEG-49, PEG-49, PEG-49, PEG-41, PEG-42, PEG-44, PEG-45, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49 ...

[0313] [000214] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0314] [000215] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, and powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the subject composition, said liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrin, and mixtures thereof.

[0315] [000216] Suspensions may contain, in addition to the subject composition, suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0316] [000217] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but become liquid at body temperature, and thus will melt in the body cavity and release the active agent(s).

[0317] [000218] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0318] [000219] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0319] [000220] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0320] [000221] The compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposure of the drug to shear, which can result in degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0321] [000222] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, and can contain antioxidants, buffers, bacteriostats, solutes that render the solution isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0322] [000223] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0323] [000224] In another aspect, an enteral pharmaceutical formulation is provided, comprising the disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and predominantly soluble in intestinal fluid at a specific pH. The small intestine is the portion of the digestive tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5.

[0324] [000225] Thus, the enteric material does not dissolve until a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit Examples of suitable enteric materials include FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be easily determined in vitro. While the foregoing is a list of possible materials, one skilled in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that will meet the objectives described herein.

[0325] [000226] Advantageously, kits are provided herein for use by a purchaser in need of, for example, cancer treatment. Such kits include an appropriate dosage form, such as those described above, and instructions describing how to use such dosage form to mediate, reduce, or prevent inflammation. The instructions instruct the purchaser or a medical professional to administer the dosage form according to an administration mode known to those skilled in the art. Such kits can be advantageously packaged and sold in single or multiple kit units. One example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil with the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through the openings.

[0326] [000227] It may be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, which numbers correspond to the days of the regimen on which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, ...etc... Week 2, Monday, Tuesday, ..." etc. Other types of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or multiple tablets or capsules. Also, a daily dose of a first compound can consist of one tablet or capsule, and a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this. [Example]

[0327] [000228] The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and workup procedures, may be selected to be standard conditions for the reaction unless otherwise specified. Those skilled in the art of organic synthesis understand that the functionality present on various portions of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. The starting materials in the examples are either commercially available or readily prepared from known materials by standard methods.

[0328] [000229] The following abbreviations are used in this disclosure and have the following definitions: "ADP" is adenosine diphosphate, "Boc" is t-butyl carbonate, "CDI" is carbodiimidazole, "conc" is concentrated, "Cs2CO3" is cesium carbonate, "CuI" is copper(I) iodide, "DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCC" is N,N'-dicyclohexylcarbodiimide, "DCE" is dichloroethane, "DCM" is dichloromethane, "DIEA" is N,N-diisopropylethylamine, "DMA" is N,N-dimethylacetamide, "DMAP" is 4-(dimethylamino)pyridine, "DMF" is N,N-dimethylformamide, and "dppf" is 1,1'-bis(diphenylphosphino)ferrocene. where "DMEM" is Dulbecco's modified Eagle's medium, "DMSO" is dimethyl sulfoxide, "DPPA" is diphenylphosphoryl azide, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, "Et2O" is diethyl ether, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hour(s), "HBTU" is (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), "H2" is hydrogen gas, "HCl" is hydrochloric acid, "Hex" is hexane, "H2O" is water, "HOBt" is hydroxybenzotriazole, and "IC" is HCl. 50" is the 50% inhibitory concentration, "K2CO3" is potassium carbonate, "K3PO4" is potassium phosphate, "LiMHDS" is lithium bis(trimethylsilyl)amide, "MeCN" is acetonitrile, "MeOH" is methanol, "Me4tBuXPhos" is di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine, "MgSO4" is magnesium sulfate, "MHz" is megahertz, "min" is minute(s), "MS" is mass spectrometry, "MTBE" is methyl tert-butyl ether, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, "NaHCO3" is sodium bicarbonate, and "Na2SO4" is sodium sulfate. where "NH4Cl" is ammonium chloride, "NaSMe" is sodium thiomethoxide, "NBS" is N-bromosuccinimide, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd / C" is palladium on carbon, "Pd2(dba)3" is tris(dibenzylideneacetone)dipalladium(0), "Pd(OAc)2" is palladium(II) acetate, "Pd(PPh3)4" is tetrakis(triphenylphosphine)palladium(0), "prep-HPLC" is preparative high performance liquid chromatography, "PyBOP" is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, "RT" is room temperature, also known as "ambient temperature," and is understood to comprise the range of normal laboratory temperatures in the range of 15-25°C, and "satd." is saturated, "T3P" is n-propanephosphonic anhydride, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, "THF" is tetrahydrofuran, "TMS" is trimethylsilyl, "Tris" is tris(hydroxymethyl)aminomethane, "Xantphos" is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "X-Phos" is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and "ZnCl2" is zinc chloride.

[0329] general chemistry [000230] Exemplary compounds described herein are accessible by the general synthetic methods shown in the following schemes, including the preparation of intermediates, and the accompanying examples. Synthesis scheme

[0330] [ka]

[0331] [000231] Scheme 1 shows an exemplary preparation of amines DIi, DI-ii, and DI-iii. Amine R, which can be aliphatic or heterocyclic, can be reacted with amine R in the presence of a base (e.g., CsCO or KCO). 4 Treatment of AI with -H affords compound BI. R can be converted to R with commercially available boronic esters / boronic acids / trifluoroborates in the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction. 2a Further treatment of BI where R is Br gives compound CI. Intermediate CI can be converted to R by mild reducing conditions, such as zinc or iron metal with ammonium chloride. 2b The intermediate CI can be selectively converted to amine DIi, where R is alkenyl, alkynyl, or cycloalkyl. The intermediate CI can be completely reduced to DI-iii by palladium-catalyzed hydrogenation. 2aIntermediate BI, where is Cl, Br, alkyl, CN, or alkoxy, may be reduced to DI-ii by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0332] [000232] In Scheme 1, examples of X include N and CH, and examples of Y include N, CH, and CF, except that X and Y are not both N and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include N-linked alkyl and N-linked heterocyclyl with appropriate optional substituents as exemplified by the table of intermediates below.

[0333] [ka]

[0334] [000233] Scheme 2 shows an exemplary preparation of amines D-II-i, D-II-ii, and D-II-iii. A-II (commercially available starting material) is reacted with amine R under reductive amination conditions (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH). 4 Reaction of R with -H gives compound B-II. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, 2a Further treatment of B-II, where R is Br, with commercially available boronic esters / boronic acids / trifluoroborates gives compound C-II. Intermediate C-II can be converted to R by mild reduction conditions, such as zinc or iron metal with ammonium chloride. 2b The intermediate C-II can be selectively converted to amine D-II-i, where R is an alkenyl, alkynyl, or cycloalkyl. Intermediate C-II can be completely reduced to D-II-iii by palladium-catalyzed hydrogenation. 2a Intermediate B-II, where is Cl, Br, alkyl, CN, or alkoxy, may be reduced to D-II-ii by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0335] [000234] In Scheme 2, examples of X include N and CH, and examples of Y include N, CH, and CF, except that X and Y are not both N and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include N-linked alkyl and N-linked heterocyclyl with appropriate optional substituents as exemplified by the table of intermediates below.

[0336] [ka]

[0337] [000235] Scheme 3 shows an exemplary preparation of amines D-III-i, D-III-ii, and D-III-iii, where L is -CH-CH-. Reduction of A-III-i with a reducing agent such as DIBAL affords aldehyde A-III-ii. Another method for preparing A-III-ii is reduction of A-III-i to the corresponding alcohol, followed by mild oxidation conditions such as using MnO. Reaction of A-III-ii with amine R under reductive amination conditions (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH) affords aldehyde A-III-ii. 4 The reaction of A-III-I with -H affords compound B-III. Another method for preparing B-III is the reduction of A-III-I to the alcohol, followed by conversion of the alcohol to the sulfonate A-III-iii. The reaction of A-III-iii with amine R in the presence of a base such as triethylamine, Hunig's base, or cesium carbonate affords B-III. 4 Reaction with -H gives B-III. The reaction with commercially available boronic esters / boronic acids / trifluoroborates in the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction gives B-III. 2a Further treatment of B-III where R is Br gives compound C-III. Intermediate C-III can be converted to R by mild reduction conditions, such as zinc or iron metal with ammonium chloride. 2bmay be selectively converted to the alkenyl, alkynyl, or cycloalkyl amine D-III-iii. Intermediate C-III can be completely reduced to D-III-ii by palladium-catalyzed hydrogenation. 2a Intermediate B-III, where is Cl, Br, alkyl, CN, or alkoxy, can be reduced to D-III-i by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0338] [000236] In Scheme 3, examples of X include N and CH, examples of Y include N, CH, and CF, except that X and Y are not both N, examples of R include methyl and ethyl, and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of include N-linked alkyl and N-linked heterocyclyl with appropriate optional substituents as exemplified by the table of intermediates below, and examples of LG include mesylate and tosylate.

[0339] [ka]

[0340] [000237] Scheme 4 shows an exemplary preparation of amine D-IV, where L is a direct bond, -CH-, -CH-CH-. Reaction of A-III-i with various amines in the presence of an amide coupling reagent (e.g., CDI, DCC, EDC, HOBt, HBTU, PyBOP, or T3P), optionally in the presence of a catalytic amount of DMAP, provides amide B-IV. R with commercially available boronic esters / boronic acids / trifluoroborates in the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction 2a Further treatment of B-IV where R is Br gives compound C-IV. Intermediate C-IV can be converted to R by mild reduction conditions, such as zinc or iron metal with ammonium chloride. 2bThe intermediate C-IV can be selectively converted to amine D-IV-i, where R is alkenyl, alkynyl, or cycloalkyl. Intermediate C-IV can be completely reduced to D-IV-iii by palladium-catalyzed hydrogenation. 2a Intermediate B-IV, where is Cl, Br, alkyl, CN, or alkoxy, may be reduced to D-IV-ii by mild reducing conditions, such as zinc or iron metal with ammonium chloride.

[0341] [000238] In Scheme 4, examples of X include N and CH, examples of Y include N, CH, and CF, except that X and Y are not both N, examples of R include methyl and ethyl, and R 2 Examples of R include alkyl and cycloalkyl. 4 An example of -(CH2) m -C(O)-B and -(CH2) m -C(O)-N(R5)R6, where m is 0, 1, or 2.

[0342] [ka]

[0343] [000239] Scheme 5 shows an exemplary preparation of amine DV. BV is reacted with a boronic ester / boronic acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to give compound CV. Many boronic esters / boronic acids / trifluoroborates are commercially available, and others can be easily prepared from the corresponding carboxylic acid (see Scheme 21). Intermediate CV can be converted to amine DV by standard reduction conditions, such as palladium-catalyzed hydrogenation, or mild reduction conditions involving zinc metal and ammonium chloride.

[0344] [000240] In Scheme 5, examples of X include N and CH, examples of Y include N, CH, and CF, and R 2 Examples of R include alkyl and cycloalkyl. 4Examples of include C-linked heterocyclyl and heteroaryl with any suitable substituents as illustrated in the table of intermediates below.

[0345] [ka]

[0346] [000241] Scheme 6 shows an exemplary preparation of D-VI from C-VI-i, where R 4 contains a nitrogen-protecting group, such as a Boc group. C-VI-i can be deprotected under acidic conditions to provide the amine salt. Further treatment of the salt with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH (reductive amination conditions) affords C-VI. Intermediate C-VI can be converted to the aniline D-VI by standard reduction conditions, such as palladium-catalyzed hydrogenation, or by mild reduction conditions involving zinc metal and ammonium chloride.

[0347] [000242] In Scheme 6, examples of X include N and CH, examples of Y include N, CH, and CF, except that X and Y are not both N, examples of PG include a Boc protecting group, and R 2 Examples of R include alkyl and cycloalkyl. 4 Examples of R include heterocyclyl; 6 Examples of include alkyl and cycloalkyl with appropriate optional substituents as exemplified by the table of intermediates below.

[0348] [ka]

[0349] [000243] In some embodiments, the general pyrazole-amines D-VII-i or D-VII-ii are prepared by two methods shown in Scheme 7. In this scheme, R 4Examples of -L-linkages 7-1 or 7-2 are shown. One method involves alkylating B-VII (readily available to those skilled in the art) with commercially available 7-1 in the presence of a base (e.g., potassium carbonate, cesium carbonate, or sodium hydride) and a polar aprotic solvent (dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc.) at ambient to 150 °C to yield nitropyrazoles C-VII-i and / or C-VII-ii. An alternative preparation of D-VII-i or D-VII-ii involves the Mitsunobu reaction of B-VII with commercially available 7-2 to yield nitropyrazoles C-VII-i and C-VII-ii. It will be understood by those skilled in the art that, if produced as a mixture, C-VII-i and C-VII-ii can be separated by SFC purification, crystallization, or chromatography. Finally, hydrogenation of the nitro-pyrazoles C-VII-i and C-VII-ii in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the pyrazole-amines D-VII-i and D-VII-ii.

[0350] [000244] In Scheme 7, examples of LG include Cl and Br, and R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of C(O)NR include heterocyclyl, C(O)NR, with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 , and N.R. 6 R 9 Contains R 6 and R 9 Each of may independently be H or an alkyl group, and examples of L include -(CH) m -, m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4is N- or C-bonded to L.

[0351] [ka]

[0352] [000245] Single R2-substituted general pyrazole-amines D-VIII-i and D-VIII-ii (i.e., R 2 Additional examples of B-VIII-i (where R is not hydrogen) are prepared as described in Scheme 8. Reaction of keto-ester A-VIII-i with either N,N-dimethylformamide dimethyl acetal or triethyl orthoformate / acetic anhydride affords A-VIII-ii (LG is a suitable leaving group required for the subsequent cyclization / pyrazole formation reaction). Reaction of A-VIII-ii with hydrazine 10-1 (readily available to those skilled in the art) in the presence of acid primarily affords either B-VIII-i or its regioisomer B-VIII-ii. The regiochemistry of the cyclization is controlled under conditions (such as temperature and solvent) well known to those skilled in the art. B-VIII-i (R 2 Conditions for the synthesis of B-VIII-ii include LG being OEt in a protic solvent (such as ethanol) at low temperature (-10°C to RT) in the presence of an acid. Conditions for the synthesis of B-VIII-ii include LG being NMe2 in a protic solvent (such as ethanol) at reflux in the presence of an acid. Either the ester B-VIII-i or B-VIII-ii is then converted to the corresponding acid C-VIII-i or C-VIII-ii using standard conditions known to those skilled in the art. Either C-VIII-i or C-VIII-ii is converted to the corresponding amine D-VIII-i or D-VIII-ii by Curtius rearrangement.

[0353] [000246] In Scheme 8, examples of LG include OMe, OEt, and N(CH3)2, and R 2 Examples of R include alkyl and cycloalkyl, which may optionally be fluorinated; 4Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L.

[0354] [ka]

[0355] [000247] Similar to Scheme 8, Scheme 9 shows the general preparation of amines D-IX. Pyrazole esters B-IX are prepared by reaction of hydrazine 10-1 with intermediate A-IX (readily available to one skilled in the art). In some embodiments, R 2 Part and R 3 The part is R 3 R 2 The ester B-IX is converted to the corresponding acid C-IX using standard conditions known to those skilled in the art. The acid C-IX is converted to the amine D-IX under standard Curtius rearrangement conditions known to those skilled in the art.

[0356] [000248] In Scheme 9, R 2 and R 3 Examples of R can independently include alkyl and cycloalkyl, where alkyl and cycloalkyl can be optionally fluorinated; 4 Examples of are heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and NR 6 R 9 Contains R 6 and R 9Each of L can independently be an alkyl group, and examples of L include -(CH) m -, m can be 0, 1, 2, or 3, and when m is 0, R 4 is C-bonded to the pyrazole, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L.

[0357] [ka]

[0358] [000249] In some embodiments, commercially unavailable hydrazine 10-1 is readily prepared by two methods shown in Scheme 10. One method involves diazotization of amine 10-2 followed by reduction using conditions well known to those skilled in the art, for example, by treatment with Sn(II)Cl in the presence of a proton source. Alternatively, hydrazine 10-1 is available from the corresponding N-tert-butoxycarbonylhydrazine 10-3 by acid-catalyzed removal of the tert-butoxycarbonyl group. Those skilled in the art will recognize that in some embodiments, conversion of carbamate 10-3 to hydrazine 10-1 is also achieved in situ within the reaction sequence. Thus, carbamate 10-3 is a substitute for hydrazine 10-1 in all schemes where hydrazine 10-1 is typically used in the presence of an acid. N-tert-butoxycarbonylhydrazine 10-3 can be prepared by reductive amination using commercially available aldehyde or ketone 10-4 and tert-butylhydrazine carboxylate.

[0359] [000250] In Scheme 10, R 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of may independently be an alkyl group, and examples of L include -(C(R7 )2) m - includes R 7 An example of is H, where m can be 0, 1, 2, or 3; when m is 0, R 4 is C-bonded to nitrogen, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L.

[0360] [ka]

[0361] [000251] In some embodiments, the general pyrazole-amines D-VII-i and D-VII-ii are prepared as shown in Scheme 11. In this scheme, R 4 An example of the -L-bond 11-1 is shown. Alkylation of B-VII (easily available to those skilled in the art) with 11-1 leads to a mixture of nitro-pyrazoles B-VII-i and B-VII-ii. These two isomers B-VII-i and B-VII-ii are separated by SFC purification, crystallization, or chromatography. Each isomer B-VII-i or B-VII-ii is activated using MsCl or TsCl to give B-VII-iii or B-VII-iv, respectively. The amine R 4 Displacement of OMs or OTs with -H provides C-VII-i or C-VII-ii, respectively. Finally, hydrogenation of nitro-pyrazoles C-VII-i or C-VII-ii under mild reducing conditions such as zinc or iron and ammonium chloride in the presence of a hydrogenation catalyst such as palladium or nickel affords the pyrazole-amines D-VII-i or D-VII-ii.

[0362] [000252] In Scheme 11, examples of LG include Cl and Br, examples of R include mesylate and tosylate, and R 2Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, m is 2 or 3, and R 4 is N-bonded.

[0363] [ka]

[0364] [000253] Scheme 12 shows the synthesis of general amines DXi and DX-ii. Thus, condensation of commercially available aldehydes with glyoxal in the presence of ammonium hydroxide gives R 2 This leads to a substituted imidazole AX. 4Examples of -L-linked 7-1 or 7-2 are shown. Nitration of imidazole AX under conditions known to those skilled in the art (e.g., nitric acid / concentrated sulfuric acid at temperatures ranging from 0°C to 100°C) affords nitroimidazole BXi. BXi is converted to a mixture of CXi and CX-ii by alkylation (7-1) or Mitsunobu reaction (7-2). In some embodiments, substituted nitroimidazoles CXi and CX-ii are available from AX via either alkylation (7-1) or Mitsunobu reaction (7-2) to give BX-ii. Subsequent nitration of BX-ii then affords CXi and CX-ii. These two regioisomers, CXi and CX-ii, can be separated by SFC purification, crystallization, or chromatography. Reduction of each of the nitro-imidazoles CXi and CX-ii 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, provides the corresponding imidazole-amines DXi and DX-ii, respectively.

[0365] [000254] In Scheme 12, examples of LG in reagent 7-1 include Cl and Br, and R 2 Examples of R include alkyl and cycloalkyl, which may optionally be fluorinated; 4 Examples of heterocyclyl and NR with appropriate optional substituents are exemplified by the table of intermediates below. 6 R 9を含み , R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, m can be 2 or 3, and L is N-bonded to the imidazole ring.

[0366] [ka]

[0367] [000255] As shown in Scheme 13, in some embodiments, substituted thiazole amines D-XI can be prepared from appropriately substituted thiazoles A-XI (readily available to one skilled in the art). This method is described in WO 2006 / 072436, the contents of which are incorporated herein by reference in their entirety. Nitration of bromothiazoles A-XI using fuming nitric acid or nitric acid and sulfuric acid affords bromo-nitrothiazoles B-XI. The bromo functionality on B-XI can be converted to various amines R using conditions well known to those skilled in the art, such as Buchwald, Ullmann, or nucleophilic aromatic substitution reactions in the presence of TEA or K2CO3. 4 -H and R4 is N-bonded C-XI Suzuki reaction of B-XI with commercially available or synthesized boronates T, including but not limited to other boron salts (see Scheme 21), can be used to provide R 4 to provide the C-bonded C-XI. Finally, hydrogenation of C-XI in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding thiazole-amine D-XI.

[0368] [000256] In Scheme 13, R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of may independently be an alkyl group.

[0369] [ka]

[0370] [000257] As shown in Scheme 14, in some embodiments, substituted thiazole amines D-XII can be prepared from appropriately substituted thiazoles A-XI (readily available to those skilled in the art). This method is described in WO2009 / 158373, WO2016 / 135163, and WO2011 / 075515, the contents of which are incorporated herein by reference in their entireties. Nitration of bromothiazole A-XI using fuming nitric acid or nitric acid and sulfuric acid affords bromo-nitrothiazoles B-XI. The bromo functionality on B-XI can be displaced with various linker (L) synthons using conditions well known to those skilled in the art, such as carbonylation (C-XII-ia), Negishi (zinc-mediated coupling conditions (C-XII-ib)), Sonogashira, or Heck coupling reactions, followed by appropriate reduction to provide the C-C bond C-XII-ic. C-XII-ia, C-XII-ib, and C-XII-ic can be reduced to primary alcohols and subsequently mesylated or tosylated to form C-XII-ii. C-XII-ii can be reacted with various nucleophiles R 4 Nucleophilic substitution with -H provides C-XII-iii. Finally, reduction of C-XII-iii in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding thiazole-amine D-XII.

[0371] [000258] In Scheme 14, examples of LG include OTs and OMs, examples of R include methyl and ethyl, and R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, and m can be 1, 2 or 3.

[0372] [ka]

[0373] [000259] In a similar reaction sequence as shown in Scheme 15, bromothiazole A-XIII (readily available to one skilled in the art) affords thiazol-amine D-XIII (Science of Synthesis, 627, 2002).

[0374] [000260] In Scheme 15, R 2 Examples of R can be alkyl, cycloalkyl, alkoxy, halogen, or CN, where alkyl, cycloalkyl, or alkoxy can be optionally fluorinated, and R 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of may independently be an alkyl group.

[0375] [ka]

[0376] [000261] As shown in Scheme 16, in some embodiments, substituted thiazole amines D-XIV can be prepared from appropriately substituted thiazoles A-XIII (readily available to one skilled in the art). This method is described in WO2009 / 158373, WO2016 / 135163, and WO2011 / 075515, the contents of which are incorporated herein by reference in their entireties. Nitration of bromothiazole A-XIII using fuming nitric acid or nitric acid and sulfuric acid provides bromo-nitrothiazole B-XIII. The bromo functionality on B-XIII can be converted to bromo-nitrothiazole B-XIII by carbonylation ( C-XIV-iaC-XIV-ii can be substituted with various R groups using conditions well known to those skilled in the art, such as the Negishi (zinc-mediated coupling conditions (C-XIV-ib)), Sonogashira, or Heck coupling reactions, followed by reduction to provide the C-C bond C-XIV-ic. C-XIV-ia, C-XIV-ib, and C-XIV-ic can be reduced to primary alcohols and subsequently mesylated or tosylated to form C-XIV-ii. ... nucleophiles R 4 Nucleophilic substitution with -H provides C-XIV-iii. Finally, reduction of C-XIV-iii in the presence of a hydrogen catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding thiazole-amine D-XIV.

[0377] [000262] In Scheme 16, examples of LG include OTs and OMs, examples of R include methyl and ethyl, and R 2 Examples of R include alkyl, cycloalkyl, alkoxy, halogen, and CN, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, and m can be 1, 2 or 3.

[0378] [ka]

[0379] [000263] Scheme 17 describes the synthesis of substituted oxazoles D-XV as reported in WO2014 / 078378, the contents of which are incorporated herein by reference in their entirety. Various acid chlorides A-XV-i can be prepared by reacting R 2Reaction with substituted aminoalkylnitrile 17-1 (readily available to one skilled in the art) provides A-XV-ii, which is converted to the oxazole-amine D-XV under acidic conditions such as acetic acid, sulfuric acid, or hydrochloric acid.

[0380] [000264] In Scheme 17, R 2 Examples of R include alkyl, cycloalkyl, and alkoxy, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 0, 1, 2 or 3.

[0381] [ka]

[0382] [000265] As shown in Scheme 18, some substituted oxazoles can be prepared from 2-diazo-3-oxo-substituted carboxylic acid esters A-XVI, as reported in Synlett, 1996, 1171, the contents of which are incorporated herein by reference in their entirety. Treatment of primary amide 18-1 (readily available to those skilled in the art) under Rh-catalyzed coupling conditions with diazoester A-XVI affords amide B-XVI. Intermediate B-XVI can be converted to oxazole ester B-XVI under dehydration cyclization conditions using a dehydrating reagent (e.g., POCl3, T3P, or Burgess's reagent). C-XVI-i Hydrolysis of the oxazole ester C-XVI-i provides the carboxylic acid C-XVI-iI, which is converted to the oxazole-amine D-XVI under a Curtius rearrangement using sodium azide or DPPA.

[0383] [000266] In Scheme 18, R2 Examples of R include alkyl, cycloalkyl, and alkoxy, where alkyl, cycloalkyl, or alkoxy may optionally be fluorinated; 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, where m can be 0, 1, 2 or 3.

[0384] [ka]

[0385] [000267] As shown in Scheme 19, in other embodiments, oxazole-amines D-XVII can be prepared from 2-haloxazoles C-XVII-i as described in WO2012 / 033195, the contents of which are incorporated herein by reference in their entirety. C-XVII-i can be reacted with various amines R under Buchwald coupling conditions to form 2-haloxazoles C-XVII-i and various amines R. 4 The reaction with -H is R 4 The Suzuki reaction of C-XVII-i with commercially available or synthesized boronates T, including but not limited to other boron salts (see Scheme 21), can be used to afford the 2-aminoalkyl-substituted oxazoles C-XVII-ii, in which R is N-linked. 4 to provide C-bonded CI-21. Hydrolysis of the oxazole ester C-XVII-ii provides the carboxylic acid, which can be converted to the oxazole-amine D-XVII under a Curtius rearrangement using sodium azide or DPPA.

[0386] [000268] In Scheme 19, R 2 Examples of R can be alkyl, cycloalkyl, alkoxy, halogen, or CN, where alkyl, cycloalkyl, or alkoxy can be optionally fluorinated, and R 4Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of R can independently be an alkyl group; 6 and R 9 Each of may independently be an alkyl group.

[0387] [ka]

[0388] [000269] In some embodiments, the general triazole-amines D-XVIII-i and D-XVIII-ii are prepared as shown in Scheme 20. In this scheme, R 4 Examples of the -L-bond 7-1 or 7-2 are shown. Triazole B-XVIII can be prepared from dinitroester A-XVIII-i by reaction with aldehyde 20-1 (easily available to those skilled in the art) using the procedures described in Asian J. of Chem., 2014, 26, 4744 and Hanneng Cailliao, 2008, 16, 49, the contents of which are incorporated herein by reference in their entirety. Alternatively, B-XVIII can be prepared by nitration of A-XVIII-ii. B-XVIII is converted to a mixture of C-XVIII-i and C-XVIII-ii by alkylation (7-1) or Mitsunobu reaction (7-2). These two regioisomers, C-XVIII-i and C-XVIII-ii, can be separated by SFC purification, crystallization, or chromatography. Reduction of nitro-triazoles CI-22 and CI-23 in the presence of a hydrogenation catalyst such as palladium or nickel, or under mild reducing conditions such as zinc or iron and ammonium chloride, affords the corresponding triazole-amines D-XVIII-i and D-XVIII-ii, respectively.

[0389] [000270] In Scheme 20, R 2Examples of R can be alkyl, cycloalkyl, alkoxy, halogen, or CN, where alkyl, cycloalkyl, or alkoxy can be optionally fluorinated, and R 4 Examples of are heterocyclyl and NR with suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 Contains R 6 and R 9 Each of L can independently be an alkyl group, and examples of L include -(CH) m -, and m can be 2 or 3.

[0390] [ka]

[0391] [000271] Scheme 21 shows a general preparation of commercially unavailable boronic acids / boronic esters T. These compounds can be readily prepared from substituted carboxylic acids. The carboxylic acid can be activated with 2-hydroxyisoindoline-1,3-dione in the presence of a coupling reagent (e.g., DCI or EtN / HATU) to afford Q. Intermediate Q can be converted to boronic ester T by nickel-catalyzed decarboxylative borylation with methyllithium and the [B2pin2Me]Li complex premixed with B2pin2 (Science, 2107, 356, 1045 (2017) and JACS, 138, 2174 (2016)), the contents of which are incorporated herein by reference in their entirety.

[0392] [000272] In Scheme 21, R 4 Examples of L include alkyl, cycloalkyl, and heterocyclyl with suitable optional substituents as exemplified by the table of intermediates below, and examples of L include -(CH) m wherein m can be 0, 1, 2, or 3; when m is 0, R 4 is C-bonded to the boronic ester, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4is N- or C-bonded to L.

[0393] [ka]

[0394] [000273] Scheme 19 shows the general preparation of LI-1 and LI-2. 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 (US 2015 / 0284341, the contents of which are incorporated herein by reference in their entirety). Difluoromethylpyrimidine L-II-1 can be converted to methylthiopyrimidine LI-1 by treatment with sodium thiomethoxide and zinc chloride in diethyl ether at a temperature below 10°C (WO 2012 / 110773, the contents of which are incorporated herein by reference in their entirety). In a manner similar to that for LI-1, trifluoromethylpyrimidine LI-2 can be prepared from commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine, L-II-2.

[0395] [ka]

[0396] [000274] Scheme 23 is a 1 A general preparation of sulfonylpyrimidines L-III (t=2) where R can be cycloalkyl is shown. Commercially available 5-bromo-2-chloro-6-(methylthio)pyrimidine is treated with a boronic ester / boronic acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to afford R 1 -substituted thiopyrimidine L-III (t=0) is obtained. 1Examples of include cycloalkyl, such as cyclopropyl. The intermediate thiopyrimidine L-III (t=0) is converted to the sulfonylpyrimidine L-III (t=2) by oxidation, for example with mCPBA.

[0397] [ka]

[0398] [000275] Scheme 24 shows the general preparation of HI. HI can be prepared by the reaction of HI with a commercially available acyl chloride (FI) in the presence of a base (Et3N or DIEA) in DCM. E-I Treatment of 1 with 1 gives the amide GI. Many acyl chlorides (FI) are commercially available, while others can be reacted with the corresponding carboxylic acid in the presence of a base (EtN or DIEA). F-I-1 and SOCl. The Boc protecting group of GI can be removed upon exposure to an acid, such as HCl or TFA. In Scheme 24, R L Examples of may include alkyl and cycloalkyl (eg, cyclobutyl).

[0399] [ka]

[0400] [000276] Scheme 25 shows the general preparation of H-II. Compound G-II can be prepared by the reaction of amine E-II with commercially available isocyanate F-II. Many isocyanates are commercially available, while others can be easily prepared from the corresponding carboxylic acid or amine (see Scheme 27). The Boc protecting group of G-II can be removed upon exposure to an acid, e.g., HCl or TFA. In Scheme 25, R 9 Examples of R may include alkyl and cycloalkyl (e.g., cyclobutyl); 6 Examples of may include H and alkyl.

[0401] [ka]

[0402] [000277] Scheme 26 shows the general preparation of H-III. Compound G-III can be prepared by reaction of amine E-III with 2,2,2-trichloroethylcarbamate F-III, which can be prepared from an amine and an acid (see Scheme 27). The Boc protecting group of G-III can be removed upon exposure to an acid, such as HCl or TFA. In Scheme 26, R 9 Examples of R may include alkyl and cycloalkyl (e.g., cyclobutyl); 6 Examples of may include H and alkyl.

[0403] [ka]

[0404] [000278] Scheme 27 shows the general preparation of isocyanates F-II and carbamates F-III. Non-commercial isocyanates F-II can be prepared from amines or carboxylic acids. Reaction of an amine with phosgene or a phosgene equivalent, such as diphosgene, triphosgene, or N,N'-dicarbonylimidazole, provides isocyanates F-II. Alternatively, isocyanates F-II can be obtained directly from carboxylic acids via the Curtius rearrangement. The acid is mixed with diphenylphosphoryl azide in a solvent, such as 1,4-dioxane or dimethylformamide, in the presence of a base, such as triethylamine, and the reaction temperature is increased to approximately 80-120 °C. Certain carbamates F-III may also be prepared via the Curtius rearrangement in the presence of a suitable alcohol, such as trichloroethanol. Trichloroethyl carbamates F-III are also readily prepared from amines by acylation with trichloroethyl chloroformate under standard conditions.

[0405] [ka]

[0406] [000279] Scheme 28 shows the general preparation of key intermediates J and K. Key intermediate J can be prepared from H (either the free base or a salt) and thiopyrimidine LI in the presence of an organic base (e.g., triethylamine or DIEA), optionally with heating, to provide key intermediate J. Similarly, key intermediate K can be prepared from H by reaction with either L-II or L-III.

[0407] [ka]

[0408] [000280] Scheme 29 shows a general preparation of key intermediate M. Treatment of H with commercially available chloroiodopyridine under Buchwald-Hartwig coupling conditions (CsCO, Xantphos, and Pd(OAc)), typically performed in an aprotic solvent (e.g., DME, DMF, DMSO, or NMP) at temperatures ranging from ambient to 140 °C, provides key intermediate M.

[0409] [ka]

[0410] [000281] Scheme 30 shows a general preparation of compounds of Formula I-1 from substitution D. Preparation of Formula I-1 can be achieved from key intermediates K and J. The first nucleophilic substitution reaction of K with an amine of Formula D is typically carried out in a polar solvent at a temperature ranging from ambient to 150°C, in some embodiments with microwave heating, optionally in the presence of an acid such as 4N HCl in 1,4-dioxane, to provide Formula I-1. The commercially unavailable compound D can be readily prepared (see Schemes 1-20). An alternative general synthesis of Formula I is achieved via a two-step process by first converting J (t=0) to the sulfoxide J (t=1) by oxidation using various oxidizing agents such as mCPBA. The sulfoxide reacts with the amine D via a nucleophilic substitution reaction, typically carried out in a polar solvent at temperatures ranging from ambient to 150° C., and in some embodiments with microwave heating, optionally in the presence of an acid such as, for example, 4N HCl in 1,4-dioxane or pTSA. 4 The compound of formula I-1 containing a nitrogen protecting group such as the Boc group above can be deprotected under acidic conditions to give the compound of formula I-1(R 4 Further treatment of IA (free base or salt) with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in the presence of a catalytic amount of acetic acid in a polar solvent such as MeOH (reductive amination conditions) can afford R 4 contains an alkyl or cycloalkyl substituted nitrogen, to give Formula I-1. For acylation and sulfonylation, the free amine (or salt) is treated with commercially available acyl chlorides or sulfonyl chlorides to give R 4 can be obtained by adding a nitrogen atom substituted with an acyl or sulfonyl to the ring of formula I-1. In Scheme 30, ring A can be phenyl or pyridyl (e.g., a ring containing X=Y) or a five-membered heteroaryl (e.g., a ring containing X-Y-X).

[0411] [ka]

[0412] [000282] Scheme 31 shows a general preparation of compounds of Formula I-2. Preparation of Formula I-2 can be achieved by a Buchwald-Hartwig coupling reaction between D and M. Many amines D that are not commercially available can be easily prepared (see Schemes 1-12). Similar to that shown in Scheme 30, reductive alkylation, acylation, and sulfonylation can be carried out to provide Formula I-2 after deprotection of Formula I-2 containing a nitrogen protecting group such as a Boc group. In Scheme 31, ring A can be phenyl or pyridyl (e.g., a ring containing X=Y) or a five-membered heteroaryl (e.g., a ring containing X1-Y-X2).

[0413] [000283] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were made: Preparation of intermediates [000284] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were made: General Method A: Aromatic Nucleophilic Substitution: Intermediate A1: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine

[0414] [ka]

[0415] [000285] A mixture of 2-bromo-4-fluoro-1-nitrobenzene (50 g, 227 mmol) and 1-methylpiperazine (24 g, 250 mmol) in DMF (400 mL) was treated with K2CO3 (63 g, 455 mmol) at room temperature, and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with ice water (500 mL), and the precipitated solid was filtered. The solid was further triturated with Et2O and n-pentane to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (58 g, 85% yield) as a yellow solid. 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 + ).

[0416] General Method B: Deprotection and Reductive Amination: Intermediate A2: 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0417] [ka]

[0418] [000286] A solution of tert-butyl 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A13, 2.57 g, 6.2 mmol) in MeOH (30 mL) was treated with 4 N HCl in 1,4-dioxane (16 mL, 62 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under vacuum to give 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (2.17 g, 100% yield) as a white solid. The material was carried forward without further purification. A suspension of 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (1.92 g, 5.5 mmol) in DCE (25 mL) was treated with DIEA (2.9 mL, 17 mmol) and formaldehyde (1.2 mL, 17 mmol). The yellow suspension became a clear orange solution. The reaction mixture was stirred at room temperature for 10 minutes, and then acetic acid (0.63 mL, 11 mmol) was added. The orange solution became a yellow suspension and was stirred for 20 minutes. Sodium triacetoxyborohydride (2.33 g, 11 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with aqueous NaHCO3 (50 mL), and the solution was extracted with DCM (3 × 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated to give a brown solid. The brown solid was purified using silica gel column chromatography (0-15% MeOH / DCM) to give 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (1.71 g, 95% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.98(d,J=9.4 Hz,1H),7.10(d,J=2.7 Hz,1H),6.89(dd,J=9.5 and 2.7 Hz,1H),3.54(d,J=11.6 Hz,2H),3.22(brs,2H),2.99-3.04(m,2H),2.22(s,3H),1.92-1.95(m,2H),1.52-1.56(m,2H);LC-MS(ESI)m / z:326.0(M+H + ).

[0419] General Method C: Alkylation: Intermediate A3: 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine

[0420] [ka]

[0421] [000287] A mixture of 1-(3-methyl-4-nitrophenyl)piperazine hydrochloride (Boc-deprotected product A4 1.5 g, 0.58 mmol) and K2CO3 (4.0 g, 2.9 mmol) in 1,4-dioxane (20 mL) was treated with 1-fluoro-2-iodoethane (2.0 mL, 2.6 mmol) [Note: the material described is prone to instability - some solids are present in the orange liquid], tightly capped, and heated to 100 °C for 24 h. The mixture was cooled to room temperature, the solid (K2CO3) was removed via filtration, rinsed with DCM, and the filtrate was concentrated to dryness to give 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine (1.52 g, 98% yield) as a yellow oil that solidified to an amber solid on standing. 1 H NMR(400MHz,DMSO-d6):d 7.97(d,J=9.6Hz,1H),6.87-6.89(m,2H),4.61(t,J=4.9Hz,1H),4.52(t,J=4.9Hz,1H),3.41(m, 4H),2.69(t,J=4.9Hz,1H),2.63(t,J=4.9Hz,1H),2.54-2.56(m,7H),LC-MS(ESI)m / z:268.2(M+H + ).

[0422] [000288] Using General Methods A-C above, the intermediates in Table A below were prepared.

[0423] [Table A-1]

[0424] [Table A-2]

[0425] [Table A-3]

[0426] [Table A-4]

[0427] [Table A-5]

[0428] [Table A-6]

[0429] Intermediate A30: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazin-2-one

[0430] [ka]

[0431] [000289] A mixture of tert-butyl (2-aminoethyl)(methyl)carbamate (4.3 g, 24 mmol) and potassium carbonate (3.8 g, 27 mmol) in DMF (50 mL) was treated with 4-fluoro-2-bromo-1-nitrobenzene (5 g, 22 mmol) at room temperature under a N atmosphere, and the mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (200 mL), the solution was extracted with EtOAc (2 × 100 mL), and the combined organics were dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give tert-butyl (2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 66% yield) as a yellow liquid. 1 H 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 + ).

[0432] [000290] A mixture of tert-butyl (2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 15 mmol) and TEA (7.6 g, 75 mmol) in DCM (100 mL) was treated with chloroacetyl chloride (5.1 g, 45 mmol) at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL), and the solution was extracted with DCM (2 x 100 mL). The combined organics were evaporated under reduced pressure, and the crude was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give tert-butyl (2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetamido)ethyl)(methyl)carbamate (5.6 g, 66% yield) as a yellow liquid. 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 + ).

[0433] [000291] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.6 g, 12 mmol) in dioxane (100 mL) was treated with 4 N HCl in 1,4-dioxane (100 mL) at 0 °C under a N atmosphere, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure, and the crude was purified by crystallization in EtO (100 mL) to give N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (4.79 g, 99% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.75(brs,2H),8.16(m,2H),7.83(d,J=7.8 Hz,1H),4.20(s,2H),3.98(t,2H),3.20(s,2H),2.56(s,3H),1.41(s,9H);LC-MS(ESI)m / z:374.1(M+H + ).

[0434] [000292] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.0 g, 12 mmol) in DMF (50 mL) was added to 60% NaH in mineral oil (1.1 g, 25 mmol) at 0 °C under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL), the solution was extracted with EtOAc (2 x 50 mL), the combined organics were evaporated under reduced pressure, and the crude was purified by silica gel column chromatography (2% MeOH / DCM, 10 CV) to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazin-2-one (3.1 g, 76% yield) as a yellow solid.1 H 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 + ).

[0435] Intermediate A31: 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine:

[0436] [ka]

[0437] [000293] 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 water) was added in portions, and the mixture was stirred under the same conditions. Iodomethane (1.7 g, 12 mmol) was added at 0 °C, and the mixture was gradually warmed to room temperature and stirred for 2 h. The reaction was diluted with EtOAc and carefully quenched with ice-water. The mixture was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (hexane / EtOAc) to give 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine (0.76 g, 72% yield). 1 H NMR(400MHz,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 + ).

[0438] General Method D: Suzuki Coupling Reaction: Intermediate C1: 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole:

[0439] [ka]

[0440] [000294] A suspension of 4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (0.80 g, 3.0 mmol) and 4-bromo-1-methyl-1H-imidazole (0.49 g, 3.0 mmol) in a mixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated with potassium carbonate (1.26 g, 9.1 mmol) and the suspension was allowed to stir. The reaction mixture was degassed with bubbling argon for 2 minutes and treated with Pd(dppf)Cl.DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours. The reaction was diluted with water and extracted with DCM (4 x 25 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated to dryness under vacuum to give a black oil. The black oil was purified using silica gel (0-15% MeOH / DCM, 15 CV) to give 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, 47% yield). 1 H 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 + ).

[0441] [000295] Using general method D above, the intermediates in Table B below were prepared.

[0442] [Table B]

[0443] General Method E: Alkylation and Mesylation: Intermediate C1: 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate

[0444] [ka]

[0445] [000296] (A) A solution of 3-methyl-4-nitro-1H-pyrazole (15 g, 118 mmol) in acetonitrile (200 mL) was treated with 2-bromoethan-1-ol (16 g, 130 mmol) and potassium carbonate (48.8 g, 354 mmol). The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by SFC purification to give 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol. 1 H NMR(400 MHz,DMSO-d6):δ 8.72(s,1H),4.96(t,J=5.2,Hz,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).

[0446] [000297] (B) A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol (5.0 g, 29 mmol) in DCM (50 mL) was treated with triethylamine (5.8 g, 58 mmol) followed by methanesulfonyl chloride (5.0 g, 44 mmol) at 0 °C under a N atmosphere. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with cold water (20 mL). The solution was extracted with DCM (2 × 200 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate (6.0 g, 83% yield) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.88(s,1H),4.57(t,J=5.2,Hz,2H),4.46(t,J=5.2 Hz,2H),3.32(s,3H),2.45(s,3H);MS(ESI)m / z:250.2(M+H) + ).

[0447] General Method F: Nucleophilic Substitution Reactions Example C2: N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-amine

[0448] [ka]

[0449] [000298] A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate (C1, 5.0 g, 20 mmol) in dry THF (70 mL) was treated with potassium carbonate (3.8 g, 28 mmol) and 2N dimethylamine in THF (60 mL, 12 mmol) under a N2 atmosphere at 10 °C. The reaction mixture was quenched with cold water (20 mL). The solution was extracted with ethyl acetate (3 x 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)ethan-1-amine (1.9 g, 48% yield). 1 H NMR (400MHz, DMSO-d6): δ8.77 (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 + ).

[0450] General Method G: Mitsunobu Reaction: Intermediate C3: 1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine

[0451] [ka]

[0452] [000299] 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), triphenylphosphine (154.7 g, 59 mmol) was added under a nitrogen atmosphere, and the mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (12 mL, 59 mmol) was added dropwise to the above mixture over 30 minutes, and stirring was continued at room temperature for 30 hours. THF was removed under reduced pressure, and then 3N aqueous HCl (30 mL) was added. The resulting solution was washed with EtOAc (3 × 20 mL), and the aqueous layer was then basified with saturated aqueous potassium carbonate (maximum pH = 9). The solution was extracted with 10% methanol in DCM (3 × 20 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (0–10% MeOH / DCM 15 CV) to give a mixture of regioisomers. The two regioisomers were separated by SFC to give the desired isomer, 1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (2.0 g, 23% yield), as a white solid. The other regioisomer, 1-methyl-4-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (1.4 g, 15% yield), was also obtained. 1 H 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 + ).

[0453] [000300] Using general methods B, C and E-G above, the intermediates in Table C below were prepared.

[0454] [Table C-1]

[0455] [Table C-2]

[0456] [Table C-3]

[0457] [Table C-4]

[0458] [Table C-5]

[0459] Preparation of Example C29:

[0460] [ka]

[0461] [000301] A solution of 5-methyl-4-nitro-1H-pyrazole (2.0 g, 16 mmol) in DMF (15 mL) was treated in portions with sodium hydride (0.94 g, 24 mmol) over 15 minutes at 0°C under Ar. After the mixture was stirred at room temperature for 2 hours, methyl 2-bromo-2-methylpropanoate (4.3 g, 24 mmol) was added. The reaction mixture was continued to stir at room temperature for 16 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (100 mL), and the solution was then extracted with EtOAc (2 x 80 mL). The combined organics were washed with water (80 mL), 10% aqueous LiCl solution (80 mL), and anhydrous Na2SO4. 4で乾燥させ The crude was purified by flash chromatography to give methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (2.9 g, 81% yield) as a white solid. 1H NMR(500 MHz,DMSO-d6):δ 8.98(s,1H),3.65(s,3H),2.42(s,4H),1.78(s,6H);LC-MS m / z:228.2(M+H + ).

[0462] [000302] A solution of methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (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 h. The reaction mixture was concentrated, diluted with water (60 mL), and acidified to pH 4 with 1N aqueous HCl. The resulting suspension was filtered, washed with water (2 x 10 mL), and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.2 g, 81% yield) as a white solid. LC-MS m / z: 214.2 (M+H) + ).

[0463] [000303] A suspension of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.3 g, 11 mmol) in DCM (30 mL) was treated with DMF dropwise, followed by oxalyl chloride (2.8 mL, 32 mmol). The suspension was stirred at room temperature for 3 hours, and then the clear solution was concentrated. The residue was dissolved in THF (30 mL), and the solution was slowly added to a solution of NH4OH (10 mL / water (40 mL)). The suspension was stirred at room temperature for 1 hour and then concentrated. The suspension (approximately 10 mL) was diluted with water (50 mL), and the solid was filtered, washed with water, and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.1 g, 92% yield). LC-MS m / z: 213.2 (M+H) + ).

[0464] General Method H: Suzuki Coupling Reaction: Intermediate D1: 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine

[0465] [ka]

[0466] [000304] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (A21, 20 g, 67 mmol) and cyclopropylboronic acid (8.6 g, 100 mmol) in toluene:HO (9:1) (200 mL) was treated with KPO (43 g, 200 mmol), and the reaction mixture was purged with nitrogen for 20 minutes. Tricyclohexylphosphine (3.7 g, 13 mmol) and Pd(OAc) (2.2 g, 10 mmol) were added to the reaction mixture, and the reaction mixture was then stirred at 100 °C for 5 hours. The reaction mixture was diluted with water (100 mL), and the solution was extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-80% EtOAc / hexanes, 15 CV) to afford 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, 69% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.89(d,J=9.3 Hz,1H),6.85(dd,J=2.4 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 + ).

[0467] Intermediate D12: 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine

[0468] [ka]

[0469] [000305] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (A21, 30 g, 100 mmol) and potassium vinyltrifluoroborate (20 g, 150 mmol) in DMSO (210 mL) was treated with K2CO3 (42 g, 301 mmol) at room temperature, and the reaction mixture was purged with nitrogen for 15 minutes. PdCl2(dppf) (3.7 g, 5.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with cold water (300 mL), and the solution was extracted with 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 material was purified by silica gel column chromatography (0-80% EtOAc / hexanes, 10 CV) to give 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (20 g, 81% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.96(d,J=9.2 Hz,1H),7.21(m,1H),6.98(m,2H),5.77(t,J=17.2 Hz,1H),5.41(d,J=11.2 Hz,1H),3.44(t,J=4.8 Hz,4H),2.42(t,J=4.8 Hz,4H),2.21(s,3H);LC-MS(ESI)m / z:247.3(M+H + ).

[0470] [000306] Using general method H above, the intermediates in Table D below were prepared.

[0471] [Table D-1]

[0472] [Table D-2]

[0473] [Table D-3]

[0474] [Table D-4]

[0475] [Table D-5]

[0476] [Table D-6]

[0477] General Method I: Reduction (A) Intermediate E1: 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline

[0478] [ka]

[0479] [000307] A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (D1, 12 g, 46 mmol) in MeOH (60 mL) at 0 °C was treated with NH4Cl (73 g, 14 mmol), and the reaction mixture was stirred at 0 °C for 10 min. Zinc dust (30 g, 459 mmol) was slowly added to the reaction mixture in an ice-water bath (the internal temperature rose to 20 °C). After stirring for 15 min, the reaction mixture was warmed to room temperature and vigorously stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite® and washed with THF (500 mL). The filtrate was concentrated under reduced pressure to give 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline (10 g, 95%) as a dark brown sticky solid. 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 E11: 2-ethyl-4-(4-methylpiperazin-1-yl)aniline

[0480] [ka]

[0481] [000308] A solution of 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (D12, 20 g, 81 mmol) in EtOAc (200 mL) was treated with Pd / C (20 g, 10% w / w, 50% water) under a nitrogen atmosphere, and the mixture was then stirred at room temperature under hydrogen balloon pressure for 3 hours. After general workup, 2-ethyl-4-(4-methylpiperazin-1-yl)aniline (16 g, 90% yield) was obtained as a brown sticky solid. 1 H NMR(400 MHz,DMSO-d6):δ 6.61(s,1H),6.52(m,2H),4.25(brs,2H),2.89(t,J=4.4 Hz,4H),2.41(m,6H),2.19(s,3H),1.09(t,J=7.6 Hz,3H);LC-MS(ESI)m / z:219.3(M+H + ).

[0482] [000309] Using general methods I(A) and I(B) above, the intermediates in Table E below were prepared.

[0483] [Table E-1]

[0484] [Table E-2]

[0485]

Table E-3

[0486]

Table E-4

[0487]

Table E-5

[0488]

Table E-6

[0489]

Table E-7

[0490] Table E-8

[0491]

Table E-9

[0492]

Table E-10

[0493]

Table E-11

[0494] Table E-12

[0495] Coupling Method J(A) and Deprotection of Boc Group: Intermediate F1: N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride

[0496] [ka]

[0497] [000310] A solution of tert-butyl (3-aminopropyl)carbamate (5.0 g, 29 mmol) in EtOAc (100 mL) was treated with saturated NaHCO3 (aq) (100 mL), and the biphasic mixture was treated dropwise with cyclobutanecarbonyl chloride (3.6 mL, 32 mmol) and stirred at room temperature for 18 h. The mixture was extracted with EtOAc (3 x 50 mL), and the combined organics were dried over anhydrous Na2SO4 and concentrated to give tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (5.6 g, 76% yield) as a white solid. 1 H NMR (DMSO-d6, 500 MHz): δ 7.57(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 + ).

[0498] [000311] A solution of tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (5.6 g, 0.022 mol) in MeOH (100 mL) was treated portionwise with 4 N HCl in 1,4-dioxane (27 mL, 0.11 mol) and stirred at room temperature for 3 h. The solution was concentrated to dryness, resuspended in MeOH, and concentrated again (this was done twice) to give N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride (4.7 g, 100% yield) as a white solid. 1H NMR(DMSO-d6,500 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 + ).

[0499] Coupling Method J(B) and Deprotection of Boc Group: Intermediate F2: N-(3-aminopropyl)-3,3-difluoro-N-methylcyclobutane-1-carboxamide TFA salt

[0500] [ka]

[0501] [000312] 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 tert-butyl (3-(methylamino)propyl)carbamate (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 x 25 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-10% MeOH / DCM, 15 CV) to give tert-butyl (3-(3,3-difluoro-N-methylcyclobutane-1-carboxamido)propyl)carbamate (0.54 g, 98% yield), which was dissolved in DCM (6 mL) and 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-carboxamide TFA salt (100% yield).

[0502] [000313] Using general method J above, the intermediates in Table F below were prepared.

[0503] [Table F]

[0504] Example L1: 2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine

[0505] [ka]

[0506] [000314] A suspension of 5-bromo-2-chloro-6-(methylthio)pyrimidine (25.0 g, 105 mmol) and cyclopropylboronic acid (13.7 g, 158 mmol) in toluene:HO (9:1) (650 mL) was treated with KPO (66.7 g, 315 mmol). The reaction mixture was purged with nitrogen for 20 minutes, and then tricyclohexylphosphine (5.9 g, 21 mmol) and Pd(OAc) (2.35 g, 10.50 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-10% EtOAc / hexanes) to give 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (14.0 g, 66% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ7.92(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 + ).

[0507] [000315] A solution of 2-chloro-5-cyclopropyl-6-(methylthio)pyrimidine (4.0 g, 20 mmol) in DCM (60 mL) at 0°C was treated with m-CPBA (4.8 g, 28 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (2 x 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-chloro-5-cyclopropyl-6-(methylsulfonyl)pyrimidine (3.6 g, 86% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.57(s,1H),2.89(s,3H),2.16(m,1H),1.16(m,2H),0.93(m,2H);MS(ESI)m / z:217.0(M+H + ).

[0508] Example L2: 4-chloro-2-(methylthio)-5(trifluoromethyl)pyrimidine

[0509] [ka]

[0510] [000316] A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 g, 0.46 mol) in diethyl ether (2 L) was treated dropwise with ZnCl (1.0 N in ether) (555 mL, 0.56 mol) at 0 °C, and the reaction mixture was stirred for 2 h. Sodium thiomethoxide (49 g, 0.94 mol) was added at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 48 h. The reaction mixture was quenched with 2 N HCl in an ice-water bath, and then the solution was extracted with EtO (3 × 500 mL). The combined organic extracts were washed with water (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure at 35 °C to give 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, 95% yield) as a colorless liquid. 1 H NMR (400 MHz, DMSO-d6): δ 9.01 (s 1H), 2.62 (s 3H).

[0511] General Method K: Substitution Reactions Intermediate K20: N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0512] [ka]

[0513] [000317] A solution of 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (L2, 0.50 g, 2.1 mmol) in DMF (10 mL) was cooled to 0 °C and treated with a suspension of N-(3-aminopropyl)cyclobutanecarboxamide HCl salt (F1, 0.50 g, 2.4 mmol) and DIEA (1.1 mL, 6.4 mmol) in DMF (10 mL), slowly heated to room temperature, and stirred for 18 h. The mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (15–40% EtOAc / hexane, 20 CV) to give N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.52 g, 70% yield) as a white solid. MS (ESI) m / z: 349.2 (M+H) + ).

[0514] [000318] Using general method K above, the intermediates in Table G below were prepared.

[0515] [Table G-1]

[0516] [Table G-2]

[0517] [Table G-3]

[0518] Preparation of intermediate K21. N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide

[0519] [ka]

[0520] A solution of tert-butyl (3-aminopropyl)carbamate (100 g, 57 mmol) in DCM (1.5 L) was treated with triethylamine (165 mL, 115 mmol). The mixture was cooled to 0 °C, and cyclobutanecarbonyl chloride (68 g, 57 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 h and then diluted with water (1 L). The solution was extracted with DCM (2 × 1 L). The combined organic extracts were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (140 g, 95% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 7.60(s,1H),6.7(s,1H),3.07(m,2H),2.97(m,1H),2.89(m,2H),2.10(m,2H),1.98( m,2H),1.85(m,1H),1.74(m,1H),1.46(m,2H),1.37(s,9H);MS(ESI)m / z:257.4(M+H + ).

[0521] A solution of tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (140 g, 55 mmol) in DCM (1.4 L) was treated with 4 N HCl in 1,4-dioxane (426 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to give the HCl salt. The salt was triturated with diethyl ether (500 mL) followed by pentane (500 mL), and the solid was filtered and dried under vacuum to give N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride (105 g, 99% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.00(m,3H),7.90(brs,1H),3.15(m,2H),3.08(m,1H),2.73(m,2H),2.12(m,2H),1.97(m,2H),1.88(m,1H),1.76(m,3H).

[0522] A solution of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.0 g, 3.2 mmol) and N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride (0.68 g, 3.58 mmol) in toluene (10 mL) was treated with CsCO (2.6 g, 8.1 mmol) and the mixture was added at room temperature. The reaction mixture was purged with nitrogen gas for 15 minutes, and then PdCl(dppf)DCM complex (0.26 g, 0.32 mmol) was added. The reaction mixture was heated at 80 °C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-3% DCM / MeOH, 15 CV) to give N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide (0.2 g, 18% yield) as a yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 8.18(s,1H),7.7(brs,1H),6.9(t,J=5.8 Hz,1H),6.83(s,1H),3.26(m,2H),3.08(m,2H),2.97(m,1H),2.11(m,2H),2 .00(m,2H),1.87(m,1H),1.75(m,1H),1.58(m,2H);MS(ESI)m / z:336.1(M+H + ).

[0523] General method M: Oxidation Intermediate M1: N-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0524] [ka]

[0525] [000319] A solution of N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (K20, 0.30 g, 0.86 mmol) in DCM (4.3 mL) was cooled to 0°C, treated with mCPBA (0.23 g, 1.0 mmol), and allowed to warm to room temperature upon expiration of the cooling bath. The mixture was stirred at room temperature for 3 h (a mixture of sulfoxide (major) and sulfone (minor) was present in a ratio of approximately 9:1). The mixture was quenched with saturated NaHCO3, and the organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to give N-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.314 g, 100% yield) as a colorless oil that solidified upon standing. MS (ESI) m / z: 365.2 (M+H + ).

[0526] [000320] Using general method M above, the intermediates in Table H below were prepared.

[0527] [Table H]

[0528] General Method N: Substitution Reaction A: Example 1: N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0529] [ka]

[0530] [000321] A mixture of 2-ethyl-4-(4-methylpiperazin-1-yl)aniline (E11, 0.053 g, 0.24 mmol), N-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutene-carboxamide (M1, 0.088 g, 0.24 mol) and some 3 Å molecular sieves in DMF (1.2 mL) was treated with 4 N HCl in 1,4-dioxane (0.060 mL, 0.24 mmol), tightly capped and heated at 80°C for 15 h. The mixture was cooled to room temperature and concentrated to dryness under high vacuum. The crude material was purified by silica gel column chromatography (3-10% MeOH / DCM, 11 CV) to give N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.068 g, 54% yield) as a pale solid. 1H NMR(400 MHz,DMSO-d6):δ 8.60(s,1H),8.02(s,1H),7.57(brs,1H),7.13(d,J=7.6 Hz,1H),6.90(t,1H),6.77(d,J=2.3 Hz,1H),6.73(dd,J=2.8 and J=8.8 Hz,1H),3.26(m,2H),3.10(brs,4H),2.93(m,3H),2.55(m,2H),2.45(brs,4H),2.25(s, 3H),2.11(q,2H),2.00(m,2H),1.88(m,1H),1.75(m,1H),1.54(brs,2H),1.07(t,J=7.6 Hz, 3H); MS (ESI) m / z: 520.3 (M + H + ).

[0531] General Method O: Substitution Reaction B Example N-Boc-21: N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0532] [ka]

[0533] [000322] A mixture of tert-butyl 4-(4-amino-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (E44, 0.097 g, 0.35 mol) and N-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (M1, 0.13 g, 0.35 mol) in anhydrous DMF (1.7 mL) was treated with several molecular sieves followed by 4 N HCl in 1,4-dioxane (0.086 mL, 0.35 mmol), tightly capped, and heated at 80°C for 16 h. The mixture was cooled to room temperature, and then the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography (2-7% MeOH / DCM, 18 CV) to give tert-butyl 4-(4-((4-((3-(cyclobutanecarboxamido)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.16 g, 81% yield) as a pale green amorphous solid. 1 H NMR(400MHz,DMSO-d6):δ 8.93(brs,1H),8.08(s,1H),7.86(brs,1H),7.63(brm,1H),7.06(brm,1H),4.20(brm,1H),4.0 3(m,2H),3.35(m,3H),2.6-3.0(m,7H),1.5-2.2(m,12H),1.39(s,9H);MS(ESI)m / z:581.4(M+H + ).

[0534] General Method P: Deprotection of the Boc Group Example 21. N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0535] [ka]

[0536] [000323] A solution of tert-butyl 4-(4-((4-((3-(cyclobutanecarboxamido)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (N-Boc-21, 0.16 g, 81% yield) in MeOH (2 mL) was treated with 4 N HCl in 1,4-dioxane (0.7 mL, 2.8 mmol) and stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in MeOH / DCM (1:1). The solution was treated with excess MP-carbonate resin and vortexed for 1 hour. The resin was removed via filtration, washed with MeOH, and the filtrate was concentrated to give N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.12 g, 86% yield) as an off-white amorphous solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.95(s,1H),8.08(s,1H),7.85(s,1H),7.67(t,J=5.7 Hz,1H),7.06(s,1H),4.11(brs,1H),3.00-3.15(m,5H),2.66(t,J=12.2 Hz,2H),2.06-2.11(m,5H),1.90-2.02(m,5H),1.68-1.89(m,5H),1.62(t,J=6.9 Hz,2H). (NH proton loss);MS(ESI)m / z:481.4(M+H + ).

[0537] General Method Q: Reductive Alkylation: Example 22: N-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0538] [ka]

[0539] [000324] A solution of N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (21, 0.050 g, 0.1 mmol) and acetone (0.25 mL, 3.40 mmol) in MeOH (0.5 mL) was treated with sodium cyanoborohydride (0.013 g, 0.21 mol), followed by catalytic acetic acid (1 drop) and stirred at room temperature for 15 hours. The mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The crude material was purified by silica gel column chromatography (4-15% (10% NHOH / MeOH) / DCM, 25 CV) to give N-(3-((2-((1-(1-isopropylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.028 g, 50% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6):δ 8.92(s,1H),8.08(s,1H),7.85(s,1H),7.64(s,1H),7.05(s,1H),3.93(br s,1H),3.37(brs,1H),2.61-2.98(m,6H),2.22(t,J=11.7 Hz,2H),2.04-2.09(m,5H),1.67-2.03(m,9 H),1.55-1.66(m,2H),0.96(d,J=6.6 Hz,6H);MS(ESI)m / z:523.4(M+H + ).

[0540] [000325] Using general methods N, O, P and Q above, the following compounds in Table I were prepared.

[0541] [Table I-1]

[0542] [Table I-2]

[0543] [Table I-3]

[0544] [Table I-4]

[0545] [Table I-5]

[0546] [Table I-6]

[0547] [Table I-7]

[0548] Preparation of Example 30: N-(3-((2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0549] [ka]

[0550] [000326] A mixture of N-(3-((2-((1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (26, 0.12 g, 0.25 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.317 g, 0.50 mmol) in EtOAc (40 mL) was treated with TEA (60 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solution was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (EtOAC / DCM) to give N-(3-((2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.036 g, 31% yield). 1 H NMR(400 MHz,DMSO-d6):δ 9.17(brs,1H),8.14(s,2H),7.64(s,1H),7.21(brs,1H),3.39(m,2H),3.03(s,2H),2.95(brs,1H),2.17(s,3 H),2.08(m,2H),1.95-2.00(m,2H),1.91(s,6 H),1.85(m,1H),1.72(m,1H),1.62(s,2H);MS(ESI)m / z:465.2(M+H + ).

[0551] Preparation of Example 31: N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide.

[0552] [ka]

[0553] A mixture of N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutane-carboxamide (K21, 0.3 g, 0.89 mmol) and 4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-amine (E39, 0.2 g, 0.98 mmol) in 1,4-dioxane (10 mL) was treated with CsCO (0.58 g, 1.78 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 15 minutes, and then X-Phos (0.1 g, 0.17 mmol) and Pd(dba) (0.081 g, 0.08 mmol) were added. The reaction mixture was heated at 90 °C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-5% DCM / MeOH, 15 CV) to give N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-cyclobutanecarboxamide (0.08 g, 19% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6):δ 8.15(s,1H),7.96(s,1H),7.86(s,1H),7.65(brs,1H),6.73(s,1H),5.92(brs,1H),5.68(s,1H),3.44(brs,4H),3.06(m,4H),2.4 1(brs,4H),2.23(s,3H),2.10(brs,5H),2.00(m,2H),1.91(s,1H),1.88(m,1H),1.75(m,1H),1.60(m,2H);MS(ESI)m / z:506.4(M+H + ).

[0554] Example 31. Biochemical Assays of ULK1.2 [000337] ULK1 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 19 nM ULK1 (Eurofins CAT# 14-959), 0.25 mg / mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). Inhibition of ULK1 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 Values ​​were calculated by fitting a four parameter sigmoidal curve to the data using Prism (GraphPad software).

[0555] ULK1 protein sequence (residues 1-314 with N-terminal His tag, SEQ ID NO: 1) MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQ NILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPVPVPSYPSSGSGSSSSSSSTSHLAS Example 32. Biochemical assays of ULK1.3 [000328] ULK1 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 0.1 nM ULK1 (from Beryllium), 0.075 mM peptide substrate (YANWLAASIYLDGKKK (SEQ ID NO: 5)), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100). Inhibition of ULK1 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 Values ​​were calculated using software routines in Prism (GraphPad software).

[0556] ULK1 protein sequence (residues 1-283, SEQ ID NO:2) MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKP QNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS Example 33. Biochemical assay of ULK2 [000329] ULK2 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 9.7 nM ULK2 (Eurofins CAT#14-772), 0.25 mg / mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100). Inhibition of ULK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was monitored continuously for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50Values ​​were calculated by fitting a four parameter sigmoidal curve to the data using Prism (GraphPad software).

[0557] ULK2 protein sequence (N-terminal GST and His-tagged residues 1-306, SEQ ID NO: 3) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFED RLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSI NKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCG SPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH

[0558] [Table 1]

[0559] [000330] In Table 1, "+" indicates an IC of greater than 1 nM and less than or equal to 25 nM. 50 "++" indicates IC > 25 nM and ≤ 100 nM 50 "+++" indicates an IC greater than 100 nM and less than or equal to 500 nM 50"++++" indicates an IC greater than 500 nM and less than 20,000 nM 50 Refers to...

[0560] Example 34. Cellular inhibition of ULK kinase substrate ATG13 protein pATG13 levels in mutant KRas A549 cells after treatment with ULK inhibitors in combination with trametinib [000331] A549 (KRAS mutant) human lung cancer cells (6,000 cells / well) were added to a 384-well tissue culture-treated plate containing 50 μL of pre-warmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin, and grown overnight at 37°C, 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control wells. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The next day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4°C for 10 min with shaking.

[0561] [000332] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background-corrected absorbance at 450 nm from the blank wells was then subtracted from the test wells. Data was compared to control wells to determine %ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0562] Example 35. pATG13 levels in mutant KRas MiaPaCa-2 cells after treatment with a ULK inhibitor in combination with trametinib [000333] MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were added to 384-well tissue culture-treated plates containing 50 μL of prewarmed DMEM medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin, and 2.5% horse serum, and grown overnight at 37°C, 5% CO2, and 95% humidity. The next day, 10 μL of medium containing trametinib or DMSO as a control was added to the wells. The final concentration of trametinib in the wells was 250 nM. A dose response of the test compound (0.6 μL per well) was added. DMSO (0.6 μL) was added to the control wells. The plate was gently shaken to mix the wells, and then incubated overnight at 37°C. The next day, the medium was aspirated, and the cells were washed with Dulbecco's phosphate-buffered saline (Gibco). The cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4°C for 10 min with shaking.

[0563] [000334] Cellular levels of phospho-serine 318 ATG13 (pATG13) were measured by ELISA. Total ATG13 antibody (Cell Signaling Cat#13273) was used to coat the wells. The plate was incubated overnight at 4°C and washed with ELISA wash buffer (Biolegend Cat#421601). The wells were then blocked with assay diluent (Biolegend Cat#421203) for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13 antibody (Rockland Immunochemicals Cat#600-401-C49) was diluted in assay diluent, added to each well, and incubated for 1 hour at room temperature. The plate wells were washed with ELISA wash buffer. Streptavidin conjugated to horseradish peroxidase (Thermo Fisher Cat#21140) was diluted in assay diluent and added to each well and incubated at room temperature for 1 hour. Plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend Cat#421101) was added to each well and incubated at room temperature for 20 minutes. The reaction was stopped with 2N sulfuric acid. Plates were analyzed on a plate reader measuring absorbance at 450 nm and 540 nm (background). Signal was calculated by first subtracting the background absorbance at 540 nm from the absorbance at 450 nm for each well. The background-corrected absorbance at 450 nm from the blank wells was then subtracted from the test wells. Data was compared to control wells to determine %ATG13 phosphorylation. IC was calculated using GraphPad Prism. 50 values ​​were calculated.

[0564] [Table 2]

[0565] [000335] In Table 2, "+" indicates an IC of greater than 10 nM and less than or equal to 100 nM. 50 "++" indicates an IC greater than 100 nM and less than or equal to 300 nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 Refers to...

[0566] Example 36. Biochemical Assay of LRRK2 (SEQ ID NO: 4) [000336] LRRK2 kinase activity was determined spectrophotometrically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al. Science (2000) 289:1938-1942). Assays were performed in 384-well plates (final volume 100 μL) using 26.4 nM LRRK2 (Thermo Fisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ (SEQ ID NO: 6)), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100). Inhibition of LRRK2 was measured by adding serially diluted test compounds (final assay concentration 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). Reaction rates were calculated using a 2-3 hour time frame. The reaction rate at each compound concentration was converted to percent inhibition using controls (i.e., reactions without test compound and reactions with known inhibitors) and calculated as IC 50 Values ​​were calculated using software routines in Prism (GraphPad software).

[0567] LRRK2 protein sequence (residues 970-2528, SEQ ID NO: 4)

[0568] [Table 3]

[0569] [000337] In Table 3, "+" indicates an IC of greater than 1 nM and less than or equal to 100 nM. 50 "++" indicates an IC greater than 100 nM and less than or equal to 300 nM 50 "+++" indicates an IC of over 300 nM and less than or equal to 600 nM 50 "++++" indicates an IC greater than 600 nM and less than 20,000 nM 50 Refers to...

[0570] Example 37. In vitro and in vivo evaluation of ULK inhibitors in pancreatic ductal adenocarcinoma (PDAC) [000338] ULK inhibitors were evaluated in the PDAC flux assay and showed Trp53 lox / + , LSL-Kras G12D , Rosa-rtTA LSL , p48Cre + IC of compounds in a panel of multiple PDAC cell lines, including cells derived from primary tumors 50 is determined using clonogenic 2D and 3D organoid assays in the absence or presence of trametinib.

[0571] [000339] Inhibition of autophagic flux using a flux reporter in PDAC tumors in vivo using a syngeneic orthotopic model after single and multiple doses will be evaluated.

[0572] [000340] The therapeutic efficacy of ULK inhibitors in PDAC models is evaluated by (i) assessing PDAC tumor kinetics subcutaneously, (ii) assessing PDAC tumor kinetics orthotopically in a syngeneic pancreatic model (KPC-engrafted C57 black mice), (iii) evaluating tumor growth kinetics in a syngeneic model with ULK inhibitors and MEK inhibitors, (iv) evaluating the compounds in an autotopic PDAC model, (v) evaluating histological changes in the tumor microenvironment, (vi) evaluating changes in immune cell infiltration in tumors upon inhibition with ULK inhibitors, and (vii) evaluating the efficacy of ULK inhibitors in combination with immune checkpoint blockade.

[0573] equivalent [000341] While specific embodiments have been discussed, the above specification is illustrative and not limiting. Many variations of the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, their full scope of equivalents, and the specification, and such variations.

[0574] [000342] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. Scope of claims at the time of international application [Section 1] A compound represented by: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is selected from the group consisting of phenyl and 5- or 6-membered or heteroaryl; W is CH or N; R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN; B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7 and R 9 may be optionally substituted on available nitrogen by D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7and R 9 may be optionally substituted on available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbons to which they are attached to form a C3-C5 cycloalkyl, R L is C1-C6 alkyl, and C3-C6 cycloalkyl, NR 11 R 12 , and [ka] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 is selected from the group consisting of r is 0, 1, or 2; q is 1, 2, or 3; R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl; R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, L is -(C(R 10 )2) m - and h is 1, 2, or 3; m is 0, 1, 2, or 3; n is 2, 3, or 4; p is 2 or 3; However, if m is 0, R 4 is C-bonded to ring A, and when m is 1, R 4 is C-bonded to L, and when m is 2 or 3, R 4 is N- or C-bonded to L, and further, when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, which is not [Section 2] A compound represented by: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein W is CH or N; X is CH or N; Y is C(R 33 ) or N, R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2is selected from the group consisting of 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 C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, and C1-C5 alkoxy is optionally substituted by 1, 2, or 3 independent occurrences of fluorine or cyano; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 33 is selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, each C1-C6 alkyl and C1-C6 alkoxy optionally being substituted by one or more independent occurrences of fluorine; R 4 B, D, NR 6 R 9 , N.R. 6 -(C(R 10 )2) p -NR 6 R 9 , C(O)-NR 6 R 9 , C(O)-B, C(O)-D, and CN; B is selected from N-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and B is selected from R 7 and R 9 may be optionally substituted on available nitrogen by D is selected from C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and D is selected from R 7 and R 9may be optionally substituted on available nitrogen by R 7 each occurrence is independently selected from H, C-C alkyl, C-C cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, and heteroaryl, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 10each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 10 are bonded together with the carbons to which they are attached to form a C3-C5 cycloalkyl, R L is C1-C6 alkyl, and C3-C6 cycloalkyl, NR 11 R 12 , and [ka] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 is selected from the group consisting of r is 0, 1, or 2; q is 1, 2, or 3; R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl; R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, and each C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, L is -(C(R 10 )2) m - and h is 1, 2, or 3; m is 0, 1, 2, or 3; n is 2, 3, or 4; p is 2 or 3; However, if both X and Y are not N, and r is 0 and q is 1, then U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, which is not [Section 3] 3. The compound of claim 1 or 2, wherein W is N. [Section 4] 4. The compound according to claim 1, wherein X is CH and Y is N. [Section 5] X is CH and Y is C(R 33 4. The compound according to claim 1, wherein [Section 6] R 4 The compound according to any one of claims 1 to 5, wherein is B. [Section 7] R 4 But, [ka] 7. The compound according to claim 1, wherein u is 1, 2 or 3. [Section 8] R 4 But, [ka] The compound according to any one of claims 1 to 7, selected from the group consisting of: [Section 9] R 4 But, [ka] The compound according to any one of claims 1 to 8, selected from the group consisting of: [Section 10] R 4 But, [ka] The compound according to any one of claims 1 to 7, selected from the group consisting of: [Section 11] R 4 The compound according to any one of claims 1 to 5, wherein is D. [Section 12] R 4 But, [ka] 12. The compound according to any one of claims 1 to 5 or claim 11, selected from the group consisting of: [Section 13] L is -(CH2) m The compound according to any one of claims 1 to 12, wherein [Section 14] 14. The compound according to claim 1, wherein m is 0. [Section 15] R 1 is selected from the group consisting of halogen, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by one, two, or three independent occurrences of fluorine. [Section 16] R 1 16. The compound according to claim 1, wherein is CF3. [Section 17] R 1 16. The compound according to claim 1, wherein is CF2H. [Section 18] R 1 16. The compound according to any one of claims 1 to 15, wherein is selected from the group consisting of chloro, bromo and fluoro. [Section 19] R 1 19. The compound of claim 18, wherein is bromo. [Section 20] R 1 The compound according to any one of claims 1 to 15, wherein is cyclopropyl. [Section 21] R 2 is selected from the group consisting of C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl, and C2-C5 alkynyl, wherein C1-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine. [Section 22] R 2 But C 1-2 Alkyl and C 3-4 22. The compound according to any one of claims 1 to 21, wherein the compound is selected from the group consisting of cycloalkyl. [Section 23] R 3 is selected from the group consisting of H, C1-C3 alkyl, and C 1- 23. The compound of any one of claims 1 to 22, wherein the C3 alkyl is optionally substituted with one or more independently occurring fluorines. [Section 24] R L is selected from the group consisting of C1-C6 alkyl, and C3-C6 cycloalkyl, each of which is optionally substituted by 1, 2, or 3 independent occurrences of fluorine. [Section 25] R L The compound according to any one of claims 1 to 24, wherein is cyclobutyl. [Section 26] R L But NR11 R 12 The compound according to any one of claims 1 to 23, wherein [Section 27] R L but, [ka] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; and U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 wherein r is 0, 1, or 2, q is 1, 2, or 3, and R 13 is selected from H and C1-C3 alkyl, R 34 each occurrence of is independently selected from H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbons to which they are attached to form a C3-C6 cycloalkyl, with the proviso that when r is 0 and q is 1, U is CR 13 and V is not O, and r or q is 1, then U is not N and V is O or NR 6 25. The compound of any one of claims 1 to 24, which is not [Section 28] 28. The compound according to any one of claims 1 to 27, wherein n is 3. [Section 29] A compound represented by: [ka] or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, or 4; R 1is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of: [ka] R 9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7combine with the atom to which they are attached to form oxo, R L is C1-C6 alkyl, and C3-C6 cycloalkyl, NR 11 R 12 , and [ka] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 is selected from the group consisting of r is 0, 1, or 2; q is 1, 2, or 3; R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 13 is selected from H and C1-C3 alkyl; R 34each occurrence of R is independently selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 34 are bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl, However, if both X and Y are not N, r is 0, and q is 1, then U is CR 13 If V is not O and r or q is 1, then U is not N and V is O or NR 6 is not a compound, or a pharmaceutically acceptable salt thereof. [Section 30] A compound represented by: [ka] or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, or 4; R 1 is selected from the group consisting of halogen, cyano, C1-C5 alkyl, and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 2 is selected from the group consisting of C1-C2 alkyl and C3-C4 cycloalkyl, and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R 3 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 4 is selected from the group consisting of: [ka] R 9are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5 , C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 5 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 7 each occurrence of is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine, or two R 7 combine with the atom to which they are attached to form oxo, R L is C1-C6 alkyl, and C3-C6 cycloalkyl, NR 11 R 12 , and [ka] wherein each C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR 13 and V is oxygen, C(R 34 )2, and NR 6 is selected from the group consisting of r is 0, 1, or 2; q is 1, 2, or 3; R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 , SO2R 5, C-linked heterocyclyl and heteroaryl having at least one nitrogen and optionally an additional ring nitrogen or oxygen, wherein C-C alkyl and C-C cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 11 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independent occurrences of fluorine; R 12 is selected from the group consisting of H, C1-C3 alkyl, and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more independ...

Claims

1. A compound represented by: 【Chemistry 1】 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, During the ceremony, X is CH; Y is C(R 33 ); W is CH or N; R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine; R ２ is halogen, cyano, C １ -C ５ Alkyl, C ３ -C ６ Cycloalkyl, and C １ -C ５ alkoxy; R ３ is H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R 33 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; R ４ is selected from the group consisting of B and D; B is selected from N-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen; B is selected from R ７ and R ９ may be optionally substituted on available nitrogen by D is selected from C-linked heterocyclyl having at least one nitrogen and optionally an additional ring nitrogen or oxygen; D is selected from R ７ and R ９ may be optionally substituted on available nitrogen by R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R ６ is H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R ９ is H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R １０ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R Ｌ is C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, and 【Chemistry 2】 Each C is selected from the group consisting of １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR １３ and V is oxygen, C(R ３４ ) ２ , and N.R. ６ selected from the group consisting of: r is 0, 1, or 2; q is 1, 2, or 3; R １３ is H and C １ -C ３ alkyl; R ３４ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; L is -(C(R １０ ) ２ ) ｍ - and m is 0, 1, 2, or 3; n is 3; However, when r is 0 and q is 1, U is CR １３ and V is not O, and when r or q is 1, U is not N and V is O or NR ６ or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, which is not

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

3. R ４ The compound according to claim 1 or 2, wherein

4. R ４ But, 【Chemistry 3】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. R ４ But, 【Chemistry 4】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

6. R ４ But, 【Chemistry 5】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

7. R ４ But, 【Chemistry 6】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

8. R ４ The compound according to claim 1 or 2, wherein is D.

9. R ４ But, 【Chemistry 7】 9. The compound of claim 1, 2 or 8, selected from the group consisting of:

10. L is -(CH ２ ) ｍ The compound according to any one of claims 1 to 9,

11. R １ But halogen, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl and C ３ -C ５ The compound of any one of claims 1 to 10, wherein the cycloalkyl is optionally substituted by one, two or three independent occurrences of fluorine.

12. R １ But, CF ３ The compound according to any one of claims 1 to 11,

13. R １ But, CF ２ The compound according to any one of claims 1 to 11, wherein R is H.

14. R １ The compound according to any one of claims 1 to 11, wherein is selected from the group consisting of chloro, bromo and fluoro.

15. R １ The compound of claim 14 , wherein is bromo.

16. R １ The compound according to any one of claims 1 to 11, wherein is cyclopropyl.

17. R ２ But, C １－２ Alkyl and C ３－４ The compound of any one of claims 1 to 16, wherein the compound is selected from the group consisting of cycloalkyl.

18. R ３ H and C １ -C ３ The compound according to any one of claims 1 to 17, wherein the compound is selected from the group consisting of alkyl.

19. R Ｌ But, C １ -C ６ Alkyl, and C ３ -C ６ 19. The compound of any one of claims 1 to 18, wherein the aryl group is selected from the group consisting of cycloalkyl, each of which is optionally substituted by one, two or three independent occurrences of fluorine.

20. R Ｌ The compound according to any one of claims 1 to 19, wherein is cyclobutyl.

21. R Ｌ but, 【Chemistry 8】 The compound according to any one of claims 1 to 18,

22. A compound represented by: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, wherein n is 3; R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R ２ is C １ -C ２ Alkyl and C ３ -C ４ is selected from the group consisting of cycloalkyl, and halogen; R ３ is H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ４ teeth, 【Chemistry 10】 selected from the group consisting of: R ９ is H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R Ｌ is C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, and 【Chemistry 11】 Each C is selected from the group consisting of １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR １３ and V is oxygen, C(R ３４ ) ２ , and N.R. ６ selected from the group consisting of: r is 0, 1, or 2; q is 1, 2, or 3; R ６ is H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R １３ is H and C １ -C ３ alkyl; R ３４ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; However, when r is 0 and q is 1, U is CR １３ and V is not O, and when r or q is 1, U is not N, and V is O or NR ６ or a pharma- ceutically acceptable salt thereof.

23. A compound represented by: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, wherein n is 3; R １ is halogen, cyano, C １ -C ５ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ５ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; R ２ is C １ -C ２ Alkyl and C ３ -C ４ is selected from the group consisting of cycloalkyl, and halogen; R ３ is H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; R ４ is selected from the group consisting of: 【Chemistry 13】 R ９ are independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R ７ Each occurrence of is independently H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R Ｌ is C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, and 【Chemistry 14】 Each C is selected from the group consisting of １ -C ６ Alkyl and C ３ -C ６ The cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR １３ and V is oxygen, C(R ３４ ) ２ , and N.R. ６ selected from the group consisting of: r is 0, 1, or 2; q is 1, 2, or 3; R ６ is H, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; R １３ is H and C １ -C ３ alkyl; R ３４ Each occurrence of is independently H, C １ -C ３ Alkyl, and C ３ -C ５ cycloalkyl; １ -C ３ Alkyl and C ３ -C ５ The cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine; However, when r is 0 and q is 1, U is CR １３ and V is not O, and when r or q is 1, U is not N, and V is O or NR ６ or a pharma- ceutically acceptable salt thereof.

24. N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-methyl-N-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-methyl-N-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutyramide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclopropanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, 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-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutyramide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylpivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, 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-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo)[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylazetidine-1-carboxamide, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidine-1-carboxamide, 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-dimethylazetidine-1-carboxamide, 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, and pharma- ceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

26. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, one or more additional therapeutic agents, and a pharma- ceutically acceptable excipient.

27. 27. The pharmaceutical composition of claim 26, wherein the composition comprises one additional therapeutic agent.

28. 28. The pharmaceutical composition of claim 26 or claim 27, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

29. 29. The pharmaceutical composition of claim 28, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

30. 30. The pharmaceutical composition of claim 29, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.

31. 30. The pharmaceutical composition of claim 29, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharma- ceutically acceptable salts thereof.

32. 30. The pharmaceutical composition of claim 29, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharma- ceutically acceptable salts thereof.

33. 30. The pharmaceutical composition of claim 29, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharma- ceutically acceptable salts thereof.

34. 28. The pharmaceutical composition of claim 26 or claim 27, wherein the additional therapeutic agent is a chemotherapeutic agent.

35. 35. The pharmaceutical composition of claim 34, wherein the chemotherapeutic agent is selected from the group consisting of antitubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytidine, gemcitabine, and methotrexate.

36. 25. A composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, for use in a method for treating a tumor in a patient in need of such treatment.

37. 25. A composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, for use in a method for treating cancer in a patient in need of such treatment.

38. 38. The composition of claim 37, wherein the cancer is selected from the group consisting of gastrointestinal stromal tumor, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer metastasizing to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.

39. 39. The composition of claim 37 or claim 38, wherein the cancer is metastatic.

40. 25. A composition comprising a compound of any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof for use in a method for treating a disorder selected from the group consisting of melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, cancer metastasizing to bone, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer in a patient in need of such treatment.

41. The composition of any one of claims 36 to 40, further comprising administering to the patient one or more additional therapeutic agents.

42. 42. The composition of claim 41, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

43. 43. The composition of claim 42, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.

44. 44. The composition of claim 43, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.

45. 44. The composition of claim 43, wherein the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, lavoxertinib, VX-11e, and pharma- ceutically acceptable salts thereof.

46. 44. The composition of claim 43, wherein the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharma- ceutically acceptable salts thereof.

47. 44. The composition of claim 43, wherein the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharma- ceutically acceptable salts thereof.

48. 42. The composition of claim 41, wherein the additional therapeutic agent is a chemotherapeutic agent.

49. 49. The composition of claim 48, wherein the chemotherapeutic agent is selected from the group consisting of antitubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate.

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