Aminopyrimidine amide autophagy inhibitors and methods of use thereof

Abstract

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

Description

[0001] This case is a divisional application of a case with an application date of June 16, 2020, an invention name of "Aminopyrimidineamide autophagy inhibitors and methods of use thereof", and an application number of 202080058281X.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to USSN 62 / 862,469 filed on June 17, 2019, USSN 62 / 862,470 filed on June 17, 2019, USSN 62 / 911,739 filed on October 7, 2019, and USSN 62 / 911,740 filed on October 7, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0004] Sequence Listing

[0005] This application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on June 9, 2020, with the file name DCP-081WO_SL.txt and a size of 27,190 bytes. Background Art

[0006] Autophagy (literally "self-eating") is a process that enables cells to recycle organelles, proteins, stored lipids, glucagon and other materials for the purpose of generating nutrients under stress. These cell contents are recycled by being engulfed in a vesicle called an autophagosome. Subsequently, the autophagosome merges with the lysosome that degrades the autophagosome contents to recycle nutrients to the cell. Tumor cells tend to activate autophagy because these cells have high metabolic demands, experience cell stress, and are usually in an oxygen-deficient environment with limited blood flow and nutrient supply. In addition, chemotherapy and targeted therapy have been shown to induce autophagy as a mechanism of treatment resistance, and it has been shown that autophagy inhibition (by gene function loss mutations in autophagy genes or by pharmacological means) and chemotherapy The combination of treatments inhibits tumor growth and triggers tumor cell apoptosis to a higher degree than single-agent chemotherapy.

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

[0008] At present, the most widely used autophagy inhibitors are chloroquine and hydroxychloroquine, which are recognized antimalarials. It is believed that these antimalarials block autophagy by being chelated in the lysosomal compartment, increasing the pH of these lysosomes and thus inactivating the proteases that degrade and recycle nutrients. These antimalarials also have multiple mechanisms of action in addition to inhibiting lysosomes, and are known to induce retinopathy in patients. Therefore, there is a need for more selectively blocking autophagy and targeting agents that do not exhibit the toxicity of these antimalarials. ULK1 kinase is an autophagy initiation protein and a serine / threonine kinase. The ULK1 kinase complex is activated in response to cell stress including nutritional deprivation and energy depletion. Nutritional deprivation activates ULK kinase activity by inhibiting mTORC1, and energy depletion activates ULK kinase activity by activation performed by AMP-activated protein kinase AMPK. Importantly, the kinase-inactivated mutants of ULK kinase block typical autophagy initiation, indicating that small molecule inhibitors of ULK kinase activity should be able to block autophagy.

[0009] Other mechanistic studies have shown that ULK1 gene deletion inhibits autophagy in cancer cells, attenuating FOX3A turnover and upregulation of the pro-apoptotic protein PUMA. In addition to the classical activation of canonical autophagy, ULK1 kinase activity has also been shown to require Bcl-2-L-13-mediated mitophagy (autophagy of damaged mitochondria). ULK1 and ULK2 kinases have also been shown to remodel cancer cell glucose metabolism. ULK inhibitors may also find utility in blocking these atypical tumor-promoting ULK activities.

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

[0011] Mutated Ras cancers rely on autophagy. In pancreatic cancer, mutant Ras signals mainly through the MAPKAP pathway. Mutated Ras activates RAF kinase, then MEK kinase, and finally ERK kinase: mutant Ras→RAF→MEK→ERK. Although mutant Ras signaling is through the MAPKAP pathway, inhibitors of this pathway do not provide or provide very little clinical benefit when used as a single agent in clinical trials. It has recently been reported that MAPKAP pathway inhibition induces autophagy as a compensatory survival mechanism. When MEK inhibitors are combined with the autophagy inhibitor hydroxychloroquine, there is synergistic activity that causes regression of multiple mutant Ras cancers or mutant BRAF cancers. Similarly, when ERK inhibitors are combined with the autophagy inhibitors hydroxychloroquine or chloroquine, there is synergistic activity that causes the inhibition of mutant Ras pancreatic cancer. It has been demonstrated that genetic depletion of RAF kinases (CRAF and BRAF) causes synergistic anti-tumor activity in mutant Ras cancer cell lines when autophagy is also genetically depleted. Recent publications highlight that dual inhibition of the MAPKAP pathway and the autophagy pathway in mutant Ras cancers in complex is a promising treatment option for patients with mutant Ras cancers. Other targeted therapies and chemotherapeutics have also been shown to activate tumor autophagy as a resistance mechanism; therefore there is a rationale for combining these targeted therapeutics or chemotherapeutics with autophagy inhibitors.

[0012] Mutations in the gene encoding the LRRK2 kinase cause Parkinson's disease. LRRK2 point mutations are found in both familial (hereditary) Parkinson's patients and sporadic Parkinson's patients. The most common LRRK2 mutation in Parkinson's disease is LRRK2 G2019S. These LRRK2 mutations are gain-of-function mutations that overactivate LRRK2 signaling. Continuous autophagy is a process used by brain neuronal cells to maintain health and homeostasis in vivo. Autophagy is a process that allows cells to recognize, locate and destroy aging organelles and structural components within cells, and specifically, in the case of proteins known to aggregate in neurons, autophagy eliminates these toxic protein aggregates to maintain neuronal health. LRRK2 activity inhibits autophagy, and the LRRK2 G2019S gain-of-function mutation is even more inhibitory of autophagy and has been associated with aggressive forms of Parkinson's disease.

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

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

[0015] 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 therapeutics. SUMMARY OF THE INVENTION

[0017] Described herein are compounds, pharmaceutical compositions, and their use as medicaments in treating conditions such as cancer, methods for their preparation, and pharmaceutical compositions containing them as active ingredients as autophagy inhibitors. These pharmaceutical compositions may include the compounds as single active agents or in combination with other active agents in the presence of pharmaceutically acceptable excipients. In one embodiment, the compounds described are inhibitors of ULK kinase activity, including ULK1 and ULK2 activity.

[0018] For example, the compounds provided herein can be described as Formula I:

[0019]

[0020] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: A is selected from: phenyl and 5- or 6-membered 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9, C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R 10 )2) m -; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restriction is that when m is 0, R 4 C is connected to ring A. When m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0021] Also described herein is a compound represented by:

[0022]

[0023] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 33 Selected from: H, halogen, C 1- C6 alkyl and C 1- C6 alkoxy, where C 1- C6 alkyl and C 1- C6 alkoxy may be optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5, C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R 10 )2) m-; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restrictions are that both X and Y are not N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

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

[0025]

[0026] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

[0027] Ring DD is selected from:

[0028]

[0029] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2, q is 1, 2 or 3; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R 10 )2) m -; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restriction is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 . DETAILED DESCRIPTION OF THE INVENTION

[0031] The features and other details of the present invention are now described more clearly. Specific terms used in this specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the present invention and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0032] definition

[0033] As used herein, the term "alkyl" refers to a saturated straight or branched hydrocarbon. Exemplary alkyls include, but are not limited to, straight or branched hydrocarbons having 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms, referred to herein as C1-C6 alkyls, C1-C5 alkyls, C1-C4 alkyls, C1-C3 alkyls, and C1-C2 alkyls, respectively. Exemplary alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0034] As used herein, the term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight or branched groups having 2-6 or 3-4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0035] As used herein, the term "alkoxy" refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups having 1-6 or 2-6 carbon atoms, referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0036] As used herein, the term "alkoxyalkyl" refers to a straight or branched chain alkyl group attached to an oxygen, attached to a second straight or branched chain alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups wherein each alkyl group independently contains 1-6 carbon atoms, referred to herein as C1-C6 alkoxy-C1-C6 alkyl. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

[0037] As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups having 2-6 or 3-6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0038] As used herein, the term "cyano" refers to the group -CN.

[0039] As used herein, the term "cycloalkyl" or "carbocyclyl" refers to a saturated or partially unsaturated hydrocarbon group having, for example, 3-6 or 4-6 carbons, referred to herein as a C3-C6 cycloalkyl or a C4-C6 cycloalkyl, respectively. Exemplary cycloalkyls include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0040] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups having 3-6 carbon atoms, referred to herein as C3-C6 cycloalkoxy groups. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0041] As used herein, the term "halo" or "halogen" refers to F, Cl, Br or I.

[0042] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 5 or 6-membered ring system containing one or more heteroatoms (e.g., 1-3 heteroatoms such as nitrogen, oxygen, and sulfur). Where possible, the heteroaryl ring may be attached to the adjacent group via 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, etc.

[0043] The term "heterocyclyl" or "heterocyclic group" is well-known in the art and refers to a saturated or partially unsaturated 4-10 ring structure, including a monocyclic, bridged or fused ring, and such a ring structure includes 1-3 heteroatoms such as nitrogen, oxygen and sulfur. When possible, the heterocyclyl ring may be connected to an adjacent group via carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, etc.

[0044] As used herein, the term "lactam" refers to a cyclic amide of a carbamic acid having a 1-azacycloalkane-2-one structure, or an analog having unsaturation or a heteroatom replacing one or more carbon atoms of the ring. "α-lactam" refers to a lactam consisting of a 3-membered ring. "β-lactam" refers to a lactam consisting of a 4-membered ring. "γ-lactam" refers to a lactam consisting of a 5-membered ring. "δ-lactam" refers to a lactam consisting of a 6-membered ring. "ε-lactam" refers to a lactam consisting of a 7-membered ring.

[0045] As used herein, the term "oxo" refers to the group =0.

[0046] "Combination therapy" is a treatment that involves administering to a patient in need thereof two or more therapeutic agents, eg, a compound of Formula I and a MAPKAP pathway inhibitor.

[0047] "Disease," "disorder," and "condition" are used interchangeably herein.

[0048] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, 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 in need of veterinary treatment, such as domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cattle, sheep, pigs, horses and the like), and experimental animals (e.g., rats, mice, guinea pigs and the like).

[0049] "MAPKAP pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. The pathway inhibitors include Ras inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib) and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996). The terms "MAPKAP pathway inhibitors" and "MAPKAP kinase inhibitors" are used interchangeably herein.

[0050] "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 required. For human administration, preparations should meet sterility, pyrogenicity and general safety and purity standards required by FDA Office of Biologics standards.

[0051] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic agents and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of these media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional or enhanced therapeutic function.

[0052] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to salts having acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions), including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (e.g., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds that are acidic in nature and included in the compositions of the present invention are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts and iron salts. Compounds included in the compositions of the present invention that include basic or acidic moieties may also form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compounds may exist in the form of acid addition salts, zwitterions or base salts.

[0054] The compounds of the present invention may contain one or more chiral centers and therefore exist as stereoisomers. When used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. Depending on the configuration of substituents around the chiral carbon atom, these compounds may be designated by the symbols "(+)", "(-)", "R" or "S", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. The compounds described in the present invention encompass various stereoisomers of these compounds and mixtures thereof. In nomenclature, a mixture of enantiomers or diastereomers may be designated as "(±)", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center.

[0055] In this specification, the term "therapeutically effective amount" refers to the amount of the compound of the present invention that will cause a biological or medical response in a tissue, system or animal (e.g., mammal or human) that a researcher, veterinarian, doctor or other clinician is seeking. The compounds described herein are administered in a therapeutically effective amount to treat a condition.

[0056] "Treatment" includes any action that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination.

[0057] The present disclosure also encompasses isotopically labeled compounds identical to the compounds described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, such as 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. For example, the compounds of the invention may have one or more H atoms replaced by deuterium.

[0058] Individual enantiomers and diastereomers of the compounds of the invention may be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the auxiliary, (2) salt formation using 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 liquid chromatography or crystallization of compounds in chiral solvents. Stereoselective syntheses, chemical or enzymatic reactions in which a single reactant forms a non-identical mixture of stereoisomers during the generation of a new stereocenter or during the conversion of a pre-existing stereocenter, are well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0059] Compound

[0060] In one aspect, the compounds provided herein can be described by the following Formula I:

[0061]

[0062] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is selected from: phenyl and 5- or 6-membered 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R10 )2) m -; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restriction is that when m is 0, R 4 C is connected to ring A. When m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0063] For example, compounds represented by Formula IA are also described herein:

[0064]

[0065] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 33 Selected from: H, halogen, C 1- C6 alkyl and C 1- C6 alkoxy, where C 1- C6 alkyl and C 1- C6 alkoxy may be optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9, C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R 10 )2) m -; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restrictions are that both X and Y are not N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0066] 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 ).

[0067] In some embodiments, R 4 For B.

[0068] In some embodiments, R 4 Selected from:

[0069]

[0070] where u is 1, 2, or 3.

[0071] In some embodiments, R 4 Selected from:

[0072]

[0073] In some embodiments, R 4 Selected from:

[0074]

[0075] In some embodiments, R 4 Selected from:

[0076]

[0077] In some embodiments, R 4 is D.

[0078] In some embodiments, R 4 Selected from:

[0079]

[0080] In some embodiments, L is -(CH2) m In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0081] 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 may be optionally substituted with one, two or three independent occurrences of fluorine. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 is selected from the group consisting of chlorine, bromine and fluorine. 1 In some embodiments, R 1 It is cyclopropyl.

[0082] In some embodiments, 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 C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl, and C2-C5 alkynyl are optionally substituted with one, two, or three independent occurrences of fluorine. 2 Selected from: C 1-2 Alkyl and C 3-4 Cycloalkyl.

[0083] In some embodiments, R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0084] In some embodiments, R LSelected from: C1-C6 alkyl and C3-C6 cycloalkyl, each of which may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

[0085] In some embodiments, R L In some embodiments, R L NR 11 R 12 .

[0086] In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0087] In some embodiments, n is 3.

[0088] In some embodiments, the compound is represented by Formula IB:

[0089]

[0090] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from:

[0091]

[0092] R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 with 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 with one or more independent occurrences of fluorine; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34and the carbon to which they are attached to form a C3-C6 cycloalkyl group; provided that neither X nor Y is N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0093] 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 may be optionally substituted with one, two or three independent occurrences of fluorine and C3-C5 cycloalkyl. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is cyclopropyl.

[0094] In some embodiments, R 2 is selected from the group consisting of: C3-C4 cycloalkyl, C1-C5 alkyl and halogen. 2 Selected from: C1-C2 alkyl, C3-C4 cycloalkyl and bromine.

[0095] In some embodiments, R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0096] In some embodiments, R 4 Selected from:

[0097]

[0098] In some embodiments, R 4 Selected from:

[0099]

[0100] In some embodiments, each R 6 and R 9 Independently selected from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0101] In some embodiments, R 7 For H.

[0102] In some embodiments, R LSelected from: C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

[0103] In some embodiments, R L In some embodiments, R L NR 11 R 12 .

[0104] In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0105] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0106]

[0107] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0108]

[0109] In some embodiments, n is 3.

[0110] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0111]

[0112] Where R 1R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0113] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0114] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0115] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0116] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0117]

[0118] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0119] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0120] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0121] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0122] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0123]

[0124] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0125] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0126] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0127] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0128] In some embodiments, the compound is represented by Formula IC:

[0129]

[0130] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from:

[0131]

[0132] R 9 Independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 with 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 with one or more independent occurrences of fluorine; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34and the carbon to which they are attached to form a C3-C6 cycloalkyl group; provided that neither X nor Y is N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0133] 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 may be optionally substituted with one, two or three independent occurrences of fluorine and C3-C5 cycloalkyl. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is cyclopropyl.

[0134] In some embodiments, R 2 is selected from the group consisting of: C3-C4 cycloalkyl, C1-C5 alkyl and halogen. 2 Selected from: C1-C2 alkyl, C3-C4 cycloalkyl and bromine.

[0135] In some embodiments, R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0136] In some embodiments, R 4 Selected from:

[0137]

[0138] In some embodiments, R 4 Selected from:

[0139]

[0140] In some embodiments, each R 6 and R 9 Independently selected from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0141] In some embodiments, R 7 For H.

[0142] In some embodiments, R LSelected from: C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

[0143] In some embodiments, R L In some embodiments, R L NR 11 R 12 .

[0144] In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0145] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0146]

[0147] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0148]

[0149] In some embodiments, n is 3.

[0150] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0151]

[0152] Where R 1R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0153] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0154] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0155] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0156] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0157]

[0158] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0159] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0160] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0161] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0162] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0163]

[0164] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9is independently selected at each occurrence from: H, C1-C3 alkyl, and C3-C5 cycloalkyl; and n is 3.

[0165] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0166] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0167] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl, bromine and chlorine; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 9 is independently selected at each occurrence from: H and C1-C3 alkyl; and n is 3.

[0168] Also described herein are compounds of Formula ID

[0169]

[0170] or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof,

[0171] Wherein: Ring DD is selected from:

[0172]

[0173] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2R 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein B may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 D is selected from: a C-linked heterocyclic group having at least one nitrogen and optionally another ring nitrogen or oxygen, and a heteroaryl group, wherein D may be optionally replaced by R on one or more available carbons 7 and optionally substituted on an available nitrogen by R 9 Replacement; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 and the carbon to which they are attached to form a C3-C5 cycloalkyl group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; L is -(C(R 10 )2) m -; h is 1, 2 or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; the restriction is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0174] In some embodiments, W is N. In some embodiments, W is CH.

[0175] In some embodiments, Ring DD is selected from:

[0176]

[0177] In some embodiments, Ring DD is selected from:

[0178]

[0179] In some embodiments, Ring DD is:

[0180]

[0181] In some embodiments, R 4 is D.

[0182] In some embodiments, R 4 Selected from:

[0183]

[0184] In some embodiments, R 4 Selected from:

[0185]

[0186] In some embodiments, R 4 For B.

[0187] In some embodiments, R 4 Selected from:

[0188]

[0189] Where u is 1 or 2.

[0190] In some embodiments, R 4 Selected from:

[0191]

[0192] In some embodiments, R 4 Selected from:

[0193]

[0194] In some embodiments, L is -(CH2) mIn some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0195] 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.

[0196] 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 may be optionally substituted with one, two or three independent occurrences of fluorine. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is cyclopropyl.

[0197] 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 C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl and C2-C5 alkynyl may be optionally substituted with one, two or three independent occurrences of fluorine. 2 Selected from: C 1-2 Alkyl and C 3-4 Cycloalkyl.

[0198] 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 are optionally substituted with one or more independent occurrences of fluorine.

[0199] In some embodiments, R L In some embodiments, R L NR 11 R 12 .

[0200] In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0201] In some embodiments, n is 3.

[0202] In some embodiments, the compound is represented by Formula IE:

[0203]

[0204] or a pharmaceutically acceptable salt thereof, wherein: Ring DD is selected from:

[0205]

[0206] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from:

[0207]

[0208] R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R5 is selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; and L is -(C(R 10 )2) m -; m is 0, 1, 2 or 3; the restriction is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0209] In some embodiments, Ring DD is:

[0210]

[0211] 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 may be optionally substituted with one, two or three independent occurrences of fluorine. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is cyclopropyl.

[0212] In some embodiments, R 2 is selected from the group consisting of: C3-C4 cycloalkyl, C1-C5 alkyl and halogen. 2 Selected from: C1-C2 alkyl, C3-C4 cycloalkyl and bromine.

[0213] In some embodiments, R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0214] In some embodiments, R 4 is D.

[0215] In some embodiments, R 4 Selected from:

[0216]

[0217] In some embodiments, R 4 Selected from:

[0218]

[0219] In some embodiments, each R 6 and R 9 Independently selected from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0220] In some embodiments, R 7 For H.

[0221] In some embodiments, R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

[0222] In some embodiments, R L In some embodiments, R L NR 11 R 12 .

[0223] In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0224] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0225] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0226]

[0227] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0228]

[0229] In some embodiments, n is 3.

[0230] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0231]

[0232] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0233] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0234] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IE.1 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IE.2 and Formula IE.3 as defined above.

[0235] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0236]

[0237] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0238] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0239] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0240] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IE.4 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IE.5 and Formula IE.6 as defined above.

[0241] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0242]

[0243] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0244] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0245] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0246] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IE.7 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IE.8 and Formula IE.9 as defined above.

[0247] In some embodiments, the compound is represented by Formula IF:

[0248]

[0249] or a pharmaceutically acceptable salt thereof, wherein: Ring DD is selected from:

[0250]

[0251] 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl may be optionally substituted with one, two or three 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 with one or more independent occurrences of fluorine; R 4 Selected from:

[0252]

[0253] R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 may be optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 Connected to the atom to which it is attached to form a bridge group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 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 with 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 with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which they are attached to form a C3-C6 cycloalkyl group; and L is -(C(R 10 )2) m -; m is 0, 1, 2 or 3; the restriction is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0254] In some embodiments, Ring DD is:

[0255]

[0256] In some embodiments, R 1is selected from the group consisting of halogen, C1-C5 alkyl and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl may be optionally substituted with one, two or three independent occurrences of fluorine. 1 is CF3. In some embodiments, R 1 is CF2H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is cyclopropyl.

[0257] In some embodiments, R 2 is selected from the group consisting of: C3-C4 cycloalkyl, C1-C5 alkyl and halogen. 2 Selected from: C1-C2 alkyl, C3-C4 cycloalkyl and bromine.

[0258] In some embodiments, R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0259] In some embodiments, R 4 is D.

[0260] In some embodiments, R 4 Selected from:

[0261]

[0262] In some embodiments, R 4 Selected from:

[0263]

[0264] In some embodiments, each R 6 and R 9 Independently selected from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine.

[0265] In some embodiments, R 7 For H.

[0266] In some embodiments, R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

[0267] In some embodiments, R L In some embodiments, RL NR 11 R 12 In some embodiments, R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

[0268] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0269] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0270]

[0271] In some embodiments, -N(R 3 )-C(O)-R L Selected from:

[0272]

[0273] In some embodiments, n is 3.

[0274] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0275]

[0276] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0277] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0278] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 7 R is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IF.1 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IF.2 and Formula IF.3 as defined above.

[0279] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0280]

[0281] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0282] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0283] In some embodiments, R 1CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0284] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from: H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IF.4 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IF.5 and Formula IF.6 as defined above.

[0285] In some embodiments, the compound is represented by a structural formula selected from the group consisting of:

[0286]

[0287] Where R 1 R is independently selected at each occurrence from: CF3, CF2H, bromine, chlorine or cyclopropyl; 2 R is independently selected at each occurrence from: C1-C2 alkyl, C3-C4 cycloalkyl and halogen; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; 9 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl; 34 is independently selected at each occurrence from H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0288] In some embodiments, R 1 Bromine at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0289] In some embodiments, R 1 CF3 at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3.

[0290] In some embodiments, R 1 CF2H at each occurrence; R 2 R is independently selected at each occurrence from: C1-C2 alkyl and C3-C4 cycloalkyl; 3 is independently selected at each occurrence from: H and C1-C2 alkyl; R 6 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl; 9 is selected at each occurrence from: H and C1-C3 alkyl; R 34 is independently selected at each occurrence from H, C1-C3 alkyl, C3-C5 cycloalkyl; and n is 3. In some embodiments, the compound is represented by Formula IF.7 as defined above. In some embodiments, the compound represents a structural formula selected from Formula IF.8 and Formula IF.9 as defined above.

[0291] Also described herein are compounds selected from the group consisting of:

[0292] 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- 1-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)-pyrimidin-4-yl)amino)-propyl)cyclobutanecarboxamide, N-(3-((5-bromo-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-oxopropyl-2-yl)-3-methyl-1H-pyrazole- 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-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, (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-(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-((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, N-(3-((2-((1-(1-isobutylpiperidin-4-yl)-3-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide 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-N-morpholinylpyridin-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]heptane-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)pivalamide, )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) 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]heptane-2-yl)phenyl)amino)-5-( 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 -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-methyltetrahydrofuran-3-carboxamide -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-dihydro- -3-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)benzene cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)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-( 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-(4-methylpiperazin-1-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]heptane-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)pyrimidin-4-yl)amino)propyl)pyrrolidine-1-carboxamide, oxazine-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)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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)-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)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) 1-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)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 amide, 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 1-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, 1-methyl-N-(3-((2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, (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,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-methylazetidine-3-carboxamide,N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)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, 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 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)oxetane-3-carboxamide, -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)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) -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, 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)-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- 1-(trifluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octane -3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-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- cyclobutanecarboxamide, 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-((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)propyl)cyclobutanecarboxamide, 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-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, -5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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) 1-methylpiperazine-1-yl)oxazol-4-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)-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-2-(1-methylpiperidin-4-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-3-carboxamide Cyclobutane-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 -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, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)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-((3-methyl-1-(1-methylpiperidin-4-yl)thiazol-5-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)cyclobutanecarboxamide, N-(3-((2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-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)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide -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)-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.

[0293] Treatment

[0294] The compounds described herein can act as autophagy inhibitors useful for treating a disorder in a patient in need thereof. For example, the disorder can be a tumor such as a solid tumor. The disorder can also be cancer.

[0295] 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, kidney cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, bone metastases, papillary thyroid cancer, non-small cell lung cancer and colorectal cancer. The cancer treated by the methods described herein can be a metastatic cancer.

[0296] In some embodiments, the compounds described herein can be used to treat cancers caused by RAS mutations. In some embodiments, cancer is caused by KRAS mutations. In some embodiments, 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, cancer is pancreatic duct adenocarcinoma. In some embodiments, cancer is lung cancer. In some embodiments, cancer is colorectal cancer.

[0297] In some embodiments, the determination of the inhibition of autophagy by the compounds described herein is by monitoring autophagic flux, for example, by monitoring the inhibition of the removal of mCherry / GFP-LC3 fusion proteins mediated by autophagy. In some embodiments, the determination of the inhibition of autophagy by the compounds described herein is by monitoring the accumulation of autophagic proteins such as p62 or LC-3. In some embodiments, the determination of the inhibition of autophagy by the compounds described herein is by the removal of the reduction of luciferase-labeled LC3 proteins. In some embodiments, the determination of the inhibition of autophagy by the compounds described herein is by monitoring the reduction of autophagosomes, for example, by measuring the fluorescent spots with autophagosome marker Cyto-ID.

[0298] In some embodiments, ULK kinase cellular inhibition by the compounds described herein is measured by inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1 or STING in tumor cells or non-tumor host tissues. In some embodiments, ULK kinase cellular inhibition by the compounds described herein is measured in host tissues including immune cells.

[0299] In some embodiments, the in vivo inhibition of autophagy by the compounds described herein is measured by inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1 or STING in tumor cells or non-tumor host tissues. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is measured in host tissues including immune cells. In some embodiments, the in vivo inhibition of autophagic flux by the compounds described herein can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is measured in animals with pancreatic cancer. In some embodiments, the in vivo inhibition of ULK kinase by the compounds described herein is measured in animals with lung cancer. In some embodiments, the in vivo inhibition of ULK kinase is measured in animals with colorectal cancer. In some embodiments, the in vivo inhibition of autophagy by the compounds described herein is determined by inhibition of autophagic flux in tumor cells or non-tumor host tissues using monitoring inhibition of autophagosome formation or by accumulation of autophagic proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is determined in host tissues including immune cells. In some embodiments, in vivo inhibition of autophagic flux can be used as a pharmacodynamic model to monitor the kinetics and extent of such ULK inhibition.

[0300] In some embodiments, the inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in xenograft studies using human RAS mutant cell lines in immunocompromised mice, such as SCID or nude mice. In some embodiments, the inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in xenograft studies using tumor xenografts (PDX) derived from human RAS mutant patients in immunocompromised mice, such as SCID or nude mice. In some embodiments, xenograft studies include the evaluation of the compounds described herein in pancreatic cancer models. In some embodiments, the inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in a genetically engineered model (GEM) of the same gene type of mutant RAS cancer. In some embodiments, the inhibition of autophagy and anti-tumor activity by the compounds described herein is evaluated in a mouse GEM isogenic orthotopic pancreatic cancer model called the following: KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / + , Pdx-1-Cre) or KPC model variations.

[0301] In some embodiments, the compounds described herein will be evaluated in combination with MEK inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with RAF inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with ERK inhibitors in xenograft or GEM cancer models. In some embodiments, the compounds described herein will be evaluated in combination with RAS G12C direct inhibitors in xenograft or GEM cancer models.

[0302] In some embodiments, autophagy inhibition and anti-tumor activity by the compounds described herein are evaluated in an immunocompetent murine cancer model for evaluating the immunomodulatory component of the mechanism of action of ULK inhibitors. In some embodiments, the immunocompetent murine model is a murine GEM syngeneic orthotopic pancreatic cancer model referred to as the KPC model (LSL-Kras G12D / + , LSL-Trp53 R172H / +, Pdx-1-Cre) or KPC model variations. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in conjunction with MEK inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in conjunction with RAF inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in conjunction with ERK inhibitors. In some embodiments, the immunomodulatory properties of the compounds described herein are evaluated in conjunction with RAS G12C direct inhibitors.

[0303] 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 acquired immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced activity of antigen presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced anti-tumor activity of myeloid cells including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced activity of effector T cells including cytotoxic T cells.

[0304] In one embodiment, a method for treating a condition described herein is provided herein, comprising: administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including but not limited to: tumor, blood, saliva, or tissue) with a phosphorylated ATG13 antibody ELISA assay to, for example, detect inhibition of ULK kinase activity based on the content of phosphorylated ATG13 in the sample. In some embodiments, the intended method comprises contacting a sample obtained from the patient (including but not limited to: tumor, blood, saliva, or tissue) with a phosphorylated ATG13 antibody ELISA assay, optionally before administering the compound, and comparing the phosphorylated ATG13 content in the sample obtained before administration with the phosphorylated ATG13 content in the sample obtained during or after the administration process. In some embodiments, phosphorylated ATG13 is p-S318ATG13.

[0305] In one embodiment, provided herein is a method for treating a condition described herein, comprising: administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including but not limited to: tumor, blood, saliva, or tissue) with a phosphorylated ATG14 antibody ELISA assay to, for example, detect inhibition of ULK kinase activity based on the content of phosphorylated ATG14 in the sample. In some embodiments, the intended method comprises contacting a sample obtained from the patient (including but not limited to: tumor, blood, saliva, or tissue) with a phosphorylated ATG14 antibody ELISA assay, optionally before administering the compound, and comparing the phosphorylated ATG14 content in the sample obtained before administration with the phosphorylated ATG14 content in the sample obtained during or after the administration process. In some embodiments, phosphorylated ATG14 is p-ATG14 Ser29.

[0306] In one embodiment, provided herein is a method for treating a condition described herein, comprising: administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including but not limited to: a tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the amount of p62 in the sample. In some embodiments, the intended method comprises contacting a sample obtained from the patient (including but not limited to: a tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay, optionally prior to administering the compound, and comparing the amount of p62 in the sample obtained before administration with the amount of p62 in the sample obtained during or after the administration process.

[0307] In one embodiment, provided herein is a method for treating a condition described herein, comprising: administering a therapeutically effective amount of a compound described herein to a patient in need thereof, and detecting the effect of the compound on ULK kinase during or after the administration process (e.g., at discrete time points, such as one week, two weeks, or monthly after the initial administration of the intended compound), wherein the detection comprises contacting a sample obtained from the patient (including but not limited to: a tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay to detect inhibition of ULK kinase activity, for example, based on the amount of pBeclin in the sample. In some embodiments, the intended method comprises contacting a sample obtained from the patient (including but not limited to: a tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay, optionally prior to administering the compound, and comparing the amount of pBeclin in the sample obtained before administration with the amount of pBeclin in the sample obtained during or after the administration process.

[0308] The compounds provided herein can provide the most preferred dosage of drug efficacy for patients (animals and humans) in need of such treatment. It should be understood that the dosage required for use in any particular application will vary with the patient, not only with the selected specific compound or composition, but also with the administration route, the nature of the condition to be treated, the age and condition of the patient, the medicine taken at the same time, or the special diet followed by the patient and other factors that will be recognized by those skilled in the art, and the appropriate dosage is ultimately handled by the attending physician at his discretion. For the treatment of the clinical conditions and diseases mentioned above, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectal administration in the form of dosage unit preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection or infusion techniques.

[0309] Treatment can continue for as long or as short a period of time as desired. The composition can be administered, for example, one to four times a day 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 1 year, or indefinitely. The treatment period can terminate when the desired result is achieved.

[0310] Combination therapy

[0311] 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 conditions described herein such as cancer. For example, the present invention provides pharmaceutical compositions comprising compounds described herein (e.g., compounds of Formula I as defined herein), one or more additional therapeutic agents, and pharmaceutically acceptable excipients. 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 separately formulated and administered. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a compound of Formula I as a therapeutic agent and one or more additional therapeutic agents such as a MAPKAP pathway inhibitor or a chemotherapeutic agent. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation. Combination therapy also encompasses other combinations. Although two or more medicaments in combination therapy can be applied simultaneously, it is not necessary to do so.For example, the application of the first medicament (or the combination of medicaments) can be several minutes, hours, days or weeks ahead of the application of the second medicament (or the combination of medicaments).Therefore, the application of two or more medicaments can be within a few minutes each other, or within 1,2,3,6,9,12,15,18 or 24 hours each other, or within 1,2,3,4,5,6,7,8,9,10,12,14 days each other, or within 2,3,4,5,6,7,8,9 weeks or weeks each other.In some cases, even longer time intervals are also possible.Although it is desired that two or more medicaments used in combination therapy are present in the patient's body simultaneously in most cases, it is not necessary to do so.

[0312] Combination therapy may also include two or more administrations of one or more of the agents in different sequential combinations using the component agents. For example, if agent X and agent Y are used in combination, they may be administered one or more times sequentially in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0313] In some embodiments, one or more additional therapeutic agents that can be administered in combination with the compounds provided herein can be MAPKAP pathway inhibitors. Such MAPKAP pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.

[0314] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, bimetinib, and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to, uritinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof. Exemplary RAF inhibitors include, but are not limited to, LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

[0315] Compounds described herein can be administered in combination with other therapeutic agents known for treating cancer. Such other therapeutic agents include radiotherapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalators, antiestrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide (thalidomide), lenalidomide (lenalidomide), antibody-drug conjugates (ADC), immunotherapeutics including immunomodulators, targeted therapeutics cancer vaccines and CAR-T cell therapies.

[0316] In some embodiments, the additional therapeutic agent may be a chemotherapeutic agent including, but not limited to, an anti-tubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansines), vinorelbine, a DNA alkylating agent (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), a DNA intercalator, or a DNA topoisomerase inhibitor (including The invention also includes anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone or epirubicin; camptothecins such as topotecan, irinotecan or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine and methotrexate.

[0317] In some other embodiments, the additional therapeutic agent may be a kinase inhibitor including, but not limited to, erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, us), abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, Loxo 292, larotrectinib and quizartinib; antiestrogens including but not limited to the following: tamoxifen, fulvestrant, anastrozole, letrozole and exemestane; antiandrogens including but not limited to the following: abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, acetate); steroid agents including, but not limited to, the following: prednisone and dexamethasone; PARP inhibitors including, but not limited to, neraparib, olaparib, talazoparib, and rucaparib; topoisomerase I inhibitors including, but not limited to, irinotecan, camptothecin, exinotecan, and topotecan; topoisomerase II inhibitors including, but not limited to, anthracyclines, etoposide, etoposide phosphate, and mitoxantrone;Including but not limited to the following histone deacetylase (HDAC) inhibitors: vorinostat, romidepsin, panobinostat, valproic acid and belinostat; including but not limited to the following DNA methylation inhibitors: DZNep and 5-aza-2'-deoxycytidine; including but not limited to the following proteasome inhibitors: bortezomib and carfilzomib; thalidomide; lenalidomide; pomalidomide; including but not limited to the following biological agents: trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitu mumab, ipilimumab, tremelimumab; anti-PD-1 agents including the following: pembrolizumab, nivolumab, pidilizumab, and cemiplimab; anti-PD-L1 agents including the following: atezolizumab, avelumab, durvalumab, and BMS-936559; anti-angiogenic agents including the following: bevacizumab and aflibercept; and antibody-drug conjugates (ADCs) including the following: DM1, DM4, MMAE, MMAF, or camptothecin payloads; brentuximab vedotin and trastuzumab emtansine; radiation therapy; therapeutic vaccines including but not limited to sipuleucel-T.

[0318] In some embodiments, the additional therapeutic agent may be an immunomodulator including but not limited to the following: anti-PD-1 or anti-PDL-1 therapeutic agents, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559 or avelumab; anti-TIM3 (anti-HAVcr2) therapeutic agents, including but not limited to TSR-022 or MBG453; anti-LAG3 therapeutic agents, including but not limited to relatlimab, LAG525 or TSR-033; anti-4-1BB (anti-CD37, anti-TNFRSF9) drugs; CD40 agonist therapeutic agents, including but not limited to SGN-40, CP-870 , CP-893 or RO7009789; anti-CD47 therapeutic agents, including but not limited to: Hu5F9-G4; anti-CD20 therapeutic agents; anti-CD38 therapeutic agents; STING agonists, including but not limited to: ADU-S100, MK-1454, ASA404 or amidobenzimidazoles; anthracyclines, including but not limited to: doxorubicin or mitoxantrone; hypomethylating agents, including but not limited to: azacytidine or decitabine; other immunomodulatory therapeutic agents, including but not limited to: epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, polylidomide, prednisone or dexamethasone.

[0319] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone releasing hormone (LHRH) analogs including goserelin and leuprolide. In some embodiments, the additional therapeutic agent is selected from: 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, dasatinib, nilotinib, decatinib, panitumumab, amrubicin, ogavuzumab, Lep-etu, noratriptide, azd2171, batabulin, atumtunab, zalimumab, atumtunab, tetrandrine, rubitecan, tesmilifene, oblimersen, tecimab, ipilimumab, cottonseed alcohol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR1KRX-0402, amine thiothione, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, lipid 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, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate[C; 59 H 84 N 18 O4-(C2H4O2) x, wherein x=1-2.4] acetate, gosereid acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, ranoxifene, bicalutamide, fluanamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, Suberoyl anal hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BCG vaccine, bleomycin, buserelin, busulfan, carboplatin, carbomustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin D, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec c), hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimbrin, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-omentic acid, phenylalanine nitrogen mustard, uracil nitrogen mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine , deoxycoformycin, calcitriol, varrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, shark cancer, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, troloxifene, iodoxifen, spironolactone, finasteride, cimitidine, trastuzumab, denileukin, gefitinib, bortezomib, irinotecan, topotecan,Doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, paclitaxel without hydrogenated castor oil, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, SE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zeocin Bone, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan), androgens, decitabine, altretamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunomycin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, apivitan, diphenhydramine, hydroxyzine, metoclopramide, lorazepam razepam), alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilimumab, vemurafenib, and mixtures thereof.

[0320] Pharmaceutical compositions and kits

[0321] Another aspect of the present invention provides a pharmaceutical composition comprising a compound as disclosed herein formulated with a pharmaceutically acceptable carrier. Specifically, the present invention provides a pharmaceutical composition comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These preparations include preparations suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, but in any given case, the most suitable form of administration will depend on the degree and severity of the condition being treated, and on the properties of the specific compound used. For example, the disclosed composition can be formulated in unit dosage form, and / or can be formulated for oral or subcutaneous administration.

[0322] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which contain one or more compounds described herein as active ingredients, admixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral administration. The active ingredients can be compounded with non-toxic, pharmaceutically acceptable carriers such as those commonly used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0323] For preparing solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier such as conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or colloid) and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into unit dosage forms of equal potency, such as tablets, pills and capsules.

[0324] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the composition of the present invention is 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, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) ) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glyceryl monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also contain a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or galactose and high molecular weight polyethylene glycols and the like.

[0325] Tablets can be made by compression or molding, optionally with one or more auxiliary agents. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding a mixture of the composition of the present invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0326] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the composition of the present invention, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame), glycerol, tetrahydrofuranylethanol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0327] Suspensions, in addition to the compositions of the present invention, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0328] Formulations for rectal or vaginal administration may be presented in the form of suppositories, which may be prepared by mixing the compositions of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0329] Dosage forms for transdermal administration of the compositions of the invention include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

[0330] Ointments, pastes, creams and gels may contain, in addition to the compositions of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0331] In addition to the compositions of the invention, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorocarbons and unsubstituted volatile hydrocarbons, for example butane and propane.

[0332] The compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Sonic nebulizers may be used because they minimize exposure of the agent to shear, which may degrade the compounds contained in the compositions of the present invention. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of the present invention with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular composition of the present invention, but typically include nonionic surfactants (Tweens, copolymers Pluronics, or polyethylene glycol); harmless 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.

[0333] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise a composition of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use, such sterile powders may contain antioxidants, buffers, bacteriostats, solutes or suspending agents or thickening agents which render the preparation isotonic with the blood of the intended recipient.

[0334] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0335] In another aspect, an enteral pharmaceutical formulation is provided, which includes a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluids at a specific pH. The small intestine is a portion of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5.

[0336] Thus, the enteric material is insoluble until, for example, the pH is 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, methyl methacrylate and methacrylic acid; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers; natural resins such as zein, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of each of the above materials is known or can be easily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art who have the benefit of the present invention will recognize that it is not comprehensive and there are other enteric materials that meet the objectives described herein.

[0337] Advantageously, kits are provided herein for use by consumers who, for example, need treatment of cancer. Such kits include suitable dosage forms, such as those described above; and instructions describing methods of using such dosage forms to mediate, reduce or prevent inflammation. The instructions will guide the consumer or medical personnel to administer the dosage form according to the mode of administration known to those skilled in the art. Such kits can advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules and the like). Blister packs generally consist of a sheet of relatively rigid material covered with a preferably transparent foil of plastic material. During the packaging process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. Subsequently, the tablet or capsule is placed in the recess and the sheet of relatively rigid material is sealed on the side of the foil opposite to the direction in which the recess is formed, relative to the plastic foil. Thus, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that a tablet or capsule can be removed from the blister pack by manually applying pressure on the groove, thereby forming an opening in the sheet at the recess placement. Subsequently, the tablet or capsule can be removed through the opening.

[0338] It may be necessary to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days in the dosing regimen when such specified tablets or capsules should be taken. Another example of such a memory aid is a schedule printed on a card, for example as follows "First week, Monday, Tuesday... etc.... Second week, Monday, Tuesday... etc. ". Other variations of memory aids are obvious. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a specified day. In addition, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this. Example

[0339] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that, unless otherwise indicated, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration and processing procedures) can be selected as standard conditions for the reaction. It should be understood by those skilled in the art that the functional groups present on multiple parts of the molecule should be compatible with the proposed reagents and reactants. Substituents that are not compatible with the reaction conditions are obvious to those skilled in the art, and therefore indicate alternative methods. The starting materials in the embodiments are commercially available or easily prepared from known materials by standard methods.

[0340] The following abbreviations are used in the present invention and have the following definitions: "ADP" is adenosine diphosphate, "Boc" is tert-butyl carbonate, "CDI" is carbonyldiimidazole, "conc." is concentrated, "Cs2CO3" is cesium carbonate, "CuI" is copper (I) iodide, "DBU" is 1,8-diazabicyclo [5.4.0] undec-7-ene, "DCC" is N,N'-dicyclohexylcarbodiimide, "DCE" is dichloroethane, "DCM" is dichloromethane, "DIEA" is N,N-diisopropylethylamine, "DMA" is N,N-dimethylacetamide, "DMAP" is 4-(dimethylamino)pyridine, "DMF" is N,N-dimethylformamide, "dppf" is 1,1'-bis (diphenylphosphino) ferrocene, and "DMEM" is Dulbecco's Modified Eagle's Medium (Dulbecco's Modified Eagle's Medium). Media), "DMSO" is dimethyl sulfoxide, "DPPA" is diphenylphosphoryl azide, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, "ESI" is electrospray ionization, "Et2O" is diethyl ether, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is one or more hours, "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, "IC 50” is the half maximal inhibitory concentration, “K2CO3” is potassium carbonate, “K3PO4” is potassium phosphate, “LiMHDS” is lithium bis(trimethylsilyl)amide, “MeCN” is acetonitrile, “MeOH” is methanol, “Me4tBuXPhos” is di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine, “MgSO4” is magnesium sulfate, “MHz” is megahertz, and “min ” is one or more minutes, “MS” is mass spectrometry, “MTBE” is methyl tert-butyl ether, “NADH” is nicotinamide adenine dinucleotide, “NaH” is sodium hydride, “NaHCO3” is sodium bicarbonate, “Na2SO4” is sodium sulfate, “NH4Cl” is ammonium chloride, “NaSMe” is sodium thiomethoxide, “NBS” is N-bromosuccinimide, “NMR” is nuclear magnetic resonance, “PBS” is phosphate buffered saline, “Pd / C” is palladium on carbon, “Pd2(dba)” is 1,1-dione. )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, which is also called "ambient temperature", which is understood to consist of the range of normal laboratory temperatures in the range of 15-25°C, and "sat" is room temperature. d." is saturated, "T3P" is n-propanephosphoric 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.

[0341] General chemical methods

[0342] The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the schemes below, including the preparation of the intermediates and the accompanying examples.

[0343] Synthesis process

[0344] Process 1

[0345]

[0346] Scheme 1 illustrates an exemplary preparation of amines DIi, DI-ii and DI-iii. In the presence of a base (e.g., Cs2CO3 or K2CO3), an amine R 4Compound BI is further treated with commercially available borate / boronic acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction. 2a The intermediate CI can be selectively converted to the amine DIi by mild reducing conditions (such as zinc or iron metal and ammonium chloride), wherein R 2b is alkenyl, alkynyl or cycloalkyl. Intermediate CI can be completely reduced to DI-iii by palladium-catalyzed hydrogenation. 2a Intermediate BI which is Cl, Br, alkyl, CN or alkoxy can be reduced to DI-ii by mild reducing conditions such as zinc or iron metal and ammonium chloride.

[0347] In Scheme 1, examples of X include N and CH, and examples of Y include N, CH and CF, wherein neither X nor Y is N, and R 2 Examples of include alkyl and cycloalkyl groups, and R 4 Examples include N-linked alkyl and N-linked heterocyclyl, wherein suitable optional substituents are exemplified by the following table of intermediates.

[0348] Process 2

[0349]

[0350] Scheme 2 illustrates an exemplary preparation of amines D-II-i, D-II-ii, and D-II-iii. A-II (commercially available starting material) is reacted with an 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 -H reaction to give compound B-II. In the presence of a palladium catalyst (Suzuki coupling) or Sonogashira coupling reaction, the R 2a B-II with Br gives compound C-II. Intermediate C-II can be selectively converted to amine D-II-i by mild reducing conditions (e.g., zinc or iron metal with ammonium chloride), wherein R 2b is alkenyl, alkynyl or cycloalkyl. Intermediate C-II can be completely reduced to D-II-iii by palladium-catalyzed hydrogenation. 2a Intermediate B-II which is Cl, Br, alkyl, CN or alkoxy can be reduced to D-II-ii by mild reducing conditions (eg zinc or iron metal with ammonium chloride).

[0351] In Scheme 2, examples of X include N and CH, and examples of Y include N, CH and CF, wherein neither X nor Y is N, and R 2 Examples of include alkyl and cycloalkyl groups, and R 4Examples include N-linked alkyl and N-linked heterocyclyl, wherein suitable optional substituents are exemplified by the following table of intermediates.

[0352] Process 3

[0353]

[0354] Scheme 3 illustrates an exemplary preparation of amines D-III-i, D-III-ii, and D-III-iii, wherein L is -CH2-CH2-. Reduction of A-III-i with a reducing agent such as DIBAL provides the aldehyde A-III-ii. Another way to prepare A-III-ii is by reduction of A-III-i to the corresponding alcohol followed by mild oxidative conditions such as using MnO2. A-III-ii is reacted with an 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 Another method for preparing B-III is to reduce A-III-I to ethanol, and then convert the ethanol to sulfonate A-III-iii. In the presence of a base (such as triethylamine, huonine or cesium carbonate), A-III-iii is reacted with an amine R 4 The reaction of -H affords B-III. The R 2a B-III with Br gives compound C-III. Intermediate C-III can be selectively converted to amine D-III-iii by mild reducing conditions (e.g., zinc or iron metal with ammonium chloride), wherein R 2b is alkenyl, alkynyl or cycloalkyl. Intermediate C-III can be completely reduced to D-III-ii by palladium-catalyzed hydrogenation. 2a Intermediate B-III which is Cl, Br, alkyl, CN or alkoxy can be reduced to D-III-i by mild reducing conditions (eg zinc or iron metal with ammonium chloride).

[0355] In Scheme 3, examples of X include N and CH, examples of Y include N, CH and CF, wherein both X and Y are not N, examples of R include methyl and ethyl, and R 2 Examples include alkyl and cycloalkyl groups, R 4 Examples of include N-linked alkyl and N-linked heterocyclic groups with optionally selected substituents, as illustrated by the following table of intermediates, and examples of LG include mesylate and tosylate.

[0356] Process 4

[0357]

[0358] Scheme 4 illustrates an exemplary preparation of amine D-IV, wherein L is a direct bond -CH2- or -CH2-CH2-. Reaction of A-III-i with various amines in the presence of a catalytic amount of DMAP (if necessary) in the presence of an amide coupling reagent (e.g., CDI, DCC, EDC, HOBt, HBTU, PyBOP or T3P) affords amide B-IV.

[0359] The R 2a B-IV with Br gives compound C-IV. Intermediate C-IV can be selectively converted to amine D-IV-i by mild reducing conditions (e.g., zinc or iron metal with ammonium chloride), wherein R 2b is alkenyl, alkynyl or cycloalkyl. The intermediate C-IV can be completely reduced to D-IV-iii by palladium-catalyzed hydrogenation. 2a Intermediate B-IV which is Cl, Br, alkyl, CN or alkoxy can be reduced to D-IV-ii by mild reducing conditions such as zinc or iron metal with ammonium chloride.

[0360] In Scheme 4, examples of X include N and CH, examples of Y include N, CH and CF, wherein both X and Y are not N, examples of R include methyl and ethyl, and R 2 Examples of include alkyl and cycloalkyl groups, and R 4 Examples include -(CH2) m -C(O)-B and -(CH2) m -C(O)-N(R5)R6, wherein m is 0, 1 or 2.

[0361] Process 5

[0362]

[0363] Scheme 5 illustrates an exemplary preparation of amine DV. BV is reacted with a borate ester / boric acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to give compound CV. Many borate esters / boric acids / trifluoroborates are commercially available, and those that are not commercially available can be readily prepared from the corresponding carboxylic acids (see Scheme 21). Intermediate CV can be converted to amine DV by standard reduction conditions, such as by palladium-catalyzed hydrogenation or by mild reduction conditions including zinc metal and ammonium chloride.

[0364] In Scheme 5, examples of X include N and CH, examples of Y include N, CH and CF, and R 2 Examples of include alkyl and cycloalkyl groups, and R 4 Examples include C-linked heterocyclic and heterocyclic groups, wherein suitable optional substituents are exemplified by the following table of intermediates.

[0365] Process 6

[0366]

[0367] Scheme 6 illustrates an exemplary preparation of D-VI from C-VI-i, wherein in C-VI-i, R 4 Contains a nitrogen protecting group, such as a Boc group. C-VI-i can be deprotected under acidic conditions to provide an amine salt. The salt is further treated with sodium cyanoborohydride or sodium triacetoxyborohydride and an aldehyde or ketone in a polar solvent such as MeOH (reductive amination conditions) in the presence of a catalytic amount of acetic acid to provide C-VI. Intermediate C-VI can be converted to aniline D-VI by standard reducing conditions (e.g., by palladium-catalyzed hydrogenation), or by mild reducing conditions including zinc metal and ammonium chloride.

[0368] In Scheme 6, examples of X include N and CH, examples of Y include N, CH and CF, wherein both X and Y are not N, examples of PG include Boc protecting group, R 2 Examples include alkyl and cycloalkyl groups, R 4 Examples include heterocyclic groups, R 6 Examples include alkyl and cycloalkyl, wherein suitable optional substituents are exemplified by the following table of intermediates.

[0369] Process 7

[0370]

[0371] In some embodiments, the universal pyrazolamine D-VII-i or D-VII-ii is prepared by two methods shown in Scheme 7. In this scheme, R is shown 4-L linked 7-1 or 7-2. One method involves alkylating B-VII (easily 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, or the like) at temperatures between ambient and 150°C to give nitro-pyrazoles C-VII-i and / or C-VII-ii. An alternative preparation of D-VII-i or D-VII-ii involves the reaction of B-VII with Mitsunobu of commercially available 7-2 to give nitro-pyrazoles C-VII-i and C-VII-ii. It will be appreciated by those skilled in the art that when produced as a mixture, C-VII-i and C-VII-ii are separated by SFC purification, crystallization, or chromatography. Finally, hydrogenation of nitro-pyrazoles C-VII-i and C-VII-ii in the presence of a hydrogenation catalyst such as palladium or nickel or mild reducing conditions such as zinc or iron and ammonium chloride affords pyrazole-amines D-VII-i and D-VII-ii.

[0372] In Scheme 7, examples of LG include Cl and Br, R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, R 4 Examples include heterocyclic groups, C(O)NR 6 R 9 and NR 6 R 9 , where R 6 and R 9 Each may independently be H or alkyl, examples of L include -(CH2) m -, where m can be 0, 1, 2 or 3, and when m is 0, R 4 is C connected to pyrazole, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 Connect to N or connect to C to L.

[0373] Process 8

[0374]

[0375] Single R 2 (That is, R 2Other examples of general pyrazole-amines D-VIII-i and D-VIII-ii substituted with (not hydrogen) are prepared as described in Scheme 8. Keto-ester A-VIII-i is reacted with N,N-dimethylformamide dimethyl acetal or triethyl orthoformate / acetic anhydride to afford A-VIII-ii (wherein LG is a suitable leaving group required in the sequential cyclization / pyrazole formation reaction). A-VIII-ii is reacted with hydrazine 10-1 (readily available to those skilled in the art) in the presence of an acid to afford primarily B-VIII-i or its regioisomer B-VIII-ii. The regiochemistry of the cyclization is controlled under conditions familiar to those skilled in the art, such as temperature and solvent. 2 The conditions for synthesizing B-VIII-ii include: wherein LG is OEt, in the presence of an acid, in a protic solvent (such as ethanol) at low temperature (-10°C to RT). The conditions for synthesizing B-VIII-ii include: wherein LG is NMe2, in the presence of an acid, in a protic solvent (such as ethanol) at reflux. Subsequently, the ester B-VIII-i or B-VIII-ii is converted to the corresponding acid C-VIII-i or C-VIII-ii using standard conditions known to those skilled in the art. C-VIII-i or C-VIII-ii is converted to the corresponding amine D-VIII-i or D-VIII-ii by Curtius rearrangement.

[0376] In Scheme 8, examples of LG include OMe, OEt and N(CH3)2, R 2 Examples include alkyl and cycloalkyl groups, wherein the alkyl and cycloalkyl groups may be optionally fluorinated, R 4 Examples include heterocyclic groups and NR having suitable optionally selected substituents as exemplified by the following table of intermediates: 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, examples of L include -(CH2)m-, wherein m may be 0, 1, 2 or 3, and when m is 0, R 4 is C connected to pyrazole, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 Connect to N or connect to C to L.

[0377] Process 9

[0378]

[0379] R 2 and R 3 = alkyl, cycloalkyl or branched alkyl. All are optionally fluorinated.

[0380] In a similar manner to Scheme 8, Scheme 9 illustrates the general preparation of amine D-IX. Pyrazole ester B-IX is prepared by reaction of hydrazine 10-1 (readily available to one skilled in the art) with intermediate A-IX. In some embodiments, R 2 and R 3 The parts vary independently, making R 3 With 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 Curtis rearrangement conditions known to those skilled in the art.

[0381] In Scheme 9, R 2 and R 3 Examples of may independently include alkyl and cycloalkyl, wherein the alkyl and cycloalkyl may be optionally fluorinated, R 4 Examples include heterocyclic groups and NR having suitable optionally selected substituents as exemplified by the following table of intermediates: 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, examples of L include -(CH2)m-, wherein m may be 0, 1, 2 or 3, and when m is 0, R 4 is C connected to pyrazole, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 Connect to N or connect to C to L.

[0382] Process 10

[0383]

[0384] In some embodiments, non-commercially available hydrazines 10-1 are readily prepared by the two methods shown in Scheme 10. One method involves diazotizing the amine 10-2, followed by reduction using conditions familiar to those skilled in the art in the presence of a proton source, such as by treatment with Sn(II)Cl2. Alternatively, hydrazine 10-1 can be obtained 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, the conversion of carbamate 10-3 to hydrazine 10-1 is also achieved in situ within the reaction sequence. Therefore, in all processes in which hydrazine 10-1 is typically used in the presence of an acid, carbamate 10-3 is a substitute for hydrazine 10-1. N-tert-butoxycarbonylhydrazine 10-3 can be prepared by reductive amination with commercially available aldehydes or ketones 10-4 and tert-butyl hydrazinecarboxylate.

[0385] In Scheme 10, R 4Examples include heterocyclic groups and NR having suitable optionally selected substituents as exemplified by the following table of intermediates: 6 R 9 , where R 6 and R 9 Each may be independently an alkyl group, and examples of L include -(C(R 7 )2) m -, where R 7 An example of is H, and wherein m may be 0, 1, 2 or 3, and when m is 0, R 4 When m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 Connect to N or connect to C to L.

[0386] Process 11

[0387]

[0388] R 2 = alkyl, cycloalkyl, branched alkyl, halogen, CN or alkoxy. All are optionally fluorinated.

[0389] In some embodiments, the universal pyrazolamines D-VII-i and D-VII-ii are prepared as shown in Scheme 11. In this scheme, R is shown 4 Alkylation of B-VII with 11-1 (easily available to those skilled in the art) affords a mixture of nitropyrazoles B-VII-i and B-VII-ii. The 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 with MsCl or TsCl to afford B-VII-iii or B-VII-iv, respectively. 4 -H displacement of OMs or OTs affords C-VII-i or C-VII-ii, respectively. Finally, hydrogenation of the nitro-pyrazole C-VII-i or C-VII-ii in the presence of a hydrogenation catalyst such as palladium or nickel or mild reducing conditions such as zinc or iron and ammonium chloride affords the pyrazole-amine D-VII-i or D-VII-ii.

[0390] In Scheme 11, examples of LG include Cl and Br, examples of R include mesylate and tosylate, and R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9, where R 6 and R 9 Each may independently be an alkyl group, examples of L include -(CH2)m, wherein m is 2 or 3, and R 4 For N connections.

[0391] Process 12

[0392]

[0393] Scheme 12 illustrates the synthesis of the universal amines DXi and DX-ii. Thus, commercially available aldehydes are condensed with glyoxal in the presence of ammonium hydroxide to afford R 2 Substituted imidazole AX. In this scheme, R 4 -L connected 7-1 or 7-2 example. Nitration of imidazole AX by conditions known to those skilled in the art (e.g., nitric acid / concentrated sulfuric acid at a temperature ranging from 0°C to 100°C) yields nitroimidazole BXi. BXi is converted into a mixture of CXi and CX-ii by alkylation (7-1) or Mitsunobu reaction (7-2). In some embodiments, substituted nitro-imidazoles CXi and CX-ii can be obtained by alkylation (7-1) or Mitsunobu reaction (7-2) from AX to give BX-ii. BX-ii is then nitrated to give CXi and CX-ii. The two regioisomers CXi and CX-ii can be separated by SFC purification, crystallization or chromatography. In the presence of a hydrogenation catalyst such as palladium or nickel or mild reducing conditions such as zinc or iron and ammonium chloride, each nitroimidazole CXi and CX-ii are reduced to give the corresponding imidazole amines DXi and DX-ii, respectively.

[0394] In Scheme 12, examples of LG in reagent 7-1 include Cl and Br, R 2 Examples include alkyl and cycloalkyl groups, wherein the alkyl and cycloalkyl groups may be optionally fluorinated, R 4 Examples include heterocyclic groups and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, examples of L include -(CH2) m -, wherein m can be 2 or 3, and L is N connected to the imidazole ring.

[0395] Process 13

[0396]

[0397] As illustrated in Scheme 13, in some embodiments, substituted thiazole amines D-XI can be prepared from appropriately substituted thiazoles A-XI (easily available to those skilled in the art). This method has been described in WO2006072436, the contents of which are hereby incorporated by reference in their entirety. Using fuming nitric acid or nitric acid with sulfuric acid, nitration of bromothiazole A-XI gives bromonithiazole B-XI. Conditions familiar to those skilled in the art (such as Buchwald, Ullmann or nucleophilic aromatic substitution reactions) can be used in the presence of TEA or K2CO3 by various amines R 4 -H replaces the bromine functional group on B-XI to give C-XI, where R 4 is N-linked. Suzuki reaction (see Scheme 21) using B-XI with commercially available or synthetic boronate esters T (including but not limited to other boron salts) provides C-XI, wherein R 4 Finally, hydrogenation of C-XI in the presence of a hydrogenation catalyst such as palladium or nickel or mildly reducing conditions such as zinc or iron and ammonium chloride affords the corresponding thiazole amine D-XI.

[0398] In Scheme 13, R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, and R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group.

[0399] Process 14

[0400]

[0401] As illustrated in Scheme 14, in some embodiments, substituted thiazole amines D-XII can be prepared from appropriately substituted thiazoles A-XI (easily available to those skilled in the art). This method has been described in WO2009158373, WO2016135163, and WO2011075515, the contents of which are hereby incorporated by reference in their entirety. Nitration of bromothiazole A-XI using fuming nitric acid or nitric acid with sulfuric acid affords bromonithiazole B-XI. The bromo functionality on B-XI can be displaced by various linker (L) synthons using conditions familiar to those skilled in the art such as carbonylation (C-XII-ia), Negishi reaction (zinc-mediated coupling conditions (C-XII-ib)), Sonogashira or Heck coupling reactions, followed by appropriate reduction to afford C-XII-ic, a C-C connection. C-XII-ia, C-XII-ib and C-XII-ic can be reduced to primary alcohols, followed by mesylation or tosylation to form C-XII-ii. 4 -H, nucleophilic substitution of C-XII-ii to give C-XII-iii. Finally, reduction of C-XII-iii in the presence of a hydrogenation catalyst such as palladium or nickel or mild reducing conditions such as zinc or iron and ammonium chloride gives the corresponding thiazole amine D-XII.

[0402] In Scheme 14, examples of LG include OTs and OMs, examples of R include methyl and ethyl, and R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, R 4 Examples include heterocyclic groups and NR having suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, and examples of L include -(CH2)m-, wherein m may be 1, 2 or 3.

[0403] Process 15

[0404]

[0405] In a similar reaction sequence as shown in Scheme 15, bromothiazole A-XIII (readily available to one skilled in the art) provides thiazole-amine D-XIII (Science of Synthesis, 627, 2002).

[0406] In Scheme 15, R 2Examples include alkyl, cycloalkyl, alkoxy, halogen or CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, and R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group.

[0407] Process 16

[0408]

[0409] As illustrated in Scheme 16, in some embodiments, substituted thiazole amines D-XIV can be prepared from appropriately substituted thiazoles A-XIII (easily available to those skilled in the art). This method has been described in WO2009158373, WO2016135163, and WO2011075515, the contents of which are hereby incorporated by reference in their entirety. Using fuming nitric acid or nitric acid with sulfuric acid, nitration of bromothiazole A-XIII gives bromonithiazole B-XIII. The bromo functionality on B-XIII can be substituted using conditions familiar to those skilled in the art such as carbonylation (C-XIV-ia), Negishi reaction (zinc-mediated coupling conditions (C-XIV-ib)), Sonogashira or Heck coupling reactions, from various R 4 C-XIV-ia, C-XIV-ib, and C-XIV-ic can be reduced to primary alcohols and then mesylated or tosylated to form C-XIV-ii. 4 -H, nucleophilic substitution of C-XIV-ii to give C-XIV-iii. Finally, reduction of C-XIV-iii under hydrogen catalysts such as palladium or nickel or mild reducing conditions such as zinc or iron and ammonium chloride gives the corresponding thiazole-amine D-XIV.

[0410] In Scheme 16, examples of LG include OTs and OMs, examples of R include methyl and ethyl, and R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen and CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, R 4 Examples include heterocyclic groups and NR having suitable optional substituents as exemplified by the table of intermediates below. 6 R 9 , where R 6 and R 9Each may independently be an alkyl group, and examples of L include -(CH2)m-, wherein m may be 1, 2 or 3.

[0411] Process 17

[0412]

[0413] Scheme 17 describes the synthesis of substituted oxazoles D-XV as reported in WO2014078378, the contents of which are hereby incorporated by reference in their entirety. 2 Substituted aminoalkanenitrile 17-1 (readily available to one skilled in the art) is reacted to afford A-XV-ii. A-XV-ii is converted to oxazolamine D-XV under acidic conditions such as acetic acid, sulfuric acid or hydrochloric acid.

[0414] In Scheme 17, R 2 Examples of include alkyl, cycloalkyl and alkoxy, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, and R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, and examples of L include -(CH2) m -, where m can be 0, 1, 2 or 3.

[0415] Process 18

[0416]

[0417] As shown in Scheme 18, some substituted oxazoles can be prepared from carboxylates A-XVI substituted with 2-diazo-3-oxo groups as reported in Synlett, 1996, 1171, the contents of which are hereby incorporated by reference in their entirety. After treating diazoester A-XVI with primary amide 18-1 (easily available to those skilled in the art) under Rh-catalyzed coupling conditions, amide B-XVI is obtained. Under cyclodehydration conditions, using a dehydrating agent (e.g., POCl3, T3P or Burgess reagent), intermediate B-XVI is used to give oxazole ester C-XVI-i. Hydrolysis of oxazole ester C-XVI-i gives carboxylic acid C-XVI-ii, which is converted to oxazole amine D-XVI using sodium azide or DPPA under Curtis rearrangement.

[0418] In Scheme 18, R 2 Examples of include alkyl, cycloalkyl and alkoxy, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, and R 4Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, and examples of L include -(CH2) m -, where m can be 0, 1, 2 or 3.

[0419] Process 19

[0420]

[0421] As shown in Scheme 19, in other embodiments, oxazolamine D-XVII can be prepared from 2-halo oxazole C-XVII-i as described in WO2012033195, the contents of which are hereby incorporated by reference in their entirety. C-XVII-i is reacted with various amines R under Buchwald coupling conditions. 4 -H reaction to obtain 2-aminoalkyl-substituted oxazole C-XVII-ii, wherein R 4 The Suzuki reaction of C-XVII-i with commercially available or synthesized boronate esters T (including but not limited to other boron salts) (see Scheme 21) is used to provide CI-21, wherein R 4 Hydrolysis of the oxazole ester C-XVII-i affords the carboxylic acid, which is converted to the oxazole amine D-XVII under Curtis rearrangement using sodium azide or DPPA.

[0422] In Scheme 19, R 2 Examples include alkyl, cycloalkyl or alkoxy, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, and R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group.

[0423] Process 20

[0424]

[0425] 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 is shown. 4-L connected 7-1 or 7-2 example. By using Asian J.of Chem, 2014, 26, 4744 and Hanneng Cailliao, 2008, 16, 49 described in the procedure and aldehyde 20-1 (those skilled in the art can easily obtain) reaction, by dinitroester A-XVIII-i prepare triazole B-XVIII, its content is hereby incorporated by reference as a whole herein. Alternatively, B-XVIII can be prepared by nitration A-XVIII-ii. By alkylation (7-1) or Mitsunobu reaction (7-2), B-XVIII is converted into a mixture of C-XVIII-i and C-XVIII-ii. These two regioisomers C-XVIII-i and C-XVIII-ii can be separated by SFC purification, crystallization or chromatography. Reduction of nitrotriazole CI-22 or CI-23 in the presence of a hydrogenation catalyst such as palladium or nickel or under mild reducing conditions such as zinc or iron and ammonium chloride affords the corresponding triazole amines D-XVIII-i and D-XVIII-ii, respectively.

[0426] In Scheme 20, R 2 Examples include alkyl, cycloalkyl, alkoxy, halogen or CN, wherein the alkyl, cycloalkyl or alkoxy may be optionally fluorinated, R 4 Examples include heterocyclic and NR having suitable optionally selected substituents as exemplified by the following table of intermediates 6 R 9 , where R 6 and R 9 Each may independently be an alkyl group, examples of L include -(CH2) m -, where m is 2 or 3.

[0427] Process 21

[0428]

[0429] Scheme 21 illustrates the general preparation of non-commercially available boronic acids / boronates T. These compounds can be readily prepared from substituted carboxylic acids. The carboxylic acid can be activated by 2-hydroxyisoindoline-1,3-dione in the presence of a coupling agent such as DCI or Et3N / HATU to afford Q. Intermediate Q is converted to boronate T by nickel-catalyzed decarboxylation borylation with [B2pin2Me]Li complex, which is premixed with methyllithium and B2pin2 (Science, 2107, 356, 1045 and JACS, 2016, 138, 2174), the contents of which are hereby incorporated by reference in their entirety.

[0430] In Scheme 21, R 4Examples of include alkyl, cycloalkyl and heterocyclyl groups with suitable optional substituents as exemplified by the following table of intermediates, and examples of L include -(CH2)m-, wherein m may be 0, 1, 2 or 3, and when m is 0, R 4 is C connected to the borate ester, when m is 1, then R 4 is connected to L, and when m is 2 or 3, then R 4 Connect to N or connect to C to L.

[0431] Process 22

[0432]

[0433] Scheme 19 illustrates 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 (US20150284341, the contents of which are hereby incorporated by reference in their entirety). Difluoromethylpyrimidine L-II-1 can be converted to methylthiopyrimidine LI-1 (WO2012110773, the contents of which are hereby incorporated by reference in their entirety) by treatment with diethyl ether containing sodium thiomethoxide and zinc chloride at a temperature below 10°C. Trifluoromethylpyrimidine LI-2 can be prepared from commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine L-II-2 in a manner similar to LI-1.

[0434] Process 23

[0435]

[0436] Scheme 23 illustrates that R 1 General formula of sulfonylpyrimidine L-III (t=2) which may be cycloalkyl

[0437] Preparation. Commercially available 5-bromo-2-chloro-6-(methylthio)pyrimidine was treated with borate / boric acid / trifluoroborate in the presence of a palladium catalyst (Suzuki coupling) to afford R 1 Substituted thiopyrimidine L-III (t = 0). R in this scheme 1 Examples 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 by mCPBA.

[0438] Process 24

[0439]

[0440] Scheme 24 illustrates the general preparation of HI. In the presence of a base (Et3N or DIEA), in DCM

[0441] Commercially available EI is treated with a commercially available acyl chloride (FI) to give the amide GI. Many acyl chlorides (FI) are commercially available, and those that are not commercially available can be readily prepared from the corresponding carboxylic acid FI-1 with SOCl2 in the presence of a base (Et3N or DIEA). 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 an alkyl group and a cycloalkyl group (eg, cyclobutyl group).

[0442] Process 25

[0443]

[0444] Scheme 25 illustrates the general preparation of H-II. Compound G-II can be prepared by reacting amine E-II with commercially available isocyanate F-II. A variety of isocyanates are commercially available, and those that are not commercially available can be readily prepared from the corresponding carboxylic acids or amines (see Scheme 27). The Boc protecting group of G-II can be removed upon exposure to an acid such as HCl or TFA. In Scheme 25, R 9 Examples of may include alkyl and cycloalkyl (eg, cyclobutyl) and R 6 Examples of may include H and alkyl.

[0445] Process 26

[0446]

[0447] Scheme 26 illustrates the general preparation of H-III. Compound G-III can be prepared by reacting amine E-III with 2,2,2-trichloroethyl carbamate 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 after exposure to an acid such as HCl or TFA. In Scheme 26, R 9 Examples of may include alkyl and cycloalkyl (eg, cyclobutyl) and R 6 Examples of may include H and alkyl.

[0448] Process 27

[0449]

[0450] Scheme 27 illustrates the general preparation of isocyanate F-II and carbamate F-III. Non-commercial isocyanate F-II can be prepared from amines or carboxylic acids. Reaction of the amine with phosgene or a phosgene equivalent (such as diphosgene, triphosgene, or N,N'-dicarbonylimidazole) provides isocyanate F-II. Alternatively, isocyanate F-II can be obtained directly from the carboxylic acid by the Curtis 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 temperature of the reactants is raised to about 80-120°C. Certain carbamates F-III can also be prepared by the Curtis rearrangement in the presence of a suitable alcohol such as triethanol. Trichloroethyl carbamate F-III is also readily prepared from amines by acylation with trichloroethyl chloroformate under standard conditions.

[0451] Process 28

[0452]

[0453] Scheme 28 illustrates the general preparation of key intermediates J and K. Key intermediate J can be prepared from H (free base or salt) and thiopyrimidine LI in the presence of an organic base (e.g., triethylamine or DIEA), optionally with heating. In a similar manner, key intermediate K can be prepared from H by reaction with L-II or L-III.

[0454] Process 29

[0455]

[0456] Scheme 29 illustrates the general preparation of the key intermediate M. Treatment of H with commercially available chloroiodopyridine under Buchwald-Hartwig coupling conditions (Cs2CO3, Xantphos, and Pd(OAc)2), typically in an aprotic solvent such as DME, DMF, DMSO, or NMP at temperatures ranging from ambient to 140°C, affords the key intermediate M.

[0457] Process 30

[0458]

[0459] Scheme 30 illustrates the general preparation of compounds of formula I-1 from substituted D. The preparation of formula I-1 can be achieved from key intermediates K and J. K is subjected to a first nucleophilic substitution reaction with an amine of formula D, typically in a polar solvent at a temperature ranging from ambient temperature to 150°C, and in some embodiments, optionally in the presence of an acid (e.g., 4N HCl in 1,4-dioxane) and microwave heating to obtain formula I-1. Non-commercially available compound D can be readily prepared (see Scheme 1-20). An alternative general synthesis of formula I is by a two-step process, first converting J (t=0) to a sulfoxide J (t=1) by oxidation using various oxidants such as mCPBA. The sulfoxide reacts with the amine D by a nucleophilic substitution reaction, typically in a polar solvent at a temperature ranging from ambient temperature to 150°C, and in some embodiments, optionally in the presence of an acid (e.g., 4N HCl in 1,4-dioxane) or pTSA and microwave heating. 4 The nitrogen protecting group of the Boc group on the formula I-1 can be deprotected under acidic conditions to obtain the formula I-1 (R 4 Formula IA (free base or salt) is further treated 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) to give Formula I-1, wherein R 4 Contains nitrogen substituted with an alkyl or cycloalkyl group. For acylation and sulfonylation, the free amine (or salt) can be treated with a commercially available acyl chloride or sulfonyl chloride to give Formula I-1, wherein R 4 Contains nitrogen substituted with acyl or sulfonyl. In Scheme 30, Ring A can be phenyl or pyridyl (eg, X = a ring containing Y) or a 5-membered heteroaryl (eg, a ring containing X1-Y-X2).

[0460] Process 31

[0461]

[0462] Scheme 31 illustrates the general preparation of compounds of formula I-2. The 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 Scheme 1-12). After deprotection of formula I-2 containing a nitrogen protecting group such as a Boc group, reductive alkylation, acylation, and sulfonylation can be performed in a manner similar to that shown in Scheme 30 to provide formula I-2. In Scheme 31, ring A can be phenyl or pyridyl (e.g., X = a ring containing Y) or a 5-membered heteroaryl (e.g., a ring containing X1-Y-X2).

[0463] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were prepared:

[0464] Preparation of intermediates

[0465] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were prepared:

[0466] General Method A: Aromatic Nucleophilic Substitution:

[0467] Intermediate A1: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine

[0468]

[0469] 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 KCO (63 g, 455 mmol) at room temperature, and the reaction mixture was stirred at 60 ° C for 16 hours. The reaction mixture was diluted with ice water (500 mL), and the precipitated solid was filtered. The solid was further triturated with EtO and n-pentane to obtain 1- (3-bromo-4-nitrophenyl) -4-methylpiperazine (58 g, 85% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):d 7.98 (d, J = 9.4Hz, 1H), 7.24 (d, J = 2.1Hz, 1H), 7.01 (dd, J = 2.2 and 9.4Hz, 1H), 3.42 (m, 4H), 2.40 (m, 4H), 2.19 (s, 3H); LC-MS (ESI) m / z: 299.0 (M+H) + ).

[0470] General method B: Deprotection and reductive amination:

[0471] Intermediate A2: 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0472]

[0473] 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 4N HCl (16 mL, 62 mmol) in 1,4-dioxane, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under vacuum to give 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (2.17 g, 100% yield) as a white solid. The material was used without further purification. A suspension of 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (1.92 g, 5.5 mmol) in DCE (25 mL) was treated with DIEA (2.9 mL, 17 mmol) and formaldehyde (1.2 mL, 17 mmol). The yellow suspension 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, which 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 an aqueous NaHCO solution (50 mL), and the solution was extracted with DCM (3×50 mL). The combined organics were dried over anhydrous NaSO, 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 (400MHz, DMSO-d6): δ7.98 (d, J = 9.4Hz, 1H), 7.10 (d, J = 2.7Hz, 1H), 6.89 (dd, J = 9.5 and 2.7Hz, 1H), 3.54 (d, J = 11.6Hz, 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) + ).

[0474] General Method C: Alkylation:

[0475] Intermediate A3: 1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine

[0476]

[0477] A mixture of 1-(3-methyl-4-nitrophenyl)piperazine hydrochloride (Boc deprotected product of A4, 1.5 g, 0.58 mmol) and KCO (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 tends to be unstable—some solids are present in the liquid], capped tightly and heated to 100° C. for 24 hours. The mixture was cooled to room temperature, the solids (KCO) were removed by 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 which solidified to an amber solid upon 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 + ).

[0478] Using General Procedures AC above, the following intermediates in Table A were prepared.

[0479] Table A

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486] Intermediate A30: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazinyl-2-one.

[0487]

[0488] A mixture of tert-butyl (2-aminoethyl)(methyl)carbamate (4.3 g, 24 mmol) and potassium carbonate (3.8 g, 27 mmol) in DMF (50 mL) was treated with 4-fluoro-2-bromo-1-nitrobenzene (5 g, 22 mmol) at room temperature under N2 atmosphere and the mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water (200 mL) and the solution was extracted with EtOAc (2 x 100 mL), the combined organics were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (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 (400MHz, DMSO-d6): δ7.98(d,J=9.0Hz,1H),6.77(S,1H),6.46(d,J=9.0Hz,1H),3. 54(s,2H),3.31(t,J=6.0Hz,2H),2.90(s,3H),1.47(s,9H); LC-MS(ESI)m / z:374.1(M+H + ).

[0489] A mixture of tert-butyl ((2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 15 mmol) and TEA (7.6 g, 75 mmol) in DCM (100 mL) was treated with chloroacetyl chloride (5.1 g, 45 mmol) at 0°C under N2 atmosphere and the mixture was stirred at room temperature for 16 hours. 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 product was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (CV)) to give tert-butyl (2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetylamino)ethyl)(methyl)carbamate (5.6 g, 66% yield) as a yellow liquid. 1 H NMR (400MHz, DMSO-d6): δ8.12(d,J=8.6Hz,1H),7.97(s,1H),6.66(d,J=7.4Hz,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 + ).

[0490] A solution of N-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamide hydrochloride (5.6 g, 12 mmol) in dioxane (100 mL) was treated with 4N HCl (100 mL) in 1,4-dioxane at 0° C. under N atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, and the crude product 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 (400MHz, DMSO-d6): δ8.75 (brs, 2H), 8.16 (m, 2H), 7.83 (d, J = 7.8Hz, 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 + ).

[0491] To 60% NaH (1.1 g, 25 mmol) in mineral oil was added 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) at 0°C under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL), and the solution was extracted with EtOAc (2 x 50 mL). The combined organics were evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (2% MeOH / DCM, 10 column volumes (CV)) to give 1-(3-bromo-4-nitrophenyl)-4-methylpiperazin-2-one (3.1 g, 76% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.0 (d, J = 9.4Hz, 1H), 7.24 (d, J = 2.3Hz, 1H), 6.99 (dd, J = 2.3 and 9.3Hz, 1H), 4.0(s,2H),3.72(t,J=5.4Hz,2H),3.45(t,J=5.4Hz,2H),2.90(s,3H); LC-MS(ESI)m / z:314.2(M+H + ).

[0492] Intermediate A31: 1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine:

[0493]

[0494] A solution of (5-(4-methylpiperazin-1-yl)-2-nitrophenyl)methanol (1.0 g, 4.0 mmol) in DMF (30 mL) was cooled to 0 °C. Sodium hydride (0.80 g, 60% in mineral) was added portionwise, and the mixture was stirred under the same conditions. Iodomethane (1.7 g, 12 mmol) was added at 0 °C, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was diluted with EtOAc and carefully quenched with ice water. The mixture was extracted with EtOAc (3×30 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 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): δ8.03(m,1H),7.08(s,1H),6.96(m,1H),4.76(s,2H),3.4 5(brs,4H),3.40(s,3H),2.42(brs,4H),2.22(s,3H); LC-MS(ESI)m / z:266.2(M+H + ).

[0495] General method D: Suzuki coupling reaction:

[0496] Intermediate C1: 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole:

[0497]

[0498] 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 stirred. The reaction mixture was degassed by bubbling argon for two minutes and treated with Pd(dppf)Cl2.DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours. The reactants were diluted with water and extracted with DCM (4×25 mL). The organic phases were combined and dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum to give a black oil. The black oil was purified using silica gel (0-15% MeOH / DCM, 15 column volumes (CV)) to give 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, 47% yield). 1HNMR (400MHz, DMSO-d6): δ8.02(d,J=8.6Hz,1H),7.84(d,J=7.7Hz,2H),7.77(d, J=8.6Hz,1H),7.72(s,1H),3.70(s,3H),2.57(s,3H); LC-MS(ESI)m / z:218.2(M+H + ).

[0499] Using General Procedure D above, the following intermediates in Table B were prepared.

[0500] Table B

[0501]

[0502] General Method E: Alkylation and Mesylation:

[0503] Intermediate C1: 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate.

[0504]

[0505] (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 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by SFC purification to obtain 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-ol. 1 HNMR (400MHz, DMSO-d6): δ8.72 (s, 1H), 4.96 (t, J = 5.2, Hz, 1H), 4.12 (t, J = 5.2Hz, 2H), 3.73 (t, J = 5.2Hz, 2H), 2.42 (s, 3H); MS (ESI) m / z: 172.1 (M+1).

[0506] (B) A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl) ethyl-1-ol (5.0 g, 29 mmol) in DCM (50 mL) was treated with triethylamine (5.8 g, 58 mmol) at 0 ° C under N2 atmosphere, followed by methanesulfonyl chloride (5.0 g, 44 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with chilled water (20 mL). The solution was extracted with DCM (2 × 200 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 2-(3-methyl-4-nitro-1H-pyrazol-1-yl) ethyl methanesulfonate (6.0 g, 83% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.88 (s, 1H), 4.57 (t, J = 5.2, Hz, 2H), 4.46 (t, J = 5.2Hz, 2H), 3.32 (s, 3H), 2.45 (s, 3H); MS (ESI) m / z: 250.2 (M + H) + ).

[0507] General Method F: Nucleophilic Substitution Reaction:

[0508] Example C2: N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethan-1-amine

[0509]

[0510] A solution of 2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl methanesulfonate (C1, 5.0 g, 20 mmol) in anhydrous THF (70 mL) was treated with potassium carbonate (3.8 g, 28 mmol) and 2N dimethylamine (60 mL, 12 mmol) in THF at 10 ° C under N2 atmosphere. The reaction mixture was quenched with chilled water (20 mL). The solution was extracted with ethyl acetate (3×100 mL), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain N,N-dimethyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)ethyl-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 = 6.4Hz, 2H), 2.41 (s, 3H), 2.15 (s, 6H).); MS (ESI) m / z: 199.2 (M+H) + ).

[0511] General Method G: Mitsunobu Reaction:

[0512] Intermediate C3: 1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine.

[0513]

[0514] To a solution of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.4 mmol) and 1-methylpiperidin-4-ol (4.5 g, 39.4 mmol) in anhydrous THF (60 mL) was added triphenylphosphine (154.7 g, 59 mmol) under 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 HCl aqueous solution (30 mL) was added. The resulting solution was washed with EtOAc (3×20 mL), and the aqueous layer was then basified with saturated potassium carbonate aqueous solution (until pH=9). The solution was extracted with 10% methanol / DCM (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH / DCM 15 column volumes (CV)) using flash chromatography to obtain a mixture of regioisomers. These two regioisomers were separated by SFC to obtain the desired regioisomer, 1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (2.0 g, 23% yield) as a white solid. And 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 (400MHz, DMSO-d6): δ8.84(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) + ).

[0515] Using General Methods B, C and EG above, the following intermediates in Table C were prepared.

[0516] Table C

[0517]

[0518]

[0519]

[0520]

[0521]

[0522] Preparation Example C29:

[0523]

[0524] A solution of 5-methyl-4-nitro-1H-pyrazole (2.0 g, 16 mmol) in DMF (15 mL) was treated with sodium hydride (0.94 g, 24 mmol) in portions at 0 ° C under Ar for 15 minutes. The mixture was stirred at room temperature for 2 hours, followed by the addition of methyl 2-bromo-2-methylpropanoate (4.3 g, 24 mmol). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was quenched with saturated NH4Cl solution (100 mL), and the solution was extracted with EtOAc (2 × 80 mL). The combined organics were washed with water (80 mL), 10% LiCl aqueous solution (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (2.9 g, 81% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ8.98(s,1H),3.65(s,3H),2.42(s,4H),1.78(s,6H); LC-MS m / z:228.2(M+H + ).

[0525] 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 hours. The reaction mixture was concentrated, diluted with water (60 mL), and acidified with 1N HCl aqueous solution until the pH was about 4. The resulting suspension was filtered, washed with water (2×10 mL) and air-dried to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2.2 g, 81% yield) as a white solid. LC-MS m / z: 214.2 (M+H + ).

[0526] 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 one drop of DMF followed by oxalyl chloride (2.8 mL, 32 mmol). The suspension was stirred at room temperature for 3 hours and then the clear solution was concentrated. The residue was dissolved in THF (30 mL) and the solution was slowly added to NH4OH solution (10 mL / water (40 mL)). The suspension was stirred at room temperature for 1 hour and then concentrated. The suspension (about 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 + ).

[0527] General Method H: Suzuki Coupling Reaction:

[0528] Intermediate D1: 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine.

[0529]

[0530] 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 reactant 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 product was purified by silica gel column chromatography (0-80% EtOAc / hexanes, 15 column volumes (CV)) to obtain 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, 69% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.89 (d, J = 9.3Hz, 1H), 6.85 (dd, J = 2.4 and 9.4Hz 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) + ).

[0531] Intermediate D12: 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine.

[0532]

[0533] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (A21, 30 g, 100 mmol) and potassium trifluorovinyl borate (20 g, 150 mmol) in DMSO (210 mL) was treated with KCO (42 g, 301 mmol) at room temperature, and the reaction mixture was purged with nitrogen for 15 minutes. PdCl(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 NaSO, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-80% EtOAc / hexanes, 10 column volumes (CV)) to obtain 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine (20 g, 81% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.96(d,J=9.2Hz,1H),7.21(m,1H),6.98(m,2H),5.77(t,J=17.2Hz,1H),5.41( d,J=11.2Hz,1H),3.44(t,J=4.8Hz,4H),2.42(t,J=4.8Hz,4H),2.21(s,3H); LC-MS(ESI)m / z:247.3(M+H + ).

[0534] Using General Procedure H above, the following intermediates in Table D were prepared.

[0535] Table D

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] General Method I: Restore

[0543] (A) Intermediate E1: 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline.

[0544]

[0545] A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (D1, 12 g, 46 mmol) in MeOH (60 mL) was treated with NH4Cl (73 g, 14 mmol) at 0°C and the reaction mixture was stirred at 0°C for 10 min. Zinc powder (30 g, 459 mmol) was slowly added (internal temperature raised to 20°C) to the reaction mixture in an ice-water bath. After 15 min stirring, the reaction mixture was allowed to warm to room temperature and allowed to stir vigorously at room temperature for 16 h. The mixture was stirred for 10 min at 37°C. Filtered and washed with THF (500 mL).The filtrate was concentrated under reduced pressure to give 2-cyclopropyl-4-(4-methylpiperazin-1-yl)aniline (10 g, 95%) as a dark brown sticky solid. 1 H NMR (400MHz, DMSO-d6): δ6.52(m,2H),6.43(d,J=2.0Hz,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 + ).

[0546] (B) Intermediate E11: 2-ethyl-4-(4-methylpiperazin-1-yl)aniline.

[0547]

[0548] 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% moisture) under nitrogen atmosphere, and then the mixture was stirred at room temperature under hydrogen balloon pressure for 3 h. After the general workup, 2-ethyl-4-(4-methylpiperazin-1-yl)aniline (16 g, 90% yield) was obtained as a brown sticky solid. 1H NMR (400MHz, DMSO-d6): δ6.61(s,1H),6.52(m,2H),4.25(brs,2H),2.89(t,J=4.4H z,4H),2.41(m,6H),2.19(s,3H),1.09(t,J=7.6Hz,3H); LC-MS(ESI)m / z:219.3(M+H + ).

[0549] Using General Methods I(A) and I(B) above, the following intermediates in Table E were prepared.

[0550] Table E

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] Coupling method J (A) and deprotection of the Boc group:

[0564] Intermediate F1: N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride.

[0565]

[0566] A solution of tert-butyl (3-aminopropyl)carbamate (5.0 g, 29 mmol) in EtOAc (100 mL) was treated with saturated NaHCO (aq) (100 mL), and the biphasic mixture was treated dropwise with cyclobutylcarbonyl 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 NaSO and concentrated to give tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (5.6 g, 76% yield) as a white solid. 1 H NMR(DMSO-d6,500MHz): δ7.57(s,1H),6.73(s,1H),2.85-3.00(m,5H),2.04-2.12(m,2H),1. 97(m,2H),1.86(m,1H),1.69-1.76(m,1H),1.47(m,1H),1.36(s,9H); MS(ESI)m / z:279.2(M+H + ).

[0567] A solution of tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (5.6 g, 0.022 mol) in MeOH (100 mL) was treated dropwise with 4N HCl (27 mL, 0.11 mol) in 1,4-dioxane and stirred at room temperature for 3 h. The solution was concentrated to dryness, resuspended in MeOH and concentrated again (twice) to give N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride (4.7 g, 100% yield) as a white solid. 1 H NMR(DMSO-d6,500MHz): δ7.96(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) + ).

[0568] Coupling method J (B) and deprotection of the Boc group:

[0569] Intermediate F2: N-(3-aminopropyl)-3,3-difluoro-N-methylcyclobutane-1-carboxamide TFA salt.

[0570]

[0571] 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 (3×25 mL). The combined organics were dried over anhydrous NaSO, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10% MeOH / DCM, 15 column volumes (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 then treated with TFA (0.18 mL). The solution was stirred at room temperature for 3 hours and then concentrated to give N-(3-aminopropyl)-3,3-difluoro-N-methylcyclobutane-1-carboxamide TFA salt (100% yield).

[0572] Using General Procedure J above, the following intermediates in Table F were prepared.

[0573] Table F

[0574]

[0575]

[0576] Example L1: 2-Chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine.

[0577]

[0578] 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 product was purified by silica gel column chromatography (0%-10% EtOAc / hexanes) to obtain 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 + ).

[0579] A solution of 2-chloro-5-cyclopropyl-6-(methylthio)pyrimidine (4.0 g, 20 mmol) in DCM (60 mL) was treated with m-CPBA (4.8 g, 28 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. 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 (400MHz, DMSO-d6): δ8.57(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 + ).

[0580] Example L2: 4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine.

[0581]

[0582] 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 diethyl ether) (555 mL, 0.56 mol) at 0 °C, and the reaction mixture was stirred for 2 hours. Sodium thiomethoxide (49 g, 0.94 mol) was added at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was quenched with 2N HCl in an ice-water bath, and the solution was then 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 obtain 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, 95% yield) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6): δ9.01 (s 1H), 2.62 (s 3H).

[0583] General Method K: Substitution Reaction:

[0584] Intermediate K20: N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide

[0585]

[0586] 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, 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), and allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (15-40% EtOAc / hexanes, 20 column volumes (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 + ).

[0587] Using General Procedure K above, the following intermediates in Table G were prepared.

[0588] Table G

[0589]

[0590]

[0591]

[0592] Preparation of Intermediate K21: N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide

[0593]

[0594] 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 cyclobutylcarbonyl chloride (68 g, 57 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours, 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 Na2SO4, filtered and concentrated under reduced pressure to obtain tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (140 g, 95% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ7.60(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 + ).

[0595] A solution of tert-butyl (3-(cyclobutanecarboxamido)propyl)carbamate (140 g, 55 mmol) in DCM (1.4 L) was treated with 4N HCl (426 mL) in 1,4-dioxane at 0°C and the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure to give the HCl salt. The salt was triturated with diethyl ether (500 mL) and pentane (500 mL), 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): δ8.00(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).

[0596] 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 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 crude product was purified by silica gel column chromatography (0-3% DCM / MeOH, 15 column volumes (CV)) to afford N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide (0.2 g, 18% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.18(s,1H),7.7(brs,1H),6.9(t,J=5.8Hz,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) + ).

[0597] General Method M: Oxidation

[0598] Intermediate M1: N-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide.

[0599]

[0600] 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 as the cooling bath time expired. The mixture was stirred at room temperature for 3 h. (A mixture of sulfoxide (major) and sulfone (minor) in a ratio of about 9:1 appeared). The mixture was quenched with saturated NaHCO3 solution, the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated 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 which solidified upon standing. MS (ESI) m / z: 365.2 (M+H + ).

[0601] Using General Procedure M above, the following intermediates in Table H were prepared.

[0602] Table H

[0603]

[0604] General Method N: Substitution Reaction A:

[0605] Example 1: N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide.

[0606]

[0607] 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 A mixture of 5-(4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (0.068 g, 54% yield) was prepared by column chromatography (3-10% MeOH / DCM, 11 column volumes (CV)) to afford N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide as a light solid. 1H NMR (400MHz, DMSO-d6): δ8.60(s,1H),8.02(s,1H),7.57(brs,1H),7.13(d,J=7.6Hz,1H) ,6.90(t,1H),6.77(d,J=2.3Hz,1H),6.73(dd,J=2.8 and J=8.8Hz,1H),3.26(m,2H),3.10(b rs,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=7.6Hz,3H); MS(ESI)m / z:520.3(M+H + ).

[0608] General Method O: Substitution Reaction B:

[0609] 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.

[0610]

[0611] 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 a small amount of molecular sieves followed by 4N 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 column volumes (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 light green amorphous solid. 1H NMR (400MHz, DMSO-d6): δ8.93(brs,1H),8.08(s,1H),7.86(brs,1H),7.63(brm,1H),7.06(brm,1H),4.20( brm,1H),4.03(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) + ).

[0612] General Method P: Deprotection of Boc Group

[0613] Example 21: N-(3-((2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide.

[0614]

[0615] 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 4N HCl (0.7 mL, 2.8 mmol) in 1,4-dioxane 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 by filtration, rinsed with MeOH and the filtrate concentrated to afford 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): δ8.95 (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 protons missing); MS (ESI) m / z: 481.4 (M+H + ).

[0616] General Procedure Q: Reductive Alkylation:

[0617] 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.

[0618]

[0619] 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 (3×10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by silica gel column chromatography (4-15% (10% NH4OH / MeOH) / DCM, 25 column volumes (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 (400MHz, DMSO-d6): δ8.92(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=11.7Hz,2H),2.04-2.09(m,5H), 1.67-2.03(m,9H),1.55-1.66(m,2H),0.96(d,J=6.6Hz,6H); MS(ESI)m / z:523.4(M+H + ).

[0620] Using General Methods N, O, P and Q above, the compounds of Table I below were prepared.

[0621] Table I.

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628] Preparation 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

[0629]

[0630] A mixture of N-(3-((2-((1-(1-amino-2-methyl-1-oxopropyl-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 NaHCO solution (40 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product 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 (400MHz, DMSO-d6): δ9.17(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,3H),2.08(m,2H),1.95-2.00(m,2H),1.91(s,6H),1.85(m,1H),1.72(m,1H),1.62(s,2H); MS(ESI)m / z:465.2(M+H+ ).

[0631] Preparation Example 31: N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide

[0632]

[0633] A solution of N-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide (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 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 NaSO, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-5% DCM / MeOH, 15 column volumes (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 HNMR (400MHz, DMSO-d6): δ8.15(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),3.0 6(m,4H),2.41(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 + ).

[0634] Example 31. Biochemical analysis of ULK1.2

[0635] The activity of ULK1 kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289: 1938-1942). The assay was performed in a 384-well plate (100 μL final volume) using an assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w / v) BSA, and 0.002% Triton X-100) containing 19 nM ULK1 (Eurofins catalog number 14-959), 0.25 mg / mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM pyruvate phosphoenolase, 0.28 mM NADH, and 1 mM ATP). ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration was 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 time range of 2-3 hours. The reaction rates of the compounds at each concentration were converted to percent inhibition using controls (i.e., no reaction with the test compound and reaction with a known inhibitor), and the IC was calculated by fitting a four-parameter sigmoid curve to the data using Prism (GraphPad software). 50 value.

[0636] ULK1 protein sequence (residues 1-314 with N-terminal His tag; SEQ.ID NO:1)MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLLSEDTIRLFLQQIAGAMRLLHSKGIIHRDL KPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPVPVPSYPSGSGSSSSSSSTSHLAS

[0637] Example 32. Biochemical analysis of ULK1.3

[0638] The activity of ULK1 kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289: 1938-1942). The assay was performed in a 384-well plate (100 μL final volume) using 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 pyruvate phosphoenolase, 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). ULK1 inhibition was measured by adding serially diluted test compounds (final assay concentration was 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 time range of 2-3 hours. The reaction rates of the compounds at each concentration were converted to percent inhibition using controls (i.e., no reaction with the test compound and reaction with a known inhibitor), and IC was calculated using software routines in Prism (GraphPad software). 50 value.

[0639] ULK1 protein sequence (residues 1-283; SEQ. ID NO: 2)

[0640] MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQ

[0641] TLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRRTLSEDTI

[0642] RLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSN

[0643] MMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLF

[0644] YEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPS

[0645] Example 33. Biochemical analysis of ULK2

[0646] The activity of ULK2 kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289: 1938-1942). The assay was performed in a 384-well plate (100 μL final volume) using 9.7 nM ULK2 (Eurofins catalog number 14-772), 0.25 mg / mL myelin basic protein, 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM pyruvate phosphoenolase, 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). ULK2 inhibition was measured by adding serially diluted test compounds (final assay concentration was 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for 6 hours at 30°C on a multimode microplate reader (BioTek). The reaction rate was calculated using a time range of 2-3 hours. The reaction rate of the compound at each concentration was converted into an inhibition percentage (i.e., no reaction with the test compound and reaction with a known inhibitor) using a control, and the IC was calculated by fitting a four-parameter sigmoid curve to the data using Prism (GraphPad software). 50 value.

[0647] ULK2 protein sequence (residues 1-306 with N-terminal GST and His tag; SEQ. ID NO: 3)

[0648] MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYY

[0649] IDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFET

[0650] LKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAF

[0651] PKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFM

[0652] EVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSINKKNLSKSQILLGKEIKI

[0653] LKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAA

[0654] AMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCG

[0655] SPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLM

[0656] PSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVS

[0657] GSSCGSSPSCRFASHHHHHH

[0658] Table 1. Inhibition of biochemical activity of ULK1 and ULK2 kinases by exemplary compounds in Table 1.

[0659] Example (Compound) No. ULK1.2 ULK1.3 ULK2.2 1 + ++ 2 + 3 + ++ 4 ++ ++ 5 +++ +++ 6 ++++ ++++ 7 ++ +++ 8 ++ +++ 9 ++ +++ 10 ++++ ++++ 11 ++++ 12 ++ +++ 13 ++++ ++++ 14 + + 15 +++ 16 + ++ 17 +++ 18 + 19 ++++ ++++ 20 + ++ 21 + ++ 22 ++ 23 + ++ 24 +++ 25 +++ 26 ++++ ++++ 27 + ++ 28 + ++ 29 ++ 30 +++ ++++ 31 +++

[0660] For Table 1, “+” means IC greater than 1 nM and less than or equal to 25 nM 50 ; "++" means IC greater than 25nM and less than or equal to 100nM 50 ; "+++" means IC greater than 100nM and less than or equal to 500nM 50 ; and "++++" refers to an IC greater than 500 nM and less than 20,000 nM 50 .

[0661] Example 34. Cellular Inhibition of ULK Kinase Substrate ATG13 Protein

[0662] pATG13 content of mutant KRas A549 cells after treatment with a ULK inhibitor and trametinib combination

[0663] A549 (KRAS mutation) human lung cancer cells (6,000 cells / well) were added to 50 μL pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, and 100 μg / mL streptomycin in a tissue culture treated 384-well plate and grown overnight at 37°C, 5% CO2, and 95% humidity. The next day, 10 μL of culture medium containing trametinib or DMSO as a control was added to the well. The final concentration of trametinib in the well was 250 nM. The dose response of the test compound was added (0.6 μL / well). DMSO (0.6 μL) was added to the control well. The plate was shaken briefly to mix the wells, and then incubated overnight at 37°C. The next day, the medium was aspirated and the cells were washed with Dulbecco's Phosphate Buffered Saline (Gibco) and lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4°C with shaking for 10 min.

[0664] The cell content of phosphoserine 318ATG13 (pATG13) was measured by ELISA method. Full ATG13 antibody (Cell Signaling catalog number 13273) was used to coat the wells. The plate was incubated overnight at 4 ° C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked with assay diluent (Biolegend catalog number 421203) for 1 hour at room temperature. The wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated at room temperature for 2 hours. The wells were washed with ELISA wash buffer. The pS318-ATG13 antibody (Rockland Immunochemicals catalog number 600-401-C49) labeled with biotin was diluted in assay diluent and added to each well, and incubated at room temperature for 1 hour. The wells were washed with ELISA wash buffer. Streptavidin (Thermo Fisher catalog number 21140) connected to horseradish peroxidase is diluted in an assay diluent and added to each well, and incubated at room temperature for 1 hour. The plate wells are washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog number 421101) is added to each well, and incubated at room temperature for 20 minutes. The reaction is terminated with 2N sulfuric acid. The plate is analyzed on a microplate detector measuring the absorbance (background) at 450nm and 540nm. For each well, the signal is calculated by first deducting the background absorbance at 540nm from the absorbance at 450nm. Subsequently, the background correction absorbance at 450nm of the blank group wells is deducted from the test wells. Data are compared with control wells to determine ATG13 phosphorylation%. GraphPad Prism is used to calculate IC 50 value.

[0665] Example 35. pATG13 content of mutant KRas MiaPaCa-2 cells after treatment with a ULK inhibitor and trametinib combination

[0666] MiaPaCa-2 human pancreatic cancer cells (10,000 cells / well) were added to 50 μL pre-warmed DMEM medium supplemented with 10% standard fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units / mL penicillin G, 100 μg / mL streptomycin and 2.5% horse serum in a 384-well tissue culture treated plate and grown overnight at 37°C, 5% CO2 and 95% humidity. The next day, 10 μL of culture medium containing trametinib or DMSO as a control was added to the well. The final concentration of trametinib in the well was 250 nM. The dose response of the test compound was added (0.6 μL / well). DMSO (0.6 μL) was added to the control well. The plate was shaken briefly to mix the wells, and then incubated overnight at 37°C. The next day, the culture medium was aspirated and the cells were washed with Dulbecco's phosphate buffered saline (Gibco). Cells were lysed with MPER lysis buffer (Pierce, Rockford, IL) containing Halt phosphatase and protease inhibitors (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) for 10 min at 4°C with shaking.

[0667] The cell content of phosphoserine 318ATG13 (pATG13) was measured by ELISA method. The wells were coated with full ATG13 antibody (Cell Signaling catalog number 13273). The plate was incubated overnight at 4 ° C and washed with ELISA wash buffer (Biolegend catalog number 421601). Subsequently, the wells were blocked with assay diluent (Biolegend catalog number 421203) for 1 hour at room temperature. The wells were washed with ELISA wash buffer. Cell lysates were added to the wells and incubated for 2 hours at room temperature. The wells were washed with ELISA wash buffer. The pS318-ATG13 antibody (Rockland Immunochemicals catalog number 600-401-C49) labeled with biotin was diluted in assay diluent and added to each well, and incubated for 1 hour at room temperature. The wells were washed with ELISA wash buffer. Streptavidin (Thermo Fisher catalog number 21140) connected to horseradish peroxidase was diluted in an assay diluent and added to each well, and incubated at room temperature for 1 hour. The plate wells were washed with ELISA wash buffer. Highly sensitive TMB substrate (Biolegend catalog number 421101) was added to each well, and incubated at room temperature for 20 minutes. The reaction was terminated with 2N sulfuric acid. The plate was analyzed on a microplate detector measuring absorbance (background) at 450nm and 540nm. For each well, the signal was calculated by first deducting the background absorbance at 540nm from the absorbance at 450nm. Subsequently, the background correction absorbance at 450nm of the blank group wells was deducted from the test wells. Data were compared with control wells to determine ATG13 phosphorylation%. GraphPad Prism was used to calculate IC 50 value.

[0668] Table 2. ULK kinase inhibition in mutant Ras cell lines by exemplary compounds from Table I.

[0669]

[0670] For Table 2, “+” refers to an IC greater than 10 nM and less than or equal to 100 nM 50 ; “++” means IC greater than 100nM and less than or equal to 300nM 50 ; "+++" means IC greater than 300nM and less than or equal to 600nM 50 .

[0671] Example 36. Biochemical analysis of LRRK2 (SEQ.ID NO.4)

[0672] The activity of LRRK2 kinase was determined spectroscopically using a coupled pyruvate kinase / lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al. Science (2000) 289: 1938-1942). The assay was performed in a 384-well plate (100 μL final volume) using an assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100) containing 26.4 nM LRRK2 (Thermo Fisher), 0.1 mM peptide substrate (RLGRDKYKTLRQIRQ (SEQ ID NO: 6)), 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM pyruvate phosphoenolase, 0.28 mM NADH, and 1 mM ATP). LRRK2 inhibition was measured by adding serially diluted test compounds (final assay concentration was 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 time range of 2-3 hours. The reaction rates of each concentration of compound were converted to percent inhibition using controls (i.e., no reaction with test compound and reaction with known inhibitor), and IC was calculated using software routines in Prism (GraphPad software) 50 value.

[0673] LRRK2 protein sequence (residues 970-2528; SEQ. ID NO: 4)

[0674] MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPY

[0675] YIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFE

[0676] TLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLD

[0677] AFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRHNQTS

[0678] HAPPINESSGTMHSDSISSLASEREYITSLDLSANELRDDIDALSQKCCISVHLEHLEKLELHQN

[0679] ALTSFPQQLCETLKSLTHLDLHSNKFTSFSYLKMSCIANLDVSRNDIGPSVVLDPTV

[0680] KCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHI

[0681] SSLSENFLEACPKVESFSARNMFLAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLD

[0682] MSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIP

[0683] PEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRF

[0684] LQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDW

[0685] PIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKP

[0686] WLFNIKARASSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNAT

[0687] EESDALAKL

[0688] RKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERNKNVPIEFPVIDRKRLLQLVRENQ

[0689] LQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCP

[0690] KHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPV

[0691] IELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIY

[0692] LNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEI

[0693] DICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAP

[0694] DLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRL

[0695] LRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIA

[0696] LHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEG

[0697] TPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLP

[0698] DPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIV

[0699] ECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVE

[0700] KESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTA

[0701] DGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFS

[0702] NDFTIQKLIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLI

[0703] DCVHFLREVMVKENKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRL

[0704] IRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLP

[0705] HEVQNLEKHIEVRKELAEKMRRTSVE

[0706] Table 3. LRRK2 inhibition by exemplary compounds shown in Table 1.

[0707]

[0708] For Table 3, “+” means IC greater than 1 nM and less than or equal to 100 nM 50 ; “++” means IC greater than 100nM and less than or equal to 300nM 50 ; "+++" means IC greater than 300nM and less than or equal to 600nM 50 ; and "++++" refers to an IC greater than 600 nM and less than 20,000 nM 50 .

[0709] Example 37. Evaluation of ULK inhibitors in pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo

[0710] ULK inhibitors were evaluated in a PDAC flux assay and in a variety of cell lines including those derived from Trp53. lox / + 、LSL-Kras G12D 、Rosa-rtTA LSL 、p48Cre + IC of compounds in a panel of various PDAC cell lines in primary tumor cells 50 , will be determined using colony formation 2D assays and 3D organoid assays in the absence or presence of trametinib.

[0711] Using a syngeneic orthotopic model, we evaluated inhibition of autophagic flux following single and multiple doses using a flux reporter in PDAC tumors in vivo.

[0712] The therapeutic efficacy of ULK inhibitors in PDAC models was evaluated by: (i) evaluating PDAC tumor kinetics subcutaneously; (ii) evaluating PDAC tumor kinetics orthotopically in the pancreas (C57 black mice implanted with KPCs) in a syngeneic model; (iii) evaluating tumor growth kinetics using ULK inhibitors and MEK inhibitors in a syngeneic model; (iv) evaluating compounds in an orthotopic model of PDAC; (v) evaluating histological changes in the tumor microenvironment; (vi) evaluating changes in immune cell infiltration in tumors after ULK inhibitor inhibition; and (vii) evaluating the efficacy of ULK inhibitors and immune checkpoint blockade combinations.

[0713] Equivalent

[0714] Although specific embodiments have been discussed, the above description is exemplary and non-limiting. Many variations of the embodiments will be apparent to those skilled in the art upon reviewing this description. The full scope of the disclosure should be determined with reference to the claims and their equivalents and the description and the full scope of such variations.

[0715] 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 attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

1. A compound represented by: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: A is selected from: phenyl and 5- or 6-membered 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 with one, two or three 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three independent occurrences of fluorine or cyano; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein B may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; D is selected from: C-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein D may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 It is connected to the atom to which it is attached to form a bridging group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C 1- C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 linked together with the carbon to which it is attached to form a C3-C5 cycloalkyl; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 linked together with the carbon to which it is attached to form a C3-C6 cycloalkyl; L is -(C(R 10 )2) m -; h is 1, 2, or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; The restriction condition is that when m is 0, R 4 C is connected to ring A. When m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

2. A compound represented by: 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 with one, two or three 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three independent occurrences of fluorine or cyano; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 33 is selected from: H, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein B may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; D is selected from: C-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein D may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 It is connected to the atom to which it is attached to form a bridging group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 linked together with the carbon to which it is attached to form a C3-C5 cycloalkyl; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 linked together with the carbon to which it is attached to form a C3-C6 cycloalkyl; L is -(C(R 10 )2) m -; h is 1, 2, or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; The restriction is that both X and Y are not N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

3. The compound according to claim 1 or 2, wherein W is N.

4. The compound according to any one of claims 1 to 3, wherein X is CH and Y is N.

5. A compound as claimed in any one of claims 1 to 3, wherein X is CH and Y is C(R 33 ).

6. A compound as claimed in any one of claims 1 to 5, wherein R 4 For B.

7. A compound as claimed in any one of claims 1 to 6, wherein R 4 Selected from: where u is 1, 2, or 3.

8. A compound as claimed in any one of claims 1 to 7, wherein R 4 Selected from:

9. A compound as claimed in any one of claims 1 to 8, wherein R 4 Selected from:

10. A compound as claimed in any one of claims 1 to 7, wherein R 4 Selected from:

11. A compound as claimed in any one of claims 1 to 5, wherein R 4 is D.

12. A compound as claimed in any one of claims 1 to 5 or 11, wherein R 4 Selected from:

13. A compound as claimed in any one of claims 1 to 12, wherein L is -(CH2) m .

14. The compound of any one of claims 1 to 13, wherein m is 0.

15. A compound as claimed in any one of claims 1 to 14, wherein R 1 Selected from: halogen, C1-C5 alkyl and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl may be optionally substituted with one, two or three independent occurrences of fluorine.

16. A compound as claimed in any one of claims 1 to 15, wherein R 1 It is CF3.

17. A compound as claimed in any one of claims 1 to 15, wherein R 1 It is CF2H.

18. A compound as claimed in any one of claims 1 to 15, wherein R 1 Selected from: chlorine, bromine and fluorine.

19. The compound of claim 18, wherein R 1 For bromine.

20. The compound of any one of claims 1 to 15, wherein R 1 It is cyclopropyl.

21. A compound as claimed in any one of claims 1 to 20, wherein R 2 Selected from: C3-C5 cycloalkyl, C1-C5 alkyl, halogen, CN, C2-C5 alkenyl and C2-C5 alkynyl, wherein C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl and C2-C5 alkynyl may be optionally substituted with one, two or three independent occurrences of fluorine.

22. A compound as claimed in any one of claims 1 to 21, wherein R 2 Selected from: C 1-2 Alkyl and C 3-4 Cycloalkyl.

23. A compound as described in any one of claims 1 to 22, wherein R 3 is selected from the group consisting of: H and C1-C3 alkyl, wherein the C1-C3 alkyl may be optionally substituted with one or more independent occurrences of fluorine.

24. A compound as described in any one of claims 1 to 23, wherein R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, each of which may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine.

25. A compound as described in any one of claims 1 to 24, wherein R L It is cyclobutyl.

26. A compound as described in any one of claims 1 to 23, wherein R L NR 11 R 12 .

27. A compound as described in any one of claims 1 to 24, wherein R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

28. The compound of any one of claims 1 to 27, wherein n is 3.

29. A compound represented by: 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 with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted with one, two or three independent occurrences of fluorine; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 connected with the atom to which it is attached to form an oxo group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 linked together with the carbon to which it is attached to form a C3-C6 cycloalkyl; The restriction is that both X and Y are not N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

30. A compound represented by: 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 with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted with one, two or three independent occurrences of fluorine; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: R 9 Independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 connected with the atom to which it is attached to form an oxo group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 linked together with the carbon to which it is attached to form a C3-C6 cycloalkyl; The restriction is that both X and Y are not N, and when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

31. A compound represented by: or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein: Ring DD is selected from: 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 with one, two or three 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 of C1-C5 alkyl, C3-C6 cycloalkyl, C2-C5 alkenyl, C2-C5 alkynyl and C1-C5 alkoxy may be optionally substituted with one, two or three independent occurrences of fluorine or cyano; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: B, D, NR 6 R 9 NR 6 -(C(R 10 )2) p -NR 6 R 9 、C(O)-NR 6 R 9 , C(O)-B, C(O)-D and CN; B is selected from: N-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein B may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; D is selected from: C-linked heterocyclic radicals having at least one nitrogen and optionally having another ring nitrogen or oxygen, and heteroaryl radicals, wherein D may be optionally replaced on one or more available carbons by R 7 and optionally substituted on an available nitrogen by R 9 replace; R 7 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and (C(R 10 )2) h -NR 6 R 9 , wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 It is connected to the atom to which it is attached to form a bridging group; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C5 alkoxy-C2-C5 alkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 10 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 10 linked together with the carbon to which it is attached to form a C3-C5 cycloalkyl; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2, q is 1, 2, or 3; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 linked together with the carbon to which it is attached to form a C3-C6 cycloalkyl; L is -(C(R 10 )2) m -; h is 1, 2, or 3; m is 0, 1, 2 or 3; n is 2, 3 or 4; and p is 2 or 3; The restriction condition is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

32. The compound of claim 31, wherein W is N.

33. The compound of claim 31 , wherein W is CH.

34. The compound of any one of claims 31-33, wherein ring DD is selected from:

35. The compound of any one of claims 31-33, wherein ring DD is selected from:

36. The compound of any one of claims 31-33, wherein ring DD is:

37. The compound of any one of claims 31-33, wherein ring DD is:

38. A compound as described in any one of claims 31 to 37, wherein R 4 is D.

39. A compound as described in any one of claims 31 to 38, wherein R 4 Selected from:

40. A compound as described in any one of claims 31 to 39, wherein R 4 Selected from:

41. A compound as described in any one of claims 31 to 37, wherein R 4 For B.

42. A compound as described in any one of claims 31-37 or 41, wherein R 4 Selected from: Where u is 1 or 2.

43. A compound as described in any one of claims 31-37 or 41, wherein R 4 Selected from:

44. A compound as described in any one of claims 31-37 or 41, wherein R 4 Selected from:

45. A compound as described in any one of claims 31-33, wherein L is -(CH2) m -.

46. ​​The compound of any one of claims 31-45, wherein m is 0.

47. The compound of any one of claims 31-45, wherein m is 2.

48. The compound of any one of claims 31-45, wherein m is 3.

49. A compound as described in any one of claims 31 to 48, wherein R 1 Selected from: halogen, C1-C5 alkyl and C3-C5 cycloalkyl, wherein C1-C5 alkyl and C3-C5 cycloalkyl may be optionally substituted with one, two or three independent occurrences of fluorine.

50. A compound as described in any one of claims 31 to 49, wherein R 1 It is CF3.

51. A compound as described in any one of claims 31 to 49, wherein R 1 It is CF2H.

52. A compound as described in any one of claims 31 to 49, wherein R 1 Selected from: chlorine, bromine and fluorine.

53. A compound as claimed in claim 52, wherein R 1 For bromine.

54. A compound as described in any one of claims 31 to 49, wherein R 1 It is cyclopropyl.

55. A compound as described in any one of claims 31 to 54, wherein R 2 Selected from: C3-C5 cycloalkyl, C1-C5 alkyl, halogen, cyano, C2-C5 alkenyl and C2-C5 alkynyl, wherein C3-C5 cycloalkyl, C1-C5 alkyl, C2-C5 alkenyl and C2-C5 alkynyl may be optionally substituted by one, two or three independent occurrences of fluorine.

56. A compound as described in any one of claims 31 to 55, wherein R 2 Selected from: C 1-2 Alkyl and C 3-4 Cycloalkyl.

57. A compound as described in any one of claims 31 to 56, wherein 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 with one or more independent occurrences of fluorine.

58. A compound as described in any one of claims 31 to 57, wherein R L It is cyclobutyl.

59. A compound as described in any one of claims 31 to 58, wherein R L NR 11 R 12 .

60. A compound as described in any one of claims 31 to 59, wherein R L for wherein each C1-C6 alkyl and C3-C6 cycloalkyl group may be optionally substituted by 1, 2 or 3 independently occurring fluorine groups; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1 or 2; q is 1, 2 or 3; R 13 is selected from: H and C1-C3 alkyl; and R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 and the carbon to which it is attached to form a C3-C6 cycloalkyl group; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

61. A compound as described in any one of claims 31-60, wherein n is 3.

62. A compound represented by: or a pharmaceutically acceptable salt thereof, wherein: Ring DD is selected from: 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 with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted with one, two or three independent occurrences of fluorine; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 connected with the atom to which it is attached to form an oxo group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and L is -(C(R 10 )2) m -; m is 0, 1, 2 or 3; The restriction condition is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

63. A compound represented by: or a pharmaceutically acceptable salt thereof, wherein: Ring DD is selected from: 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 may be optionally substituted with one, two or three independent occurrences of fluorine; R 2 is selected from: C1-C2 alkyl and C3-C4 cycloalkyl and halogen, wherein C1-C2 alkyl and C3-C4 cycloalkyl are optionally substituted with one, two or three independent occurrences of fluorine; R 3 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 4 Selected from: R 9 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 5 is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl and heterocyclyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 7 R is independently selected at each occurrence from: H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 7 connected with the atom to which it is attached to form an oxo group; R L Selected from: C1-C6 alkyl and C3-C6 cycloalkyl, NR 11 R 12 and wherein each C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with 1, 2 or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from: oxygen, C(R 34 )2 and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 5 、SO2R 5 , C-linked heterocyclic radicals having at least one nitrogen and optionally another ring nitrogen or oxygen, and heteroaryl, wherein C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine; R 11 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 12 is selected from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more independent occurrences of fluorine; R 13 Selected from: H and C1-C3 alkyl; R 34 R is independently selected at each occurrence from: H, C1-C3 alkyl and C3-C5 cycloalkyl, wherein C1-C3 alkyl and C3-C5 cycloalkyl may be optionally substituted with one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C3-C6 cycloalkyl; and L is -(C(R 10 )2) m -; m is 0, 1, 2 or 3; The restriction condition is that when m is 0, R 4 is C connected to the pyrazolyl ring, when m is 1, R 4 is connected from C to L, and when m is 2 or 3, R 4 is N connected or C connected to L; and the other restrictions are that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .

64. A compound selected from: 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)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide -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-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, (1-(1-amino-2-methyl-1-oxopropyl-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-cyanopropyl-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)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide 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-(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 )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 , 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-((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-(4-methylpiperazin-1-yl)pyridin-3-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)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]heptane-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 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)isobutyramide, -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)oxetane-3-carboxamide, 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)tetrahydrofuran-3-carboxamide )-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-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-methyl pivalamide, 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-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-((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-methyloxetane-3-carboxamide, )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] heptane-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)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide )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]heptane-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]heptane-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 amide, 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-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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 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)-1,1-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)azetidine-1-carboxamide 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)-3,3-dimethylazetidine-1-carboxamide 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)propyl)cyclobutanecarboxamide,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)-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)cyclobutanecarboxamide, N-(3-((5-chloro-2-((3-methyl-1-(1-methylpiperidin- 4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)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)cyclobutanecarboxamide 1-(trifluoromethyl)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)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 amine, 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 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) 1-(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)-5-(trifluoromethyl)pyrimidin-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-(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, 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, 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-methylazetidine-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)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)cyclobutanecarboxamide, -yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-1-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- pivalamide, 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, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-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)-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 -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)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutane-1-carboxamide, N-(3-((5-(difluoromethyl)-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((5-bromo-2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) 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, 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)propyl)cyclobutanecarboxamide, N-(3-((2-((5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, cyclobutanecarboxamide, 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-((4-methyl-2-(4-methylpiperazin-1-yl)oxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, 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 )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)-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 azetidine-3-carboxamide, 1-methyl-N-(3-((2-((5-methyl-2-(1-methylpiperidin-4-yl)thiazol-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 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 yl)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, N-(3-((2-((4-methyl-2-(1-methylpiperidin-4-yl)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-((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, -methyl-4-piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azetidine-3-carboxamide, 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)-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. 、 65. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 64 and a pharmaceutically acceptable excipient.

66. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 64, one or more additional therapeutic agents and a pharmaceutically acceptable excipient.

67. The pharmaceutical composition of claim 66, wherein the composition comprises an additional therapeutic agent.

68. The pharmaceutical composition of claim 66 or 67, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

69. The pharmaceutical composition of claim 68, 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.

70. The pharmaceutical composition of claim 69, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, bimetinib and pharmaceutically acceptable salts thereof.

71. The pharmaceutical composition of claim 69, wherein the ERK inhibitor is selected from the group consisting of: uritinib, SCH772984, LY3214996, lavotinib, VX-11e and pharmaceutically acceptable salts thereof.

72. The pharmaceutical composition of claim 69, wherein the RAF inhibitor is selected from the group consisting of: LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof.

73. The pharmaceutical composition of claim 69, wherein the Ras inhibitor is selected from the group consisting of: AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

74. The pharmaceutical composition of claim 66 or 67, wherein the additional therapeutic agent is a chemotherapeutic agent.

75. The pharmaceutical composition of claim 74, wherein the chemotherapeutic agent is selected from the group consisting of anti-tubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate.

76. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-64.

77. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-64.

78. The method of claim 77, wherein the cancer is selected from the group consisting of gastrointestinal stromal tumors, esophageal cancer, gastric cancer, melanoma, glioma, glioblastoma, ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, bone metastases, papillary thyroid cancer, non-small cell lung cancer, and colorectal cancer.

79. The method of claim 77 or 78, wherein the cancer is metastatic.

80. A method of treating a condition in a patient in need thereof, wherein the condition is selected from the group consisting of melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, osteosarcoma, multiple myeloma, cervical cancer, bone metastases, papillary thyroid cancer, non-small cell lung cancer, and colon cancer, the method comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1-64.

81. The method of any one of claims 76-80, further comprising administering one or more additional therapeutic agents to the patient.

82. The method of claim 81, wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.

83. The method of claim 82, 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.

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

85. The method of claim 83, wherein the ERK inhibitor is selected from the group consisting of: uritinib, SCH772984, LY3214996, lavotinib, VX-11e, and pharmaceutically acceptable salts thereof.

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

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

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

89. The method of claim 88, wherein the chemotherapeutic agent is selected from the group consisting of anti-tubulin agents, vinorelbine, DNA alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate.

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