Inhibitors of WDR5 protein-protein binding

Abstract

The present application relates to a compound of formula I: [Formula 1] The present invention relates to compounds, including these compounds, and their uses, for example, as pharmaceutical agents for the treatment of diseases, disorders, or conditions mediated or treatable by inhibition of binding between the WDR5 protein and its binding partners. [Selection diagram] None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from U.S. Provisional Patent Application No. 62 / 301,673, filed March 1, 2016, the contents of which are incorporated herein by reference in their entirety. Field

[0002] The present application relates to compounds, processes for their preparation, compositions containing them, and their use for the treatment of diseases, disorders, and conditions mediated by binding between WDR5 and its binding partners, such as, but not limited to, MLL1. [Background technology]

[0003] Histones are the most basic units for packaging DNA into nucleosomes, and covalent modifications of histones, such as methylation, acetylation, and phosphorylation, play a central role in regulating gene transcription [Nat. Rev. Mol. Cell Biol. 2001, 2: 422-432; Cell 2007, 128: 693-705]. Epigenetics refers to inherited changes that control how the genome is utilized in different cell types during embryonic development and cell differentiation [Genes. Dev. 2009; 23: 781-783]. This potential allows for functional specialization among cells without changing the DNA sequence.

[0004] It is now well recognized that misregulation of histone modifications plays an important role in a wide range of human diseases, including, but not limited to, cancer [Cell., 2007, 10: 693-705; Nat. Rev. Cancer., 2010, 10: 457-469]. The mixed leukemia 1 (MLL1) protein is a histone H3 lysine 4 (H3K4) methyltransferase that is frequently misregulated in a subset of acute leukemias [Trends Mol. Med., 2004, 10: 500-507, Cell. Stem. Cell., 2007, 1: 324-337]. Although MLL1 itself has weak H3K4 methyltransferase activity, its enzymatic activity is dramatically enhanced when MLL1 is present in a core complex composed of MLL1, WD-repeat domain 5 protein (WDR5), Absent, Small, or Homeotic-2-Like (ASH2L), and retinoblastoma binding protein 5 (RbBP5). Recent studies have clearly demonstrated that the binding between MLL1 and WDR5 is optimal for MLL1 activity but is not required for the activity of other MLL family members, including MLL2, MLL3, and MLL4 [Mol. Cell., 2014, 53:247-261]. Therefore, blocking the protein-protein binding of MLL1 to WDR5 can specifically inhibit MLL1 H3K4 methyltransferase activity, and such inhibition has potential for the treatment of human diseases, such as a subset of acute leukemias, the onset and progression of which depend on MLL1 activity.

[0005] WDR5 is the common subunit of all six mammalian histone H3K4 methyltransferases [Dev. Biol., 2010,339 (2):240-249]. WDR5 contains 334 amino acids and seven typical WD40 repeat domains, each approximately 40 amino acids long [Nat. Struct. Mol. Biol., 2009, 16 (7):678-680]. Structural studies suggest that the WD40 repeats form a seven-bladed propeller fold, with each blade consisting of a four-stranded antiparallel sheet. This structural feature suggests that WDR5 has many exposed surfaces, making it a useful adaptor for interacting with other proteins. Furthermore, pull-down assays indicate that WDR5 prefers to bind dimethylated histone H3K4 peptides [Nat. Struct. Mol. Biol., 2009, 16 (7):678-680].

[0006] Two recent studies have suggested an important role for WDR5 in the MLL1 complex. The WDR5-interacting (WIN) motif, consisting of amino acid residues 3762–3773 adjacent to the SET domain in MLL1, was independently discovered to mediate the binding of MLL1 to WDR5 [J. Biol. Chem., 2008, 283(47):32158–32161; J. Biol. Chem., 2008, 283(50):35258–35264]. The crystal structure of a WIN motif peptide carrying WDR5 reveals that the WIN motif (an analog of the H3 N-terminal peptide) adopts a 310-helical structure and binds to WDR5 in the central cavity of the β-propeller by inserting Arg3765 into the central channel. Thus, the binding between MLL1 and WDR5 is mediated by a well-defined pocket in WDR5 and a WIN motif (residues 3762-3773) in MLL1. Previous studies have demonstrated that the 3-residue peptide, Ac-ARA-NH2(K i =0.12 mmol / L) inhibited the 12-residue WIN peptide (K i=0.16 mmol / L) [J. Med. Chem., 2010, 53: 5179-5185; J. Am. Chem. Soc., 2013, 135: 669-682].

[0007] Without wishing to be bound by theory, WDR5 is an essential component of histone methylation, acetylation, and chromatin remodeling complexes, and thus is thought to function as an adaptor protein for complex structure. However, it may also contribute to other physiological phenomena. WDR5 is a critical component for the assembly or stability of the virus-induced signaling adaptor (VISA)-associated complex, which plays an important role in the induction of virus-induced type I interferon (IFN) and antiviral innate immune responses [Proc. Natl. Acad. Sci. USA, 2010, 107(2):815-820]. Previous studies have demonstrated that VISA is located in the outer membrane of mitochondria. Interestingly, this study revealed that WDR5 is not only localized in the nucleus as previously thought, but is also abundant in the cytoplasm. Viral infection triggered the translocation of WDR5 from the nucleus to the VISA complex present in mitochondria, where it played a role in the assembly and stability of the VISA complex. These studies demonstrate for the first time a cytoplasmic function for WDR5, particularly in virus-induced signaling that results in the induction of type I IFN [Proc. Natl. Acad. Sci. USA, 2010,107(2):815-820].

[0008] The MLL1-WDR5 complex in leukemogenesis Leukemia is characterized by an abnormal increase in white blood cells in the blood or bone marrow. Among all types of cancer, the incidence of leukemia is highest in patients under 35 years of age. More than 70% of infant leukemia patients have translocations involving chromosome 11, resulting in the fusion of the MLL1 gene with another gene [Nat. Rev. Cancer., 2007, 7(11):823-833]. MLL1 translocations are also found in approximately 10% of adult acute myeloid leukemia (AML) patients, who were previously treated with topoisomerase II inhibitors for other types of cancer [Nat. Rev. Cancer., 2007, 7(11):823-833].

[0009] MLL1 is the human homolog of the Saccharomyces cerevisiae gene Set1 and the Drosophila gene Trx. The gene encodes an enzyme that catalyzes the methylation of H3K4 [Nat. Rev. Cancer., 2007, 7(11):823-833]. Trimethylation of histone 3 (H3K4) at lysine 4 is a hallmark of active gene transcription, and alterations in this process often result in altered gene expression patterns. MLL1 translocations are also associated with altered transcription of key genes involved in stem cell maintenance and expression, thus leading to leukemogenesis. The MLL1 gene was first discovered in a patient with leukemia in 1991 [Nat. Rev. Cancer., 2007, 7(11):823-833]. The cDNA for the MLL1 gene contains approximately 12 kb of nucleotides and encodes a peptide over 4000 amino acids long. In cells, the immature MLL1 protein is digested by Taspase, resulting in two peptides: a 300 kDa N-terminal fragment and a 170 kDa C-terminal fragment. The two cleaved peptides form a heterodimer, which complexes with other components, such as WDR5, RBBP5, ASH2L, and DPY30. In some leukemia patients, chromosomal translocations result in the fusion of approximately 4.2 kb of DNA in the MLL1 N-terminal coding region with several other genes [Cancer. Cell., 2003, 4(3):197-207].

[0010] The generation of MLL1 fusion proteins is sufficient to induce leukemia, as demonstrated in animal models [Nat. Rev. Cancer., 2007, 7(11):823-833]. The mechanism of MLL1 fusion-mediated leukemia has been extensively studied over the past 20 years. MLL / SET1 family members are most enzymatically active when they are part of a "core complex" (WRAD2), which contains a catalytic SET-domain-containing subunit bound to a subcomplex composed of homodimers of the proteins WDR5, RbBP5, Ash2L, and DPY-30. The requirement for MLL / SET1 members to bind to WRAD2 for full activity is the basis for specialized drug development strategies, which require disrupting the binding between the MLL / SET1 subunit and WDR5. Recent efforts to pharmacologically target MLL1 catalytic activity have focused on disrupting MLL1-WDR5 binding with Win-motif mimetic peptides and small-molecule peptidomimetics [J. Med. Chem., 2010, 53: 5179-5185; J. Am. Chem. Soc., 2013, 135: 669-682; Mol. Cell., 2014, 53: 247-261]. However, like most peptide-based inhibitors, MLL1-WDR5 peptidic inhibitors exhibit poor cell-based activity and lack oral bioavailability due to poor cell permeability and peptide chemistry (e.g., susceptibility to peptidases).

[0011] The role of WDR5 in other cancers bladder cancer WDR5 also plays an important role in embryonic stem cell self-renewal [Cell. 2011; 145 (2):183-97] and epithelial-mesenchymal transition [Mol. Cell., 2011; 43(5):811-22]. Recent studies have found that the protein H2A.Z is overexpressed in bladder cancer and activates oncogenic transcription by recruiting WDR5 and bromodomain PHD finger transcription factor (BPTF) to its target genes [Epigenetics. Chromatin., 2013; 6 (1):34], suggesting that WDR5 may play a role in bladder cancer, but its expression pattern, role, and mechanism in bladder cancer remain unclear. WDR5 is upregulated in bladder cancer tissues compared with normal tissues, as determined by immunohistochemistry (IHC), and correlates with advanced tumor stage and overall survival in bladder cancer patients. A recent study found that WDR5 is overexpressed in prostate cancer tissues compared with normal tissues [Mol. Cell., 2014 May 22; 54 (4):613-25]. Taken together, high expression levels of WDR5 may serve as a novel molecular marker for bladder cancer.

[0012] Silencing WDR5 reduces cell proliferation in breast and prostate cancer [Mol. Cell., 2014, 54 (4):613-25; Cell Rep., 2013 5 (2):302-13], but the detailed mechanism and role of WDR5 in vivo remain unknown. Gain or loss of function of WDR5 promotes bladder cancer cell proliferation in vitro and tumor growth in vivo, and WDR5 silencing primarily induces G0 / G1 cell cycle arrest. The cell cycle is regulated by cyclins and cyclin-dependent kinases. Cyclin E1 and cyclin E2 regulate the G1-S phase transition, while cyclin B1 regulates the G2-M phase transition. Furthermore, cyclin E is associated with high-grade, high-stage, and invasive bladder cancer [Cell. Cycle., 2012; 11(7):1468-76; Am. J. Pathol., 2000;157(3):787-94]. UHMK1 (also designated KIS) is overexpressed in leukemia and promotes the G1-S phase transition [Leuk. Res., 2008; 32(9):1358-65]. Mechanistically, WDR5 knockdown inhibits cyclin E1, cyclin E2, and UHMK1, leading to G0 / G1 cell cycle arrest, which may counteract the effect of cyclin B1 downregulation on the G2-M phase transition. Additional studies showed that knockdown of MLL1, another core component of the MLL / SET1 complex, suppressed HeLa cell proliferation by reducing cyclin B expression and inducing G2 / M cell cycle arrest [Oncogene. 2013;32(28):3359-70]. These data suggest that WDR5 promotes bladder cancer cell proliferation in vitro and in vivo by regulating the cell cycle, although the role and mechanism are not identical to those of MLL1.

[0013] WDR5 is thought to play a role in cancer stem cells (CSCs). CSCs are a small subpopulation of cells in tumors that can self-renew, differentiate into multiple lineages, and have strong tumorigenic potential. CSCs have been widely identified in many malignant tumors, and their presence in bladder cancer was discovered by Chan et al. [Proc. Natl. Acad. Sci. USA, 2009; 106 (33):14016-21]. Several studies have found that sphere culture is an effective method for enriching cancer stem cells [Cell. 2007; 131(6):1109-23; Urol Oncol. 2012;30(3):314-8]. WDR5 and pluripotency transcription factors were observed to be upregulated in UM-UC-3 and T24 spheres. Gain or loss of function of WDR5 has been shown to promote UM-UC-3 and T24 cell self-renewal in vitro and upregulate the homeobox protein transcription factor Nanog. Emerging evidence indicates that Nanog is overexpressed in poorly differentiated tumors and correlates with poor survival outcomes in patients with various types of cancer, including bladder cancer [Nat. Genet., 2008; 40(5):499-507; Onco. Targets. Ther., 2013; 6:1207-20]. Furthermore, Nanog plays an important role in CSC self-renewal and targeting. Nanog has shown promising therapeutic potential in several types of cancer [Cell Stem Cell. 2011;9 (1):50-63; Oncogene. 2013;32(37):4397-405]. WDR5 directly activates Nanog by mediating its promoter H3K4me3 levels. Taken together, recent findings suggest that WDR5 plays a role in the self-renewal of bladder cancer cells by regulating Nanog.

[0014] Further studies demonstrated that WDR5 silencing increased cell apoptosis and reduced bladder cancer cell resistance to cisplatin. Conversely, overexpression of WDR5 enhanced chemo-resistance to cisplatin. Furthermore, WDR5 directly regulates the expression of key inhibitors of apoptosis proteins, MCL1 [FEBS Lett. 2010; 584(14):2981-9; Sci Rep. 2014; 4:6098] and BIRC3 [Expert Opin Ther Targets. 2009; 13(11):1333-45], via H3K4me3.

[0015] In summary, WDR5 is upregulated in bladder cancer and promotes bladder cancer cell proliferation, self-renewal, and chemotherapy resistance through H3K4me3 activation of a series of oncogenes, making WDR5 a potential biomarker for bladder cancer and a promising target for drug development [Sci Rep. 2015; 5: 8293, Genom Data. 2015 ;5:27-9.] Acute myeloid leukemia (AML)

[0016] The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of the short (30-kDa) CCAAT-enhancer-binding protein-α (C / EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanism underlying p30-mediated transformation remains unclear. Recent studies have demonstrated that C / EBPα p30, but not the normal p42 isoform, preferentially interacts with WDR5, a key component of the SET / MLL (SET-domain / mixed lineage leukemia) histone methyltransferase complex. Thus, p30-bound genomic regions are enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation require WDR5, as downregulation of the latter inhibited proliferation and restored differentiation in a p30-dependent AML model. A small molecule inhibitor of WDR5-MLL binding selectively inhibits proliferation and induces differentiation in p30-expressing human AML cells, revealing a mechanism of p30-dependent transformation and establishing the p30 cofactor WDR5 as a therapeutic target in CEBPA-mutated AML [Nat Chem Biol. 2015 ;11(8):571-8].

[0017] MYCN-amplified neuroblastoma MYCN gene amplification in neuroblastoma drives a gene expression program that strongly correlates with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a prerequisite for this transcriptional program. WDR5 is a histone H3K4 presenter that has been found to play an essential role in H3K4 trimethylation. For this reason, this study investigated the relationship between WDR5-mediated H3K4 trimethylation and the N-Myc transcriptional program in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements in their promoters, such as MDM2. WDR5 has been shown to form a protein complex with N-Myc, but not p53, at the MDM2 promoter, leading to histone H3K4 trimethylation and activation of MDM2 transcription [Cancer Res 2015; 75(23); 5143-54]. RNAi-mediated attenuation of WDR5 upregulated wild-type, but not mutant, p53 expression, an effect associated with growth inhibition and apoptosis. Similarly, a small molecule antagonist of WDR5 reduced N-Myc / WDR5 complex formation, N-Myc target gene expression, and cell proliferation in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in premalignant ganglia and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, these results identify WDR5 as a relevant cofactor for N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastoma [Cancer Res 2015; 75(23); 5143-54, Mol Cell. 2015; 58(3):440-52.] Summary of the Invention

[0018] The structural features described in the background section suggest that WDR5-MLL binding is a desirable drug target. Thus, agents that bind to WDR5 protein and compete for binding with WDR5-interacting partners can reverse the transcriptional activity of WDR5-containing complexes. Given the current need to treat WDR5-driven tumor types, such as leukemia and bladder cancer, as well as the challenges generally associated with inhibiting protein-protein interactions, complementary approaches, such as virtual screening, focused library screening, and traditional structure-activity relationship (SAR) studies, have been implemented. These studies have led to the identification of compounds that inhibit WDR5 protein-protein binding. Additionally, structure-activity relationship studies have demonstrated that certain chemical features contribute to the longer residence time of these compounds for binding to WDR5. Studies have shown that longer residence times can be engineered into WDR5 inhibitors and contribute to the ligand-induced antiproliferative effects observed in hematological and solid tumors.

[0019] A novel class of compounds of formula (I) have been prepared that exhibit potent disruption of WDR5-MLL1 protein-protein binding and therefore have utility in the treatment of cancer and other WDR5-mediated diseases, disorders and conditions.

[0020] Thus, in one aspect, the present application includes compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 1 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, OR 4 , S.R. 4 , N.R. 5 R 6 , C 1-6 Alkylene OR 4 , C 1-6 Alkylene SR 4 and C1-6 Alkylene NR 5 R 6 heterocycloalkyl substituted with one or more substituents selected from 1 contains at least one basic nitrogen atom; R 2 is C 6-10 aryl and heteroaryl, and R 2 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 7 , S.R. 7 and N.R. 8 R 9 substituted with one or more substituents selected from: R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 10 , S.R. 10 , SO2R 10 , N.R. 11 R 12 , R 13 , C 1-6 Alkylene R 13 , C 1-6 Alkenylene R 13 , O.C. 1-6 Alkylene R 13 , SC 1-6 Alkylene R 13 , C 1-6 Alkylene NR 11 R 12 , C 1-6 Alkylene OR 10 , C 1-6 Alkylene SR 10 , O.C. 1-6 Alkylene NR 11 R 12 , SC 1-6 Alkylene NR 11 R 12 , O.C. 1-6 Alkylene OR 10 , SC1-6 Alkylene OR 10 , O.C. 1-6 Alkylene SR 10 , SC 1-6 Alkylene SR 10 , C(O)OR 10 , C(S)OR 10 , C(S)NR 11 R 12 and C(O)NR 11 R 12 substituted with one or more substituents selected from: R 4 is H, C 1-6 Alkyl C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; R 5 and R 6 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OC 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 cycloalkyl; or R 5 and R 6 are taken together with the nitrogen atom attached to them and are unsubstituted or halo, CN, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl, OC 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from cycloalkyl; R 7 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; R 8 and R 9 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; or R 8 and R 9 are taken together with the nitrogen atom attached to them and are unsubstituted or halo, OH, CN, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl and OC 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkylene heterocycloalkyl and is unsubstituted or selected from halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 substituted with one or more substituents selected from: R 11 and R 12 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C(O)OC 1-6 Alkyl, C(O)OC 1-6 Fluoroalkyl, C(O)OC 6-10Aryl, C(O)OC 3-10 Cycloalkyl, C(O)O heteroaryl, C(O)O heterocycloalkyl, C(O)NHC 1-6 Alkyl, C(O)NHC 1-6 Fluoroalkyl, C(O)NHC 6-10 Aryl, C(O)NHC 3-10 Cycloalkyl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, SO2C 1-6 Alkyl, SO2C 1-6 Fluoroalkyl, SO2C 6-10 Aryl, SO2C 3-10 Cycloalkyl, SO2 heteroaryl, SO2 heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and R 11 and R 12 each independently is unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 or R 11 and R 12 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents independently selected from: R 13 is C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C 3-10Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 13 is unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 and is substituted with one or more substituents independently selected from R 14 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 14 is unsubstituted or halo, CN, C1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 15 and R 16 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 15 and R 16 each of which is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 15 and R 16 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from: alkyl; X 1 and X 2 are CR 17 and N are independently selected; R 17 are H, F, and C 1-6 Alkyl and C 1-6 fluoroalkyl; A is F, and All alkyl and alkylene groups are optionally fluoro-substituted.

[0021] In another aspect, the present application includes compositions comprising one or more compounds of the application and a carrier.

[0022] In another aspect, the present application includes a method for inhibiting binding of WDR5 to its binding partner in a cell, either in a biological sample or in a patient, comprising administering to the cell an effective amount of one or more compounds of the application.

[0023] The present application also includes a method for treating a disease, disorder, or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partner, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof. In one embodiment of the present application, the disease, disorder, or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partner is cancer.

[0024] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the application, are provided by way of example only, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.

[0025] Embodiments of the application will now be described in more detail with reference to the accompanying drawings. [Brief explanation of the drawings]

[0026] [Figure 1] Figure 1 shows WDR5 as an adaptor protein in multiple complexes and related biological processes. DETAILED DESCRIPTION OF THE INVENTION

[0027] I. Definition Unless otherwise stated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application described herein that are suitable as understood by those of skill in the art.

[0028] The terms "compounds of the application" or "compounds of the present application" and the like, as used herein, refer to compounds of Formula I, including compounds Ia, Ib, Ic, and Id, and pharmaceutically acceptable salts and / or solvates thereof.

[0029] The terms "composition of the application" or "composition of the present application" and the like, as used herein, refer to a composition comprising one or more compounds of Formula I, including compounds of Formula Ia, Ib, Ic, and / or Id, or pharmaceutically acceptable salts and / or solvates thereof, such pharmaceutical compositions.

[0030] The term "and / or" is used herein to mean that the listed items are present or used individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. The term "and / or," in reference to pharmaceutically acceptable salts and / or solvates thereof, means that the compounds of the application are present as individual salts and hydrates of the compounds of the application, as well as combinations thereof, e.g., solvate salts.

[0031] In this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present certain aspects having one compound, or two or more additional compounds.

[0032] In embodiments that include an "additional" or "second" component, e.g., an additional or second compound, the second component, as used herein, is chemically distinct from the other or first component. A "third" component is distinct from the other, first, and second components, and further listed or "additional" components are similarly distinct.

[0033] As used in this application and claim(s), the words "comprising" (and any form of comprising, e.g., "comprises" and "comprising"), "having" (and any form of having, e.g., "has" and "having"), "containing" (and any form of containing, e.g., "containing" and "containing") or "including" (and any form of including, e.g., "including" and "including") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0034] The term "comprising of" and its derivatives as used herein are intended to be closed terms that specify the presence of stated features, elements, components, groups, integers, and / or steps and exclude the presence of other unstated features, elements, components, groups, integers, and / or steps.

[0035] The term "consisting essentially of" is used herein to specify the presence of stated features, elements, components, groups, integers, and / or steps and that do not materially affect the basic and novel characteristic(s) of those features, elements, components, groups, integers, and / or steps.

[0036] The term "suitable" is used herein to mean that the selection of a particular compound or conditions will depend on the particular synthetic operation being performed, the identity of the molecule(s) being converted, and / or the particular use for the compound, but the selection is well within the skill of one trained in the art.

[0037] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. When compounds have more than one asymmetric center, they may exist as diastereomers. It should be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. While the stereochemistry of a compound may be as shown in any given compound listed herein, it should be further understood that such compounds may also contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the present application having an alternative stereochemistry. Any optical isomers, pure or partially purified optical isomers, or racemic mixtures thereof, as separated, are intended to be encompassed within the scope of the present application.

[0038] The compounds of the present application may also exist in different tautomeric forms, and it is intended that any tautomeric forms that the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0039] The compounds of the present application may further exist in different polymorphic forms, and any polymorph, or mixture thereof, is contemplated as being within the scope of the present application.

[0040] This description refers to numerous chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0041] The terms "about," "substantially," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term such that the end result is not significantly altered. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified term unless this deviation would negate the meaning of the word it modifies or unless the context would suggest otherwise to one of ordinary skill in the art.

[0042] As used herein with respect to a reaction or process step disclosed herein, the phrase "progresses to a sufficient extent" means that the reaction or process step proceeds to an extent that maximizes conversion of starting material or substrate to product. Conversion can be maximized when more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the starting material or substrate is converted to product.

[0043] The term "basic nitrogen," as used herein, refers to a nitrogen atom having a lone pair of electrons available to participate in an interaction with a hydrogen atom. In one embodiment, the interaction is a hydrogen bond, an ionic bond, or a covalent bond. Generally, the basic nitrogen atom is either a primary, secondary, or tertiary alkylamine nitrogen atom in either a straight-chain, branched, or cyclic group. In some embodiments, the pKa of the conjugate acid of the basic nitrogen atom is greater than about 8-10.

[0044] The term "alkyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain, saturated alkyl group. The number of carbon atoms possible in the recited alkyl group is indicated by the prefix "C n1-n2 For example, C 1-10 The term alkyl refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0045] The term "alkylene," whether used alone or as part of another group, refers to a straight or branched, saturated alkylene group, i.e., a saturated carbon chain containing substituents on two of its ends. The number of carbon atoms possible in the recited alkylene group is indicated by the prefix "C n1-n2 For example, C 2-6 The term alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0046] The term "alkenyl," as used herein, whether used alone or as part of another group, refers to a straight or branched chain, unsaturated alkyl group containing at least one double bond. The number of carbon atoms possible in the recited alkylene group is indicated by the prefix "C n1-n2 For example, C 2-6 The term alkenyl refers to an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0047] The term "fluoroalkyl," as used herein, refers to an alkyl group in which one or more, including all of the hydrogen atoms, have been replaced by a fluorine atom. In one embodiment, the fluoroalkyl contains at least one -CHF group. In another embodiment, the fluoroalkyl contains at least one -CF group.

[0048] The term "fluoro-substituted," as used herein, refers to a chemical group in which one or more, including all of the hydrogen atoms, have been replaced by a fluorine atom.

[0049] The term "cycloalkyl," as used herein, whether used alone or as part of another group, refers to a saturated carbocyclic group containing a number of carbon atoms and one or more rings. The number of possible carbon atoms in a given cycloalkyl group is indicated by the numerical prefix "C n1-n2 For example, C 3-10 The term cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0050] The term "aryl," whether used alone or as part of another group, refers herein to a cyclic group containing 6 to 20 carbon atoms and at least one aromatic ring. In one embodiment of the application, the aryl group contains 6, 9, or 10 carbon atoms, such as phenyl, indanyl, or naphthyl.

[0051] The term "heterocycloalkyl," as used herein, whether used alone or as part of another group, refers to a heterocycloalkyl group containing 3 to 20 atoms, preferably 3 to 10 atoms, and at least one non-aromatic ring, where one or more of the atoms is O, S, S(O), SO, N, NH, and NC. 1-6 Alkyl, preferably O, S, N, NH and NC 1-6 Heterocycloalkyl groups refer to cyclic groups containing a heterocyclic group (hetero group selected from alkyl). Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds) and contain one or more rings (i.e., are polycyclic). When a heterocycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds. When a heterocycloalkyl group is prefixed with C, it is understood that the prefix C refers to a cyclic group containing a heterocyclic group (hetero group selected from alkyl). Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds) and contain one or more rings (i.e., are polycyclic). When a heterocycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds. n1-n2 When containing the prefix "-", this indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced with a hetero moiety as defined above.

[0052] A first ring group is "fused" to a second ring group means that the first ring and the second ring share at least two atoms between them.

[0053] The term "heteroaryl" as used herein refers to a heteroaryl group containing 5 to 20 atoms, preferably 5 to 10 atoms, at least one aromatic ring, and one or more of the following: O, S, S(O), SO, N, NH, and NC. 1-6 Alkyl, preferably O, S, N, NH and NC 1-6"C" refers to a cyclic group containing at least one hetero moiety selected from alkyl. Heteroaryl groups contain one or more rings (i.e., are polycyclic). When a heteroaryl group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds. Heteroaryl groups are denoted by the prefix C. n1-n2 When containing the prefix "-", this indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced with a hetero moiety as defined above.

[0054] The term "available," as in "available hydrogen atom" or "available atom," refers to an atom known to those skilled in the art to be available for replacement by a substituent.

[0055] The terms "halo" or "halogen," as used herein, whether used alone or as part of another group, refer to a halogen atom and include fluoro, chloro, bromo, and iodo.

[0056] The term "amine" or "amino," as used herein, whether used alone or as part of another group, refers to a group of the general formula NRR', where R and R' are, respectively, hydrogen and alkyl groups, such as C 1-6 alkyl.

[0057] The term "atm" is used herein to refer to atmospheric pressure.

[0058] The term "MS" is used herein to refer to mass spectrometry.

[0059] The term "aq." is used herein to refer to aqueous.

[0060] DCM herein refers to dichloromethane.

[0061] DIPEA herein refers to N,N-diisopropylethylamine.

[0062] DMF herein refers to dimethylformamide.

[0063] DMSO herein refers to dimethyl sulfoxide.

[0064] EtOAc as used herein refers to ethyl acetate.

[0065] HATU herein refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0066] MeOH as used herein refers to methanol.

[0067] MeCN refers herein to acetonitrile.

[0068] HCl as used herein refers to hydrochloric acid.

[0069] TFA as used herein refers to trifluoroacetic acid.

[0070] TBAF as used herein refers to tetra-n-butylammonium fluoride.

[0071] CsF as used herein is cesium fluoride.

[0072] μwave herein refers to a microwave reactor.

[0073] SnAr, as used herein, represents nucleophilic aromatic substitution.

[0074] LCMS as used herein refers to liquid chromatography-mass spectrometry.

[0075] The term "protecting group" or "PG" as used herein refers to a chemical moiety that protects or masks a reactive portion of a molecule, preventing side reactions at those reactive portions of the molecule while allowing a different portion of the molecule to be manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portion of the molecule. The selection of a suitable protecting group can be performed by one skilled in the art. Many conventional protecting groups are known in the art and are described, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973; Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999; and Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0076] The term "subject," as used herein, includes all members of the animal kingdom, including mammals, and preferably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary use. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0077] The term "pharmaceutically acceptable" means compatible with the treatment of a subject, eg, a human.

[0078] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with an active ingredient to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0079] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a subject.

[0080] Acid addition salts suitable for or compatible with the treatment of subjects are any non-toxic organic or inorganic acid addition salts of any basic compound.Basic compounds that form acid addition salts include, for example, compounds containing amine groups.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Exemplary such organic acids include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In one embodiment, mono- or di-acid salts are formed, and such salts exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. Criteria for selecting an appropriate salt are known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as, but not limited to, oxalates, may be used, for example, for experimental purposes or in isolating the compounds of the application for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0081] Base addition salts suitable for or compatible with the treatment of subjects include any non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form base addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, for example, SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19). For example, selecting an appropriate salt can be useful to prevent hydrolysis of ester functional groups (if any) elsewhere in the compound. The criteria for selecting an appropriate salt are known to those skilled in the art.

[0082] The term "solvate" as used herein refers to a compound, or a salt or prodrug of a compound, in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is physiologically tolerated at the administered dosage. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate." The formation of solvates of the compounds of the application varies depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried under ambient conditions or azeotroped. The selection of suitable conditions for forming a particular solvate can be performed by one skilled in the art.

[0083] The terms "treating" or "treatment," as used herein, and as well understood in the art, refer to an approach for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results include, but are not limited to, the reduction or amelioration of one or more symptoms or conditions, whether detectable or undetectable, the reduction in the extent of the disease, the stabilization of the disease state (i.e., not worsening), the prevention of the spread of the disease, the delay or slowing of disease progression, the remission or alleviation of the disease state, the reduction in recurrence of the disease, and remission (whether partial or total). "Treating" and "treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. "Treating" and "treatment," as used herein, also include prophylactic treatment. For example, a subject with early-stage cancer can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the application to prevent recurrence. A method of treatment includes administering to a subject a therapeutically effective amount of one or more compounds of the application, optionally consisting of a single dose or including a series of doses. For example, the compound of the present application is administered at least once a week. However, in other embodiments, the compound is administered to a subject about once every two weeks, three weeks, or one month. In other embodiments, the compound is administered about once a week to about once a day. In other embodiments, the compound is administered two, three, four, five, or six times daily. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be recognized that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may occur and be evident using standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the compound is administered to a subject in an amount sufficient and for a sufficient duration to treat the subject.

[0084] To "ameliorate" a disease, disorder, or condition means that the severity and / or undesirable clinical symptoms of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to without treatment of the disorder.

[0085] The terms "prevention" or "prophylaxis," or synonyms thereof, as used herein, refer to a reduction in the risk or probability of a patient suffering from a disease, disorder, or condition, or of experiencing symptoms associated with a disease, disorder, or condition.

[0086] "Disease," "disorder," or "condition," as used herein, refers to a disease, disorder, or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, particularly MLL1, using, among other things, WDR5 protein inhibitors, e.g., the compounds of the applications described herein.

[0087] The term "mediated by or treatable by inhibition of binding between WDR5 protein and its binding partner" as used herein means that the disease, disorder, or condition being treated is affected, modulated, and / or has some biological basis (direct or indirect) involving WDR5 binding to its binding partner, e.g., MLL1, particularly increased WDR5 binding. Such biological basis includes, for example, WDR5 and / or MLL1 gene overexpression, WDR5 and / or MLL1 protein overaccumulation, or overexpression of a protein that is a product or precursor of WDR5-mediated and / or MLL1 gene expression. In a precise context, "mediated by or treatable by inhibition of binding between WDR5 protein and its binding partner" refers to an effect mediated by inhibition of binding between WDR5 and MLL1. In a broader context, "mediated by or treatable by inhibition of binding between WDR5 protein and its binding partner" can include numerous diseases caused by aberrant methylation of histone 3 lysine 4 (H3K4) residues resulting from aberrant WDR5 and / or MLL1 activity. As used herein, WDR5 refers to the protein identified under GenBank accession number NM_017588 [J. Biol. Chem. 2001, 276 (49), 46515-46522] and isoforms containing this sequence, as well as shorter versions. Similarly, other WDR5 proteins are characterized and described in any of the protein databases. As used herein, MLL1 refers to the protein identified under GenBank accession number NM_005933 [Proc. Natl. Acad. Sci. USA 1991, 88 (23), 10735-10739; DNA Cell Biol. 1995, 14 (6), 475-483] and isoforms containing this sequence, as well as shorter versions. Similarly, other MLL1 proteins are characterized and described in any of the protein databases.

[0088] The term "binding" as used herein refers to any interaction between two entities, for example, two proteins, that leads to a functional effect.

[0089] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of one or more compounds of the present application effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition mediated or treatable by inhibition of binding between a WDR5 protein and its binding partner, an effective amount is, for example, an amount that increases said inhibition compared to the inhibition without administration of one or more compounds. In one embodiment, an effective amount varies according to factors such as the disease state, age, sex, and / or weight of the subject. In a further embodiment, the amount of a given compound or compounds that corresponds to an effective amount varies depending on factors such as the drug(s) or compound(s) given, pharmaceutical formulation, route of administration, type of condition, disease, or disorder, and identity of the subject being treated, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0090] The term "administered" as used herein means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell, tissue, organ or subject.

[0091] The term "neoplastic disorder," as used herein, refers to a disease, disorder, or condition characterized by cells having the capacity for self-proliferation or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. The term "neoplasm," as used herein, refers to a mass of tissue resulting from the abnormal proliferation and / or division of cells in a subject with a neoplastic disorder. Neoplasms can be benign (e.g., uterine fibroids and pigmented nevi), potentially malignant (e.g., carcinoma in situ), or malignant (i.e., cancer). Exemplary neoplastic disorders include so-called solid tumors and liquid tumors, including, but not limited to, carcinomas, sarcomas, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders (e.g., leukemias, lymphomas, myelomas, and other malignant plasma cell disorders), metastatic tumors, and other cancers.

[0092] The term "cancer" is used herein to refer to a cell-proliferative disease state.

[0093] II. COMPOUNDS AND COMPOSITIONS OF THE APPLICATION The present application includes compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 1 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, OR 4 , S.R. 4 , N.R. 5 R 6 , C 1-6 Alkylene OR 4 , C 1-6 Alkylene SR 4 and C 1-6 Alkylene NR 5 R 6 heterocycloalkyl substituted with one or more substituents selected from 1 contains at least one basic nitrogen atom; R 2 is C 6-10 aryl and heteroaryl, and R 2 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 7 , S.R. 7 and N.R. 8 R 9 substituted with one or more substituents selected from: R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR10 , S.R. 10 , SO2R 10 , N.R. 11 R 12 , R 13 , C 1-6 Alkylene R 13 , C 1-6 Alkenylene R 13 , O.C. 1-6 Alkylene R 13 , SC 1-6 Alkylene R 13 , C 1-6 Alkylene NR 11 R 12 , C 1-6 Alkylene OR 10 , C 1-6 Alkylene SR 10 , O.C. 1-6 Alkylene NR 11 R 12 , SC 1-6 Alkylene NR 11 R 12 , O.C. 1-6 Alkylene OR 10 , SC 1-6 Alkylene OR 10 , O.C. 1-6 Alkylene SR 10 , SC 1-6 Alkylene SR 10 , C(O)OR 10 , C(S)OR 10 , C(S)NR 11 R 12 and C(O)NR 11 R 12 substituted with one or more substituents selected from: R 4 is H, C 1-6 Alkyl C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; R 5 and R 6 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6Fluoroalkyl, C(O)OC 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 cycloalkyl; or R 5 and R 6 are taken together with the nitrogen atom attached to them and are unsubstituted or halo, CN, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl, OC 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from cycloalkyl; R 7 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; R 8 and R 9 is H, C 1-6Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; or R 8 and R 9 are taken together with the nitrogen atom attached to them and are unsubstituted or halo, OH, CN, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl and OC 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkylene heterocycloalkyl and is unsubstituted or selected from halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 substituted with one or more substituents selected from: R 11 and R 12 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C(O)OC 1-6 Alkyl, C(O)OC 1-6 Fluoroalkyl, C(O)OC 6-10 Aryl, C(O)OC 3-10 Cycloalkyl, C(O)O heteroaryl, C(O)O heterocycloalkyl, C(O)NHC 1-6 Alkyl, C(O)NHC 1-6 Fluoroalkyl, C(O)NHC 6-10 Aryl, C(O)NHC 3-10 Cycloalkyl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, SO2C 1-6 Alkyl, SO2C 1-6 Fluoroalkyl, SO2C 6-10 Aryl, SO2C 3-10 Cycloalkyl, SO2 heteroaryl, SO2 heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6alkyleneheterocycloalkyl, and R 11 and R 12 each independently is unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 or R 11 and R 12 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents independently selected from: R 13 is C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 13 is unsubstituted, or halo, CN, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14, C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 and is substituted with one or more substituents independently selected from R 14 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 14 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 15 and R 16 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 15 and R 16 each of which is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 15 and R 16 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from: alkyl; X 1 and X 2 are CR 17 and N are independently selected; R 17 are H, F, and C 1-6 Alkyl and C 1-6 fluoroalkyl; A is F, and All alkyl and alkylene groups are optionally fluoro-substituted.

[0094] The present application also includes compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 1 is unsubstituted or halo, C1-6 Alkyl, C 1-6 Fluoroalkyl, OR 4 , S.R. 4 , N.R. 5 R 6 , C 1-6 Alkylene OR 4 , C 1-6 Alkylene SR 4 and C 1-6 Alkylene NR 5 R 6 heterocycloalkyl substituted with one or more substituents selected from 1 contains at least one basic nitrogen atom; R 2 is C 6-10 aryl and heteroaryl, and R 2 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 7 , S.R. 7 and N.R. 8 R 9 substituted with one or more substituents selected from: R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 10 , S.R. 10 , N.R. 11 R 12 , R 13 , C 1-6 Alkylene R 13 , O.C. 1-6 Alkylene R 13 , SC 1-6 Alkylene R 13 , C 1-6 Alkylene NR 11 R 12 , C 1-6 Alkylene OR 10 , C 1-6 Alkylene SR 10 , O.C. 1-6Alkylene NR 11 R 12 , SC 1-6 Alkylene NR 11 R 12 , O.C. 1-6 Alkylene OR 10 , SC 1-6 Alkylene OR 10 , O.C. 1-6 Alkylene SR 10 , SC 1-6 Alkylene SR 10 , C(O)OR 10 , C(S)OR 10 , C(S)NR 11 R 12 and C(O)NR 11 R 12 substituted with one or more substituents selected from: R 4 is H, C 1-6 Alkyl C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; R 5 and R 6 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; or R 5 and R 6 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl, OC 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 7 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C1-6 alkyl; R 8 and R 9 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl, or R 8 and R 9 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl and OC 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkylene, heterocycloalkyl, and is unsubstituted or selected from halo, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 substituted with one or more substituents selected from: R 11 and R 12 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and R 11 and R 12 each independently is unsubstituted, or halo, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 or R 11 and R 12 are taken together with the nitrogen atom to which they are attached and are unsubstituted, or halo, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents independently selected from: R 13 is C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 13 is unsubstituted, or halo, OR 14 , S.R. 14 , N.R. 15 R 16 , C 1-6 Alkyl, C(O)R 14 , C(O)OR 14 , C(O)NR 15 R 16 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 14 , C 1-6 Alkylene OR 14 , C 1-6 Alkylene SR 14 and C 1-6 Alkylene NR 15 R 16 and is substituted with one or more substituents independently selected from R 14 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 14 is unsubstituted or halo, C 1-6Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 15 and R 16 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 15 and R 16 each of which is unsubstituted, or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 15 and R 16 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C1-6 Alkyl)(C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from: alkyl; X 1 and X 2 are CR 17 and N are independently selected; R 17 is H, C 1-6 Alkyl and C 1-6 fluoroalkyl; A is F; and All alkyl and alkylene groups are optionally fluoro-substituted.

[0095] In some embodiments, R 1 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, NR 5 R 6 and C 1-6 Alkylene NR 5 R 6 and heterocycloalkyl substituted with 1, 2, or 3 substituents selected from: 1 contains at least one basic nitrogen atom. 1 is halo, C 1-6 Alkyl, and NR 5 R 6 and R is a heterocycloalkyl substituted with one or two substituents selected from 1 contains at least one basic nitrogen atom. 1 is C 1-6 Alkyl, and NR 5 R 6 and R is a heterocycloalkyl substituted with one or two substituents selected from 1 contains at least one basic nitrogen atom. 1 contains one or two nitrogen atoms (at least one of which is basic) 5-6 Heterocycloalkyl

[0096] In some embodiments, R 1 is selected from: [ka] TIFF0007624690000005.tif96160

[0097] In some embodiments, R 1 is selected from: [ka]

[0098] In some embodiments, R 1 is selected from: [ka]

[0099] In some embodiments, R 1 is selected from: [ka]

[0100] In some embodiments, R 1 is selected from: [ka]

[0101] R 1 is selected from: [ka]

[0102] In some embodiments, R 2 is C 6-10 aryl and heteroaryl; R 2is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, OR 7 , S.R. 7 and N.R. 8 R 9 In some embodiments, R 2 is C 6-10 aryl and heteroaryl; R 2 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O and NR 8 R 9 In some embodiments, R 2 is C 6-10 aryl and heteroaryl; R 2 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 In some embodiments, R is substituted with one or two substituents selected from fluoroalkyl and =O. 2 is selected from phenyl and C6-heteroaryl, R 2 is substituted with 1 to 3 substituents selected from F, CF2H, CF3 and =O.

[0103] In some embodiments, R 2 is selected from: [ka]

[0104] In some embodiments, R 2 is selected from the following or a tautomer thereof: [ka]

[0105] In some embodiments, R 2 is selected from the following or a tautomer thereof: [ka]

[0106] In one embodiment, R 2 The tautomer of the group is [ka] is.

[0107] In some embodiments, R 2 is selected from the following or a tautomer thereof: [ka]

[0108] In some embodiments, R 2 is selected from: [ka]

[0109] In some embodiments, R 2 teeth [ka] is.

[0110] In some embodiments, R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 Halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 10 , N.R. 11 R 12 , R 13 , C 1-6 Alkylene R 13 , O.C. 1-6 Alkylene R 13 , C 1-6 Alkylene NR 11 R 12, C 1-6 Alkylene OR 10 , O.C. 1-6 Alkylene NR 11 R 12 , O.C. 1-6 Alkylene OR 10 , C(O)OR 10 and C(O)NR 11 R 12 In some embodiments, R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 is halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 10 , N.R. 11 R 12 , R 13 , C 1-6 Alkylene R 13 , O.C. 1-6 Alkylene R 13 , C 1-6 Alkylene NR 11 R 12 , C 1-6 Alkylene OR 10 , O.C. 1-6 Alkylene NR 11 R 12 and O.C. 1-6 Alkylene OR 10 In some embodiments, R 3 is C 6-10 selected from aryl, heteroaryl, and heterocycloalkyl, and R 3 is unsubstituted or halo, CN, C 1-6 Alkyl, OR 10 , N.R. 11 R 12 , R 13 and O.C. 1-6 Alkylene R 13 In some embodiments, R 3 is heteroaryl, and R 3 Halo, CN, C 1-6Alkyl, OR 10 , N.R. 11 R 12 , R 13 and O.C. 1-6 Alkylene R 13 In some embodiments, R 3 is heteroaryl, and R 3 is R 13 In some embodiments, R 3 is phenyl. In some embodiments, R 3 is a monocyclic C 5-6 Heterocycloalkyl and Monocyclic C 5-6 In some embodiments, R is selected from heteroaryl. 3 is phenyl, pyrimidinyl, pyridinyl, dihydropyridine, dihydropyrrolyl, aziridinyl, oxiranyl, furanyl, thienyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridine, In some embodiments, R is selected from lysinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxydyl. 3 is selected from phenyl, pyridinyl, pyrimidinyl and dihydropyridinyl.

[0111] In some embodiments, R 5 and R 6 is H, C 1-6 In some embodiments, R is independently selected from alkyl and heterocycloalkyl. 5 and R6 is H and C 1-6 In some embodiments, R 5 and R 6 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo and C 1-6 In some embodiments, R forms a 3- to 10-membered heterocycle substituted with 1, 2, or 3 substituents selected from alkyl, aryl, arylsulfonyl ... 5 and R 6 taken together with the nitrogen atom to which they are attached form an unsubstituted 3- to 10-membered heterocyclic ring.

[0112] In some embodiments, R 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 In some embodiments, R is selected from alkyleneheterocycloalkyl. 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 In some embodiments, R is selected from alkyleneheterocycloalkyl. 10 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl and C 1-6 Alkylene C 3-10 In some embodiments, R 10 is C 1-6 Alkyl and C 1-6In some embodiments, R 10 is an unsubstituted or substituted monocyclic heterocycloalkyl selected from the following: dihydropyridinyl, pyridinyl, pyrimidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3 In some embodiments, R is selected from the group consisting of 2,6-tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxydyl. 10 is morpholinyl.

[0113] In some embodiments, R 11 and R 12 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 In some embodiments, R 11 and R 12 are H and C, respectively. 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 3-10 Cycloalkyl and C1-6 In some embodiments, R 11 and R 12 are H and C, respectively. 1-10 Alkyl and C 3-10 In some embodiments, R 11 and R 12 taken together with the nitrogen atom to which they are attached form an unsubstituted, 3- to 10-membered heterocyclic ring.

[0114] In some embodiments, R 13 is C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 In some embodiments, R 13 is C 3-10 In some embodiments, R is selected from cycloalkyl and heterocycloalkyl. 13 is heterocycloalkyl. In some embodiments, R 13 is an unsubstituted or substituted monocyclic heterocycloalkyl selected from: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, In some embodiments, R is selected from the group consisting of 2,3-dihydropyranyl, 4,7-dihydro-1H-azepinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxydyl. 13 is morpholinyl.

[0115] In some embodiments, X1 and X 2 are CR 17 and N, where R 17 is H and C 1-6 In some embodiments, X is selected from alkyl. 1 and X 2 Both are CR 17 where R 17 is H. In some embodiments, X 1 and X 2 One of them is CR 17 and X 1 and X 2 The other is N, where R 17 is H.

[0116] In some embodiments, the compound of formula I is selected from: 4-Fluoro-N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(6-morpholin-4-ylpyridin-3-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(1,3-benzodioxol-5-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[(3R)-3,4-dimethylpiperazin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[(3S)-3,4-dimethylpiperazin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(cyclohexylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-ethoxypyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-methylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclohexylamino)pyridin-3-yl]-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-hydroxypyrimidin-5-yl)-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-pyrimidin-5-ylphenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,4-dimethoxypyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[2-[3-(dimethylamino)pyrrolidin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-methylbenzamide; 6-acetamido-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,5-dimethylbenzamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[6-(oxan-4-yloxy)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-methylpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-pyridin-3-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-pyridin-4-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[6-(morpholin-4-ylmethyl)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(2',6-difluoro-4-(4-methylpiperazin-1-yl)-5'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(3'-((cyclopentylamino)methyl)-6-fluoro-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4-(3,4-dimethylpiperazin-1-yl)-6-fluoro-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholinopyridin-4-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(5-(morpholinomethyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; (R)—N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(5-(((tetrahydrofuran-3-yl)amino)methyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; (R)—N-(4-(3,4-dimethylpiperazin-1-yl)-6-fluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; (S)—N-(4-(3,4-dimethylpiperazin-1-yl)-6-fluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(6-fluoro-3'-(morpholinomethyl)-4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-6-fluoro-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholin-4-ylpyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-(Difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-4-fluorobenzamide; N-[5-(1,3-benzodioxol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-methoxy-6-oxo-1H-pyridine-3-carboxamide; N-[5-[2-(cyclopropylmethoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-[(cyclohexylamino)methyl]phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3-chloro-4-morpholin-4-ylphenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-acetamidopyrimidin-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-phenyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-methoxybenzamide; 3,5-Dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridazine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]furan-2-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-(2-methoxyethoxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(3-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-methoxybenzamide; 2-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 5-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-methoxybenzamide; N-[4-fluoro-5-[4-(2-methoxyethoxy)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[5-chloro-6-(2-methylpropoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[3-chloro-4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 4-Fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,5-dimethylbenzamide; N-[5-(3-chloro-5-cyano-4-hydroxyphenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-cyano-6-phenylmethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-cyanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3-cyanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5,6-dimethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-benzodioxole-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-methoxybenzamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(3-fluoro-5-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-methoxybenzamide; 3,4-Difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(4-methoxyphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(4-pyrrolidin-1-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-acetamido-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methylindazole-3-carboxamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methylindazole-3-carboxamide; N-[4-fluoro-5-[3-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[3-[(4-fluoropiperidin-1-yl)methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl)-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methylpyrazole-4-carboxamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methylpyrazole-4-carboxamide; N-[5-(5-cyano-6-hydroxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[3-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-(Dimethylamino)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-oxazole-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-propan-2-yloxypyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(6-cyanopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(6-cyano-5-methylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyanopyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-methoxy-6-(trifluoromethyl)pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-methoxy-6-methylpyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-cyano-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-methoxypyridine-3-carboxamide; 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2,6-Dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 3-chloro-2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; tert-Butyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[4-(trifluoromethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[4-(trifluoromethoxy)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-phenyl-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-chlorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[(4-methoxyphenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-methylpyridazin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(2-methylpropyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[1-(3,3,3-trifluoropropyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(pyridin-3-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[1-(thiophen-3-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[5-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-piperazin-1-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-chloro-5-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 3,5-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[1-(1,3-thiazol-2-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[(2-methyl-1,3-oxazol-5-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[(1-methylpyrazol-4-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[(4-morpholin-4-ylphenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(oxan-4-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3,5-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]benzamide; 3,5-dichloro-N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]benzamide; N-[5-(5-cyano-6-morpholin-4-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(5-methyl-6-morpholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[5-(tert-butylcarbamoyl)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-(trifluoromethyl)benzamide; 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-(trifluoromethyl)benzamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-1H-pyrazole-4-carboxamide; N-[4-fluoro-5-(5-methylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-carbamoylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[5-(trifluoromethyl)pyridin-3-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-methyl-1,3-thiazole-2-carboxamide; 2-[(Dimethylamino)methyl]-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1,3-thiazole-4-carboxamide; 4-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1H-pyrazole-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-(trifluoromethyl)benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(trifluoromethyl)pyrimidine-5-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide; 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-(trifluoromethyl)benzamide; 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-methoxybenzamide; 3,5-Dichloro-N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methylpyrazole-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1H-pyrazole-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-methyl-1,3-thiazole-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-methyl-1,3-thiazole-5-carboxamide; N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide; 3,5-Dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-(5-cyanopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-chloropyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyclohexyloxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[2-(4-methoxyphenyl)acetyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-(2-methoxyethoxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-(trifluoromethyl)thiophene-2-carboxamide; 3,5-Dichloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2,3-Dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-[3-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-ethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-[6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[5-cyano-6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(dimethylamino)-5-fluoropyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-chloro-6-morpholin-4-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-(Difluoromethyl)-N-(2-((S)-3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-5-yl)phenyl)-4-fluorobenzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-(3,3,4-trimethylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(4-pyrrolidin-1-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 2,3-Difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[5-(1-cyclopentyl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[1-(4-methoxyphenyl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(1-butan-2-yl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-piperidin-4-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-propan-2-yloxypyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(1-methylpiperidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(2,2-dimethylpropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-(1-methylsulfonyl-2,5-dihydropyrrol-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3,5-Dichloro-N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2-chloro-N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-fluorobenzamide; N-[5-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; Ethyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; 2-Methylpropyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[5-[1-(3,3-dimethylbutanoyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-fluoropyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[4-(dimethylamino)piperidin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[2-[(dimethylamino)methyl]morpholin-4-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-pyrrolidin-1-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-cyano-6-pyrrolidin-1-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,2-difluoro-1,3-benzodioxol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-methoxybenzamide; 3-chloro-2,4-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(6-cyano-4-methylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-pyridin-2-yl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[1-(6-methoxypyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(5-chloropyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; Ethyl 2-[4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridin-1-yl]pyrimidine-4-carboxylate; N-[4-fluoro-2-[3-(methylamino)pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[2-[3-[(dimethylamino)methyl]pyrrolidin-1-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-hydroxy-5-(trifluoromethyl)benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-hydroxybenzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3-hydroxyquinoline-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[5-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(pyrrolidine-1-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(4-methylpiperazine-1-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; Phenyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-fluoro-5-[1-[(2R,6S)-2,6-dimethyloxan-4-yl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-hydroxy-2-(trifluoromethyl)benzamide; 2,3-Difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-hydroxybenzamide; N-[5-[2-(cyclobutylmethoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(2,2-dimethylpropoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(diethylamino)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 3,4,5-trifluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 3,5-dichloro-N-[4-fluoro-2-[3-(methylamino)pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]benzamide; N-[4-fluoro-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[4-(4-methylpiperazin-1-yl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-2-[3-[methyl(propyl)amino]pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 3,5-dichloro-N-[4-fluoro-2-[3-[methyl(propyl)amino]pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]benzamide; N-[5-[1-[2-(dimethylamino)acetyl]-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-[4-[5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]pyrimidin-2-yl]piperazin-1-yl]-4-oxobutanoic acid; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-2-morpholin-4-yl-5-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; tert-Butyl 4-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 1-ethyl-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 2,3-Dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; tert-Butyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; tert-Butyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; tert-Butyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate; tert-Butyl 5-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; tert-Butyl 3-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; tert-Butyl 3-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-(1,2,3,6-tetrahydropyridin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2,5-dihydro-1H-pyrrol-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[5-(2-butan-2-yloxypyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-(dimethylamino)-4-methoxypyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-pyrimidin-2-yl-2,5-dihydropyrrol-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(8-pyrimidin-2-yl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-yl-1,4,5,6-tetrahydropyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-[ethyl(methyl)amino]-4-fluoropyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[ethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-[ethyl(methyl)amino]-4-fluoropyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-propan-2-ylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-propan-2-ylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-7-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide; N-[5-[2-(7-azabicyclo[2.2.1]heptan-7-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-[ethyl(methyl)amino]-4-methoxypyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[methyl-[(3R)-oxolan-3-yl]amino]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[methyl-[(3R)-oxolan-3-yl]amino]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[1-(6-methoxypyrimidin-4-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-fluoropyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(4,6-dimethylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-formylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; Ethyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-fluoro-5-[1-(pyrrolidine-1-carbonyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-fluoropyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-[2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-5-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridazin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(4-pyrimidin-2-ylpiperazin-1-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-(hydroxymethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-methylsulfonylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(2-piperazin-1-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyanopyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-[5-[(dimethylamino)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-(morpholin-4-ylmethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-[(4-methylpiperazin-1-yl)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-Methylpropyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-fluoro-5-[1-(5-formylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-(hydroxymethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-[5-[(dimethylamino)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-(morpholin-4-ylmethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-[(4-methylpiperazin-1-yl)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S)-3-[ethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(diethylamino)pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S)-3-[ethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(diethylamino)pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methoxypyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(6-methoxypyrimidin-4-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-methylpyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(5-fluoropyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(pyrrolidine-1-carbonyl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(pyrazine-2-carbonyl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-Methylpropyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; N-[4-fluoro-5-[1-(5-formylpyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-methylpyrazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-cyano-1,3-thiazol-2-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-cyano-1,3-thiazol-2-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[5-[2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[1-[5-[(dimethylamino)methyl]pyrimidin-2-yl]-2,5-dihydropyrrol-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-(morpholin-4-ylmethyl)pyrimidin-2-yl]-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-[5-[(4-methylpiperazin-1-yl)methyl]pyrimidin-2-yl]-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-piperazin-1-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; (1-Methylcyclobutyl) 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (1-Methylcyclobutyl)5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (1-Methylcyclobutyl)3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyrazin-2-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-1-propyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,4,5-tetramethylpiperazin-4-ium-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-4-carboxamide; N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-4-carboxamide; N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-4-carboxamide; N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-4-carboxamide; N-[4-fluoro-5-[4-(morpholine-4-carbonyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; (3-methyloxetan-3-yl)4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3-methyloxetan-3-yl)5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3-methyloxetan-3-yl)3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; N-[4-fluoro-5-[5-(morpholin-4-ylmethyl)thiophen-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-thiophen-2-ylphenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-5-thiophen-3-ylphenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[5-(morpholin-4-ylmethyl)thiophen-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-5-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-5-carboxamide; N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-5-carboxamide; N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-5-carboxamide; N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-5-carboxamide; N-[4-fluoro-5-[5-(morpholine-4-carbonyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[5-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 5-amino-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[1-(6-cyclopropylpyridazin-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(6-ethylpyridazin-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 5-amino-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-1-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(2,2,2-trifluoroethyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-(cyclopropylmethyl)-4-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-2-carboxamide; N-(cyclopropylmethyl)-4-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-2-carboxamide; N-cyclohexyl-4-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-2-carboxamide; N-cyclohexyl-4-[2-fluoro-5-[[1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-2-carboxamide; N-[4-fluoro-5-[2-(morpholine-4-carbonyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(4-piperazin-1-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(6-piperazin-1-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-(cyclopropylmethyl)-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-2-carboxamide; N-(cyclopropylmethyl)-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-2-carboxamide; N-Cyclohexyl-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1,3-thiazole-2-carboxamide; N-cyclohexyl-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-methyl-1,3-thiazole-2-carboxamide; N-[4-fluoro-5-[2-(morpholine-4-carbonyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(cyclohexylamino)pyrimidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(methylamino)pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(2-cyanopyrimidin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[2-(dimethylamino)pyrimidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[4-(methylamino)piperidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[6-[(2R)-2-methylmorpholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(2-piperazin-1-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-(6-piperazin-1-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(4-piperazin-1-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 2-fluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; 2-fluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; 2-fluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; N-[5-[2-(4-tert-butylpiperazin-1-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[5-[2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[5-[2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[5-[2-[4-(cyclopropylmethyl)piperazin-1-yl]pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[2-(4-cyclopropylpiperazin-1-yl)-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(5-fluoro-6-oxo-1H-pyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; Benzyl N-[5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]pyridin-3-yl]carbamate; N-[4-fluoro-5-(5-fluoro-1-methyl-6-oxopyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(4-methoxybenzoyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-methyl-2-oxopyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-methyl-6-oxopyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(cyclohexanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; tert-Butyl N-[1-[2-[(3,5-dichlorobenzoyl)amino]-5-fluoro-4-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]pyrrolidin-3-yl]-N-methylcarbamate; 3,5-dichloro-N-[4-fluoro-2-[3-[3-methoxypropyl(methyl)amino]pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]benzamide; N-[4-fluoro-2-[3-[3-methoxypropyl(methyl)amino]pyrrolidin-1-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(pyrazine-2-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(methylsulfonyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(methylsulfonyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-methoxy-4-[2-methoxyethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-fluoro-4-[2-methoxyethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[2-methoxyethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-fluoro-4-[2-methoxyethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[2-methoxyethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(6-methylsulfonylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(methanesulfonamido)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyanopyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[cyclopropylmethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[cyclopropylmethyl(methyl)amino]pyrrolidin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-[1-(5-cyanopyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[4-fluoro-3-(methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(4-morpholin-4-ylpyrimidin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; propan-2-yl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,5-dihydropyrrole-1-carboxylate; Propan-2-yl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; Propan-2-yl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[4-fluoro-3-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[4-fluoro-3-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(6-fluoropyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[6-(trifluoromethyl)pyridin-2-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,5-dimethylbenzamide; 4-(Difluoromethyl)-N-(4-fluoro-5-(1-(pyrrolidine-1-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-yl-1,3-thiazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 2,4-difluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide; 2,4-difluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide; N-[5-[2,4-difluoro-5-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[5-[2,4-difluoro-5-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide (S)-4-(Si fluoromethyl)-N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(1-(pyrrolidine-1-carbonyl)-2,5-dihydro-1H-pyrrol-3-yl)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; 1-Methylcyclobutyl 3-(5-(4-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; 1-Methylcyclobutyl (S)-3-(5-(4-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; N-[5-(5-carbamoyl-2,4-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(5-carbamoyl-2,4-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 2,4-difluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2,4-difluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; 4-fluoro-N-[4-fluoro-5-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 3,3-Difluorocyclobutyl 3-(5-(4-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)-2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; 3,3-Difluorocyclobutyl (S)-3-(5-(4-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxamido)-4-(3,4-dimethylpiperazin-1-yl)-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; (S)—N-(5-(1-(2-cyanopyrimidin-5-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-4-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-[1-(4-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-Fluoro-5-[1-(1,3-oxazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide 4-(Difluoromethyl)-N-[4-fluoro-5-(1-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[1-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[1-(5-formylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[1-(6-methoxypyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; Ethyl 5-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; 4-fluoro-N-[4-fluoro-5-(1-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[1-(5-formylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; (1-Methylcyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 2-(Difluoromethyl)-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; 2-(Difluoromethyl)-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; 2,6-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2,6-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[5-(4-carbamoyl-3,5-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-carbamoyl-3,5-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-1-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[5-[2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 2,3-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide; 2,3-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide; 2,3-Difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; 2,3-Difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]benzamide; N-[5-[2,3-difluoro-4-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(4-carbamoyl-2,3-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; Propan-2-yl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,3,6,7-tetrahydroazepine-1-carboxylate; N-[4-fluoro-5-(1-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(3-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(1,3-benzothiazol-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(1,3-benzothiazol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-(1,3-benzothiazol-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(1-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(3-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(1,3-benzothiazol-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(1,3-benzothiazol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-(1,3-benzothiazol-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-1-methyl-6-oxopyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-fluoro-2-(trifluoromethyl)benzamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; N-[4-fluoro-5-[2-(oxan-4-yloxy)pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; (1-Methylcyclobutyl) 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,3,6,7-tetrahydroazepine-1-carboxylate; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-2,3,6,7-tetrahydroazepin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[1-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; (3,3-Difluorocyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3,3-Difluorocyclobutyl)4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3,3-Difluorocyclobutyl)5-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3,3-Difluorocyclobutyl)5-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3,3-Difluorocyclobutyl)5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (3,3-Difluorocyclobutyl)4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; N-[5-[1-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[1-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-(cyclohexylcarbamoyl)-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-[(2,2-dimethylcyclohexyl)carbamoyl]-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-(cyclopropylmethylcarbamoyl)-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(6-morpholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 2-(Difluoromethyl)-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]benzamide; Propan-2-yl 4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,3,6,7-tetrahydroazepine-1-carboxylate; propan-2-yl 4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; propan-2-yl 5-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; propan-2-yl 5-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; Propan-2-yl 4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; Propan-2-yl 5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate; (1-Methylcyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,3,6,7-tetrahydroazepine-1-carboxylate; (3,3-Difluorocyclobutyl)4-[5-[[4-(difluoromethyl)-6-oxo-1H-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-2,3,6,7-tetrahydroazepine-1-carboxylate; N-[5-[1-(5-cyano-1,3-thiazol-2-yl)-2,3,6,7-tetrahydroazepin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; N-[5-[4-(cyclohexylcarbamoyl)-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-[cyclopropylmethyl(methyl)carbamoyl]-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-[(4,4-difluorocyclohexyl)carbamoyl]-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[5-[4-(cyclopropylmethylcarbamoyl)-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-fluoro-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(3R)-3-methylmorpholin-4-yl]pyrimidin-5-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-1-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl]pyrimidin-4-yl]phenyl]-2-(trifluoromethyl)benzamide; 4-fluoro-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-2-(trifluoromethyl)benzamide; N-[5-[1-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-4-(difluoromethyl)-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[4-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-(6-piperazin-1-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[5-[4-[(2,2-dimethylcyclohexyl)carbamoyl]-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[5-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; 4-(Difluoromethyl)-N-[4-fluoro-5-[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1-methyl-6-oxopyridine-3-carboxamide; N-[4-fluoro-5-[4-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; N-[4-fluoro-5-[5-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide; 2-(Difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-4-fluorobenzamide; 2-(difluoromethyl)-4-fluoro-N-(4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)benzamide; and 2-(difluoromethyl)-4-fluoro-N-(4-fluoro-5-(2-((R)-2-methylmorpholino)pyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)benzamide, 3-(Difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-fluoropicolinamide; 3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)picolinamide; (S)-3-(difluoromethyl)-N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-4-yl)phenyl)-5-fluoropicolinamide; 3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-((R)-2-methylmorpholino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)picolinamide; 3-(Difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-fluoropicolinamide; N-(4'-(cyclohexyl(methyl)carbamoyl)-3',5',6-trifluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-(4'-(cyclopentyl(methyl)carbamoyl)-3',5',6-trifluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; 6-oxo-N-(3',5',6-trifluoro-4'-(((R)-tetrahydrofuran-3-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; 3-(difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-5-fluoropicolinamide; and 3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)picolinamide; or a pharmaceutically acceptable salt and / or solvate thereof.

[0117] In some embodiments, the compound of formula I is selected from the following, or a pharmaceutically acceptable salt and / or solvate thereof: [ka] TIFF0007624690000019.tif204159TIFF0007624690000020.tif159160TIFF0007624690 000021.tif196160TIFF0007624690000022.tif207161TIFF0007624690000023.tif64161

[0118] In some embodiments, the compound of formula I is selected from the following, or a pharmaceutically acceptable salt and / or solvate thereof: [ka] TIFF0007624690000025.tif138160TIFF0007624690000026.tif103160

[0119] In some embodiments, the compound of formula I is selected from the following, and pharmaceutically acceptable salts and / or solvates thereof: [ka]

[0120] The present application also includes compounds of formula (Ia), or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 18 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, OR 21 , S.R. 21 , N.R. 22 R 23 , C 1-6 Alkylene OR 21 , C 1-6 Alkylene SR 21 and C 1-6 Alkylene NR 22 R 23 heterocycloalkyl substituted with one or more substituents selected from 18 contains at least one basic nitrogen atom; R 19 is C 6-10 aryl and heteroaryl, and R 19 unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 24 , S.R. 24 and N.R. 25 R26 substituted with one or more substituents selected from: R 20 H, halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 27 , S.R. 27 , SO2R 27 , N.R. 28 R 29 , R 30 , C 1-6 Alkylene R 30 , C 1-6 Alkenylene R 30 , O.C. 1-6 Alkylene R 30 , SC 1-6 Alkylene R 30 , C 1-6 Alkylene NR 28 R 29 , C 1-6 Alkylene OR 27 , C 1-6 Alkylene SR 27 , O.C. 1-6 Alkylene NR 28 R 29 , SC 1-6 Alkylene NR 28 R 29 , O.C. 1-6 Alkylene OR 27 , SC 1-6 Alkylene OR 27 , O.C. 1-6 Alkylene SR 27 , SC 1-6 Alkylene SR 27 , C(O)OR 27 , C(S)OR 27 , C(S)NR 28 R 29 and C(O)NR 28 R 29 Selected from; R 21 is H, C 1-6 Alkyl C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; R 22 and R 23 is H, C1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OC 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 cycloalkyl; or R 22 and R 23 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, CN, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl, OC 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, SO2C 1-6 Alkyl, SO2HNC 1-6 Alkyl, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 Alkylene C 3-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from cycloalkyl; R 24 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C(O)C 1-6alkyl; R 25 and R 26 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; or R 25 and R 26 are taken together with the nitrogen atom attached to them and are unsubstituted or halo, OH, CN, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl and OC 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 27 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkylene heterocycloalkyl and is unsubstituted or selected from halo, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 substituted with one or more substituents selected from: R 28 and R 29 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C(O)OC 1-6 Alkyl, C(O)OC 1-6 Fluoroalkyl, C(O)OC 6-10 Aryl, C(O)OC 3-10 Cycloalkyl, C(O)O heteroaryl, C(O)O heterocycloalkyl, C(O)NHC 1-6 Alkyl, C(O)NHC 1-6 Fluoroalkyl, C(O)NHC 6-10 Aryl, C(O)NHC 3-10 Cycloalkyl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, SO2C 1-6 Alkyl, SO2C 1-6 Fluoroalkyl, SO2C 6-10 Aryl, SO2C 3-10 Cycloalkyl, SO2 heteroaryl, SO2 heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6alkyleneheterocycloalkyl, and R 28 and R 29 each independently is unsubstituted, or halo, CN, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 or R 28 and R 29 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, CN, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents independently selected from: R 30 is C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 30 is unsubstituted, or halo, CN, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 and is substituted with one or more substituents independently selected from R 31 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 31 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 32 and R 33 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 15 and R 16 each of which is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 32 and R 33 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from: alkyl; X 3 and X 4 are CR 34 and N are independently selected; R 34 is H, C 1-6 Alkyl and C 1-6 fluoroalkyl; A 2 is F; and The alkyl and alkylene groups are optionally fluoro-substituted.

[0121] The present application also includes compounds of formula (Ia), or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 18 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 21 , S.R. 21 , N.R. 22 R 23, C 1-6 Alkylene OR 21 , C 1-6 Alkylene SR 21 and C 1-6 Alkylene NR 22 R 23 heterocycloalkyl substituted with one or more substituents selected from 1 contains at least one basic nitrogen atom; R 19 is C 6-10 aryl and heteroaryl, and R 19 unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 24 , S.R. 24 and N.R. 25 R 26 substituted with one or more substituents selected from: R 20 H, halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 27 , S.R. 27 , N.R. 28 R 29 , R 30 , C 1-6 Alkylene R 30 , O.C. 1-6 Alkylene R 30 , SC 1-6 Alkylene R 30 , C 1-6 Alkylene NR 28 R 29 , C 1-6 Alkylene OR 27 , C 1-6 Alkylene SR 27 , O.C. 1-6 Alkylene NR 28 R 29 , SC 1-6 Alkylene NR 28 R 29 , O.C. 1-6 Alkylene OR 27 , SC 1-6 Alkylene OR 27 , O.C. 1-6 Alkylene SR27 , SC 1-6 Alkylene SR 27 , C(O)OR 27 , C(S)OR 27 , C(S)NR 28 R 29 and C(O)NR 28 R 29 Selected from; R 21 is H, C 1-6 Alkyl C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; R 22 and R 23 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 fluoroalkyl; or R 22 and R 23 are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl, OC 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl and C(O)C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 24 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; R 25 and R 26 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C(O)C 1-6 alkyl; or R 25 and R 26are taken together with the nitrogen atom attached thereto and are unsubstituted, or are halo, OH, C 1-6 Alkyl OC 1-6 Alkyl, C 1-6 Fluoroalkyl and OC 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from fluoroalkyl; R 27 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkylene heterocycloalkyl and is unsubstituted or selected from halo, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR32 R 33 substituted with one or more substituents selected from: R 28 and R 29 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and R 28 and R 29 each independently is unsubstituted, or halo, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 or R 28 and R 29 are taken together with the nitrogen atom to which they are attached and are unsubstituted, or halo, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents independently selected from: R 30 is C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 30 is unsubstituted, or halo, OR 31 , S.R. 31 , N.R. 32 R 33 , C 1-6 Alkyl, C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 31 , C 1-6 Alkylene OR 31 , C 1-6 Alkylene SR 31 and C 1-6 Alkylene NR 32 R 33 and is substituted with one or more substituents independently selected from R 31 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 31 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 32 and R 33 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 15 and R 16 each of which is unsubstituted, or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 32 and R 33 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6Alkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 forming a 3- to 10-membered heterocyclic ring substituted with one or more substituents selected from: alkyl; X 3 and X 4 are CR 34 and N are independently selected; R 34 is H, C 1-6 Alkyl and C 1-6 fluoroalkyl; A 2 is F; and The alkyl and alkylene groups are optionally fluoro-substituted.

[0122] In some embodiments, R 18 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, NR22 R 23 and C 1-6 Alkylene NR 22 R 23 and heterocycloalkyl substituted with 1, 2, or 3 substituents selected from: 18 contains at least one basic nitrogen atom. 18 Ha, Halo, C 1-6 Alkyl and NR 22 R 23 and R is a heterocycloalkyl substituted with one or two substituents selected from 18 contains at least one basic nitrogen atom. 18 is C 1-6 Alkyl and NR 22 R 23 and heterocycloalkyl substituted with 1, 2, or 3 substituents selected from: 18 contains at least one basic nitrogen atom. 18 is a C containing one or two nitrogen atoms (at least one of which is basic) 5-6 It is heterocycloalkyl.

[0123] In some embodiments, R 18 is selected from: [ka] TIFF0007624690000031.tif63159

[0124] In some embodiments, R 18 is selected from: [ka]

[0125] In some embodiments, R 18 is selected from: [ka]

[0126] R 18 is selected from: [ka]

[0127] R 18 is selected from: [ka]

[0128] In some embodiments, R 19 is C 6-10 aryl and heteroaryl, and R 19 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, OR 24 , S.R. 24 and N.R. 25 R 26 In some embodiments, R 19 is C 6-10 aryl and heteroaryl, and R 19 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O and NR 25 R 26 In some embodiments, R 19 is C 6-10 aryl and heteroaryl, and R 19 is unsubstituted or halo, C 1-6 Alkyl, C 1-6 In some embodiments, R is substituted with one or two substituents selected from fluoroalkyl and =O. 19 is selected from phenyl and C6-heteroaryl, and R19 is substituted with 1 to 3 substituents selected from F, CF2H, CF3 and =O.

[0129] In some embodiments, R 19 is: [ka] or its tautomer. 19 The tautomer of the group is [ka] is.

[0130] In some embodiments, R 19 is selected from the following, or a tautomer thereof: [ka]

[0131] In some embodiments, R 19 teeth [ka] is.

[0132] In some embodiments, R 20 H, halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 27 , N.R. 28 R 29 , R 30 , C 1-6 Alkylene R 30 , O.C. 1-6 Alkylene R 30 , C 1-6 Alkylene NR 28 R 29 , C 1-6 Alkylene OR 27 , O.C. 1-6 Alkylene NR 28 R 29 , O.C. 1-6 Alkylene OR27 , C(O)OR 27 and C(O)NR 28 R 29 In some embodiments, R 20 H, halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 27 , N.R. 28 R 29 , R 30 , C 1-6 Alkylene R 30 , O.C. 1-6 Alkylene R 30 , C 1-6 Alkylene NR 28 R 29 , C 1-6 Alkylene OR 27 , O.C. 1-6 Alkylene NR 28 R 29 and O.C. 1-6 Alkylene OR 27 In some embodiments, R 20 H, halo, CN, C 1-6 Alkyl, OR 27 , N.R. 28 R 29 , R 30 , C 1-6 Alkylene R 30 and O.C. 1-6 Alkylene R 30 In some embodiments, R 20 is C 1-6 Alkyl and R 30 is selected from.

[0133] In some embodiments, R 22 and R 23 is H, C 1-6 In some embodiments, R is independently selected from alkyl and heterocycloalkyl. 22 and R 23 H and C 1-6 alkyl.

[0134] In some embodiments, R 22 and R23 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo and C 1-6 In some embodiments, R forms a 3- to 10-membered heterocycle substituted with one or two substituents selected from alkyl. 22 and R 23 taken together with the nitrogen atom to which they are attached form an unsubstituted, 3- to 10-membered heterocyclic ring.

[0135] In some embodiments, R 27 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 In some embodiments, R is selected from alkyleneheterocycloalkyl. 27 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 In some embodiments, R is selected from alkyleneheterocycloalkyl. 27 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, heterocycloalkyl and C 1-6 Alkylene C 3-10 In some embodiments, R 27 is C 1-6 Alkyl, C 1-6 In some embodiments, R is selected from fluoroalkyl and heterocycloalkyl. 27is an unsubstituted or substituted monocyclic heterocycloalkyl selected from: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, nyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxydyl.

[0136] In some embodiments, R 28 and R 29 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 In some embodiments, R 28 and R 29 are H and C, respectively. 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 In some embodiments, R 28 and R 29 are H and C, respectively. 1-10Alkyl and C 3-10 cycloalkyl.

[0137] In some embodiments, R 28 and R 29 taken together with the nitrogen atom to which they are attached form an unsubstituted, 3- to 10-membered heterocyclic ring.

[0138] In some embodiments, R 30 is C(O)C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 In some embodiments, R 30 is C 3-10 In some embodiments, R is selected from cycloalkyl and heterocycloalkyl. 30 is heterocycloalkyl. In some embodiments, R 30 is an unsubstituted or substituted monocyclic heterocycloalkyl selected from: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, nyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxydyl.

[0139] In some embodiments, X 3 and X 4 are CR 34 and N, where R 34 is H and C 1-6In some embodiments, X is selected from alkyl. 3 and X 4 is CR 34 where R 34 is H. In some embodiments, X 1 and X 2 is CR 34 and X 1 and X 2 The other is N, where R 34 is H. In some embodiments, X 3 and X 4 Both of these are N.

[0140] The present application also includes compounds of formula (Ib) or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 35 is phenyl, C 5-6 Heteroaryl and C 5-6 heterocycloalkyl, and R 35 Halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 40 , S.R. 40 , SO2R 40 , N.R. 41 R 42 , R 43 , C 1-6 Alkylene R 43 , C 1-6 Alkenylene R 43 , O.C. 1-6 Alkylene R 43 , SC 1-6 Alkylene R 43 , C 1-6 Alkylene NR 41 R 42 , C 1-6 Alkylene OR 40 , C 1-6 Alkylene SR 40 , O.C. 1-6 Alkylene NR 41 R 42, SC 1-6 Alkylene NR 41 R 42 , O.C. 1-6 Alkylene OR 40 , SC 1-6 Alkylene OR 40 , O.C. 1-6 Alkylene SR 40 , SC 1-6 Alkylene SR 40 , C(O)OR 40 , C(S)OR 40 , C(S)NR 41 R 42 and C(O)NR 41 R 42 substituted with one substituent selected from R 36 is selected from CF2H and CF3; R 37 is selected from H and CH3; R 38 and R 39 are independently selected from H and CH3 R 40 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl and is unsubstituted or selected from halo, CN, OR 44 , S.R. 44 , N.R. 45 R 46 , C 1-6 Alkyl, C(O)R 44 , C(O)OR 44 , C(O)NR 45 R 46 , S(O)C 1-6Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 44 , C 1-6 Alkylene OR 44 , C 1-6 Alkylene SR 44 and C 1-6 Alkylene NR 45 R 46 substituted with 1 to 3 substituents selected from: R 41 and R 42 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C(O)OC 1-6 Alkyl, C(O)OC 1-6 Fluoroalkyl, C(O)OC 6-10 Aryl, C(O)OC 3-10 Cycloalkyl, C(O)O heteroaryl, C(O)O heterocycloalkyl, C(O)NHC 1-6 Alkyl, C(O)NHC 1-6 Fluoroalkyl, C(O)NHC 6-10 Aryl, C(O)NHC 3-10 Cycloalkyl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, SO2C 1-6 Alkyl, SO2C 1-6 Fluoroalkyl, SO2C 6-10 Aryl, SO2C 3-10Cycloalkyl, SO2 heteroaryl, SO2 heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and R 41 and R 42 each independently is unsubstituted, or halo, CN, OR 44 , S.R. 44 , N.R. 45 R 46 , C 1-6 Alkyl, C(O)R 44 , C(O)OR 44 , C(O)NR 45 R 46 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 44 , C 1-6 Alkylene OR 44 , C 1-6 Alkylene SR 44 and C 1-6 Alkylene NR 45 R 46 or R 41 and R 42 are taken together with the nitrogen atom attached thereto and are unsubstituted, or halo, CN, OR 44 , S.R. 44 , N.R.45 R 46 , C 1-6 Alkyl, C(O)R 44 , C(O)OR 44 , C(O)NR 45 R 46 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkylene R 44 , C 1-6 Alkylene OR 44 , C 1-6 Alkylene SR 44 and C 1-6 Alkylene NR 45 R 46 forming a 3-6 membered heterocyclic ring substituted with 1 to 3 substituents independently selected from R 43 is C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 43 is unsubstituted, or halo, CN, OR 44 , S.R. 44 , N.R. 45 R 46 , C 1-6 Alkyl, C(O)R 44 , C(O)OR 44 , C(O)NR 45 R 46 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 44 , C 1-6 Alkylene OR 44 , C 1-6 Alkylene SR 44 and C 1-6 Alkylene NR 45 R 46 substituted with 1 to 3 substituents independently selected from R 44 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 44 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 45 and R 46 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 45 and R 46 each of which is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 45 and R 46 together with the nitrogen atom attached thereto are unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl).

[0141] In some embodiments, R 35 is selected from phenyl, pyrimidinyl, pyridinyl, dihydropyridine, pyrrolyl, and dihydropyrrolyl, each of which is selected from halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 40 , S.R. 40 , SO2R40 , N.R. 41 R 42 , R 43 , C 1-6 Alkylene R 43 , C 1-6 Alkenylene R 43 , O.C. 1-6 Alkylene R 43 , SC 1-6 Alkylene R 43 , C 1-6 Alkylene NR 41 R 42 , C 1-6 Alkylene OR 40 , C 1-6 Alkylene SR 40 , O.C. 1-6 Alkylene NR 41 R 42 , SC 1-6 Alkylene NR 41 R 42 , O.C. 1-6 Alkylene OR 40 , SC 1-6 Alkylene OR 40 , O.C. 1-6 Alkylene SR 40 , SC 1-6 Alkylene SR 40 , C(O)OR 40 , C(S)OR 40 , C(S)NR 41 R 42 and C(O)NR 41 R 42 is substituted with one substituent selected from

[0142] In some embodiments, R 35 is C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 40 , N.R. 41 R 42 , R 43 , C 1-6 Alkylene R 43 , O.C. 1-6 Alkylene R 43 , C 1-6 Alkylene NR 41 R 42 , C 1-6 Alkylene OR40 , O.C. 1-6 Alkylene NR 41 R 42 , O.C. 1-6 Alkylene OR 40 , C(O)OR 40 and C(O)NR 41 R 42 is substituted with one substituent selected from

[0143] In some embodiments, R 35 is R 43 or C 1-6 Alkylene R 43 where R 43 is C 5-6 Cycloalkyl, C 5-6 Heterocycloalkyl, C 5-6 selected from heteroaryl and phenyl, and R 43 is unsubstituted, or halo and C 1-6 In some embodiments, R 43 is C-heterocycloalkyl. In some embodiments, R 43 is selected from piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxidyl. 43 is morpholinyl optionally substituted with one or two Me.

[0144] In some embodiments, R 35 is selected from: [ka] In the formula, R is a substituent.

[0145] In some embodiments, the compound of formula Ib is selected from the following, or a pharmaceutically acceptable salt and / or solvate thereof: [ka] TIFF0007624690000043.tif209162TIFF0007624690000044.tif65159

[0146] The present application also includes compounds of formula (Ic) or pharmaceutically acceptable salts and / or solvates thereof: [ka] During the ceremony: R 47 is phenyl, C 5-6 Heteroaryl and C 5-6 heterocycloalkyl, and R 47 Halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 53 , S.R. 53 , SO2R 53 , N.R. 54 R 55 , R 56 , C 1-6 Alkylene R 56 , C 1-6 Alkenylene R 56 , O.C. 1-6 Alkylene R 56 , SC 1-6 Alkylene R 56 , C 1-6 Alkylene NR 54 R 55 , C 1-6 Alkylene OR 53 , C 1-6 Alkylene SR 53 , O.C. 1-6 Alkylene NR 54 R 55 , SC 1-6 Alkylene NR 54 R 55 , O.C. 1-6 Alkylene OR 53 , SC1-6 Alkylene OR 53 , O.C. 1-6 Alkylene SR 53 , SC 1-6 Alkylene SR 53 , C(O)OR 53 , C(S)OR 53 , C(S)NR 54 R 55 and C(O)NR 54 R 55 substituted with one substituent selected from R 48 , R 49 and R 50 are independently selected from H, F, CF3 and CF2H, with the proviso that R 48 , R 49 and R 50 provided that at least one of is not H; R 51 and R 52 are independently selected from H and CH3 R 53 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, heteroaryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and is unsubstituted or substituted with 1 to 3 substituents selected from; R 54 and R 55 are H and C, respectively. 1-10 Alkyl, C 1-10 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C(O)OC 1-6 Alkyl, C(O)OC 1-6 Fluoroalkyl, C(O)OC 6-10 Aryl, C(O)OC 3-10 Cycloalkyl, C(O)O heteroaryl, C(O)O heterocycloalkyl, C(O)NHC 1-6 Alkyl, C(O)NHC 1-6 Fluoroalkyl, C(O)NHC 6-10 Aryl, C(O)NHC 3-10 Cycloalkyl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, SO2C 1-6 Alkyl, SO2C 1-6 Fluoroalkyl, SO2C 6-10 Aryl, SO2C 3-10 Cycloalkyl, SO2 heteroaryl, SO2 heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl, C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene heteroaryl and C 1-6 alkyleneheterocycloalkyl, and R 54 and R 55 each independently is unsubstituted, or halo, CN, OR 57 , S.R. 57 , N.R. 58 R 58 , C 1-6 Alkyl, C(O)R 57 , C(O)OR 57 , C(O)NR 58 R 59 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 57 , C 1-6 Alkylene OR 57 , C 1-6 Alkylene SR 57 and C 1-6 Alkylene NR 58 R 59 or R 54 and R 55 are unsubstituted together with the nitrogen atom attached thereto, or halo, CN, OR 57 , S.R. 57 , N.R. 58 R 58 , C 1-6 Alkyl, C(O)R 57 , C(O)OR 57 , C(O)NR 58 R 59 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 57 , C 1-6 Alkylene OR 57 , C 1-6 Alkylene SR 57 and C 1-6 Alkylene NR 58 R 59 forming a 3-6 membered heterocyclic ring substituted with 1 to 3 substituents independently selected from R 56 is C(O)C 1-6 Alkyl, C(O)C1-6 Fluoroalkyl, C(O)C 6-10 Aryl, C(O)C 3-10 Cycloalkyl, C(O)heteroaryl, C(O)heterocycloalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, heteroaryl and C 6-10 aryl, and R 56 is unsubstituted, or halo, CN, OR 57 , S.R. 57 , N.R. 58 R 58 , C 1-6 Alkyl, C(O)R 57 , C(O)OR 57 , C(O)NR 58 R 59 , S(O)C 1-6 Alkyl, SO2C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene R 57 , C 1-6 Alkylene OR 57 , C 1-6 Alkylene SR 57 and C 1-6 Alkylene NR 58 R 59 substituted with 1 to 3 substituents independently selected from R 57 is H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 57 is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl); R 58and R 59 are H and C, respectively. 1-6 Alkyl, C 1-6 Fluoroalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-10 Aryl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl and C 1-6 alkyleneheterocycloalkyl, and R 58 and R 59 each of which is unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC1-6 Alkyl, C 1-6 Alkylene SH, C 1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl), or R 58 and R 59 together with the nitrogen atom attached thereto are unsubstituted or halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, OH, SH, OC 1-6 Alkyl, OC 1-6 Fluoroalkyl, SC 1-6 Alkyl, SC 1-6 Fluoroalkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)C 1-6 Alkyl, C(O)C 1-6 Fluoroalkyl, C(O)OH, C(O)OC 1-6 Alkyl, C(O)NH2, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), SO2C 1-6 Alkyl, S(O)C 1-6 Alkyl, C 6-10 Aryl, heteroaryl, C 3-10 Cycloalkyl, heterocycloalkyl, C 1-6 Alkylene C 6-10 Aryl, C 1-6 Alkylene C 3-10 Cycloalkyl, C 1-6 Alkylene Heteroaryl, C 1-6 Alkyleneheterocycloalkyl, C 1-6 Alkylene OH, C 1-6 Alkylene OC 1-6 Alkyl, C 1-6 Alkylene SH, C1-6 Alkylene SC 1-6 Alkyl, C 1-6 AlkyleneNH2, C 1-6 Alkylene NHC 1-6 Alkyl and C 1-6 Alkylene N(C 1-6 Alkyl)(C 1-6 alkyl).

[0147] In some embodiments, R 47 is selected from phenyl, pyrimidinyl, pyridinyl, dihydropyridine, pyrrolyl, and dihydropyrrolyl, each of which is selected from halo, CN, C 1-6 Alkyl, C 1-6 Fluoroalkyl, ═O, ═S, OR 53 , S.R. 53 , SO2R 53 , N.R. 54 R 55 , R 56 , C 1-6 Alkylene R 56 , C 1-6 Alkenylene R 56 , O.C. 1-6 Alkylene R 56 , SC 1-6 Alkylene R 56 , C 1-6 Alkylene NR 54 R 55 , C 1-6 Alkylene OR 53 , C 1-6 Alkylene SR 53 , O.C. 1-6 Alkylene NR 54 R 55 , SC 1-6 Alkylene NR 54 R 55 , O.C. 1-6 Alkylene OR 53 , SC 1-6 Alkylene OR 53 , O.C. 1-6 Alkylene SR 53 , SC 1-6 Alkylene SR 53 , C(O)OR 53 , C(S)OR53 , C(S)NR 54 R 55 and C(O)NR 54 R 55 is substituted with one substituent selected from

[0148] In some embodiments, R 47 is C 1-6 Alkyl, C 1-6 Fluoroalkyl, OR 53 , N.R. 54 R 55 , R 56 , C 1-6 Alkylene R 56 , O.C. 1-6 Alkylene R 56 , C 1-6 Alkylene NR 54 R 55 , C 1-6 Alkylene OR 53 , O.C. 1-6 Alkylene NR 54 R 55 , O.C. 1-6 Alkylene OR 53 , C(O)OR 53 and C(O)NR 54 R 55 is substituted with one substituent selected from

[0149] In some embodiments, R 47 is R 56 or C 1-6 Alkylene R 56 where R 56 is C 5-6 Cycloalkyl, C 5-6 Heterocycloalkyl, C 5-6 selected from heteroaryl and phenyl, and R 56 is unsubstituted, or halo and C 1-6 In some embodiments, R 56 is C-heterocycloalkyl. In some embodiments, R 56is selected from piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethyleneoxidyl. 56 is morpholinyl optionally substituted with one or two Me.

[0150] In some embodiments, R 47 is selected from: [ka] In the formula, R is a substituent.

[0151] In some embodiments, R 48 , R 49 and R 50 is located on the phenyl ring as follows: [ka] where R 48 is selected from CF3 and CF2H, and R 49 and R 50 is independently selected from H and F. In some embodiments, R 49 and R 50 and R are both F. In some embodiments, R 49 is F, and R 50 is H.

[0152] In some embodiments, the compound of Formula Ic is selected from the following, or a pharmaceutically acceptable salt and / or solvate thereof: [ka]

[0153] The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Accordingly, the present application also includes compositions comprising one or more compounds of the present application and a carrier. The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the present application further includes pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In an embodiment of the application, the pharmaceutical composition is used in the treatment of any of the diseases, disorders or conditions described herein.

[0154] The compounds of the present invention can be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of the present invention can be administered orally, by inhalation, parenterally, bucally, sublingually, nasally, rectally, intravaginally, by patch, pump, topically, or transdermally, and pharmaceutical compositions can be formulated accordingly. In some embodiments, administration is performed by a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions can be found, for example, in Remington's Pharmaceutical Sciences (2000-20th Edition) and The National Formulary of the United States Pharmacopeia, 1999 (USP 24 NF19).

[0155] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time.

[0156] In some embodiments, the compounds of the present application are orally administered, for example, with an inert diluent or an assimilable edible carrier, or enclosed in hard or soft-shell gelatin capsules, or compressed into tablets, or directly incorporated with dietary food. In some embodiments, the compounds are combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, etc. For tablets, carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, a pH-sensitive enteric coating designed to control the release of the active ingredient, such as Eudragits™, is optionally used. Oral dosage forms also include modified-release formulations, such as immediate-release and timed-release formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), timed-release, controlled-release (CR), or continuous-release (CR or Contin) formulations, used in the form of, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles such as molecular sieve-type particles, or fine hollow permeable fiber bundles agglomerated or held in fiber packets, or chopped hollow permeable fibers. Timed-release compositions are formulated, for example, in which the active compound is protected by liposomes or differentially degradable coatings, such as microencapsulation, multiple coatings, etc.Liposome delivery system includes, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.In some embodiments, liposome is formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.For oral administration in capsule form, useful carrier or diluent includes lactose and dried cornstarch.

[0157] In some embodiments, liquid preparations for oral administration may take the form of, for example, a solution, syrup, or suspension, or they are preferably provided as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the present invention is preferably suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0158] It is also possible to lyophilize the compounds of the application and use the resulting lyophilizates, for example, for the preparation of injectable products.

[0159] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application are prepared in water, preferably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, and in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent microbial growth. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are usually prepared, and the pH of the solution is preferably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to make the preparation isotonic. For intraocular administration, ointments or droppable solutions are delivered, for example, by intraocular delivery systems known in the art, such as applicators or eyedroppers. In some embodiments, such compositions comprise a mucus mimetic, such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, a preservative, such as sorbic acid, EDTA or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier is selected to be suitable for allowing the formation of an aerosol.

[0160] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Injectable preparations are provided, for example, in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. In some embodiments, the compositions take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0161] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders.For intranasal administration or inhalation administration, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is pressed and pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer.Aerosol formulations typically contain a solution or a microparticle suspension of an active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container, such as a cartridge or refill for use with a spray device.Alternatively, the sealed container is a single-dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve intended for disposal after use.When the dosage form includes an aerosol dispenser, it contains a propellant, such as a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide or other suitable gas. In the case of pressurized aerosol, the dosage unit is preferably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or insufflators are formulated to contain, for example, a powder mix of the compound of the application and a suitable powder base, such as lactose or starch. Aerosol dosage forms can also be in the form of a pump-atomizer.

[0162] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the compound of the present invention is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0163] Suppository forms of the compounds of the present application are useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally constructed from a mixture of materials that are solid at room temperature but melt at body temperature. Materials commonly used to form such vehicles include, but are not limited to, cocoa butter (also known as cacao butter), glycerin gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further discussion of suppository formulations, see, for example, Remington's Pharmaceutical Sciences, 16th Edition, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0164] In some embodiments, the compounds of the present application are coupled to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine (substituted with palmitoyl residues). Furthermore, in some embodiments, the compounds of the present application are coupled to biodegradable polymer classes useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0165] The compounds of the present application, including their pharmaceutically acceptable salts and / or solvates, are preferably used per se, but are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present application (the active ingredient) are associated with a pharmaceutically acceptable carrier. Depending on the method of administration, the pharmaceutical composition contains from about 0.05 wt% to about 99 wt%, or from about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt%, or from about 30 wt% to about 99.90 wt% of the pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0166] The compounds of the present application may be used alone or in combination with other known agents useful for treating diseases, disorders, or conditions mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner, and those treatable with WDR5 inhibitors, such as the compounds disclosed herein. When used in combination with other agents useful for treating diseases, disorders, or conditions mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner, it is an embodiment for the compounds of the present application to be administered simultaneously with those agents. As used herein, "co-administration" of two substances to a subject means providing each of the two substances so that both are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other and may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other if pharmacokinetics are favorable. Designing suitable administration regimens is routine for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present application that the combination of active agents is administered to a subject in a non-simultaneous manner. In one embodiment, the compound of the present application is administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0167] The dosage of the compounds of the present application will vary depending on many factors, such as the pharmacodynamic properties of the compound, the method of administration, the recipient's age, health, and weight, the nature and severity of the symptoms, the frequency of treatment and type of concomitant treatment (if any), and the clearance rate of the compound in the treated subject. Those skilled in the art will be able to determine appropriate dosages based on the above factors. In some embodiments, the compounds of the present application are initially administered at a suitable dosage, adjusted as needed depending on clinical response. Dosages are generally selected to maintain serum levels of the compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, oral dosages of one or more compounds of the present application range from about 1 mg / day to about 1000 mg / day for adults, preferably between about 1 mg / day and about 500 mg / day, and more preferably between about 1 mg / day and about 200 mg / day. For parenteral administration, a typical dose is about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For oral administration, a typical dose is about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For administration in the form of a suppository, a typical dose is about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In one embodiment of the application, the composition is formulated for oral administration, and the one or more compounds are suitably in tablet form containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of active ingredient per tablet. In an embodiment of the application, the one or more compounds of the application are administered in a single daily, weekly, or monthly dose, or the total daily dose is divided into two, three, or four doses per day.

[0168] In the above, the term "compound" also includes embodiments where one or more compounds are referred to.

[0169] III. Application Method and Use Treatment Methods and Uses The compounds of the present application have been shown to be inhibitors of the binding of WDR5 to MLL1.

[0170] Thus, the present application includes a method for inhibiting the binding of WDR5 to its binding partner in a cell, either in a biological sample or in a patient, comprising administering to the cell an effective amount of one or more compounds of the application. The application also includes the use of one or more compounds of the application for inhibiting the binding of WDR5 to its binding partner in a cell, as well as the use of one or more compounds of the application for preparing a medicament for inhibiting the binding of WDR5 to its binding partner in a cell. The application further includes one or more compounds of the application for use in inhibiting the binding of WDR5 to its binding partner in a cell.

[0171] In all aspects, it is an embodiment of the present application that the binding partner for WDR5 is MLL1, or a portion thereof. In some embodiments, the binding partner for WDR5 is the WDR5-interacting (WIN) motif, which consists of amino acid residues 3762-3773 next to the SET domain in the MLL1 protein [J. Biol. Chem., 2008, 283(47):32158-32161; J. Biol. Chem., 2008, 283(50):35258-35264].

[0172] Since the compounds of the present application have been shown to be able to inhibit the binding of WDR5 to its binding partner, the compounds of the present application are useful for treating diseases, disorders, or conditions that are mediated or treatable by inhibiting the binding between WDR5 protein and its binding partner. Therefore, the compounds of the present application are useful as pharmaceuticals. Therefore, the present application includes the compounds of the present application for use as pharmaceuticals.

[0173] The present application also includes a method for treating a disease, disorder, or condition mediated or treatable by inhibition of binding between a WDR5 protein and its binding partner, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the application.

[0174] The present application also includes the use of one or more compounds of the application for treating a disease, disorder, or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partner, as well as the use of one or more compounds of the application for the preparation of a medicament for treating a disease, disorder, or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partner. The application further includes one or more compounds of the application for use in the treatment of a disease, disorder, or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partner.

[0175] In one embodiment, the disease, disorder, or condition mediated or treatable by inhibition of binding between the WDR5 protein and its binding partner is a neoplastic disorder. Accordingly, the present application also includes a method of treating a neoplastic disorder, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof. The present application also includes the use of one or more compounds of the present application for the treatment of a neoplastic disorder, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a neoplastic disorder. The application further includes one or more compounds of the present application for use in the treatment of a neoplastic disorder. In one embodiment, the treatment is administered in a subject in need of such treatment with an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reducing cell proliferation or reducing tumor volume.

[0176] In another embodiment of the present application, the disease, disorder, or condition mediated or treatable by inhibiting the binding between the WDR5 protein and its binding partner is cancer. Accordingly, the present application also includes a method of treating cancer, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof. The present application also includes the use of one or more compounds of the present application for the treatment of cancer, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of cancer. The application further includes one or more compounds of the present application for use in the treatment of cancer. In one embodiment, the compound is administered to a subject, for example, a mammal, having a predisposition to cancer, for the prevention of cancer.

[0177] In one embodiment, the cancer is selected from, but is not limited to: acute lymphocytic leukemia, adult; acute lymphocytic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, pediatric cerebellum; astrocytoma, pediatric brain; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, brain astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain tumor, myeloma Blastoma, pediatric;Brain tumor, supratentorial primitive neuroectodermal tumor, pediatric;Brain tumor, visual pathway and hypothalamic glioma, pediatric;Brain tumor, pediatric (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, pediatric;Breast cancer, male;Bronchial adenoma / carcinoid, pediatric;Carcinoid tumor, pediatric;Carcinoid tumor, gastrointestinal;Carcinoma, adrenal cortical;Carcinoma, islet cell;Carcinoma of unknown primary;Central nervous system lymphoma, primary;Cerebellar astrocytoma, pediatric;Cerebral astrocytoma / malignant glioma, pediatric;Cervical cancer;Childhood cancer;Chronic lymphocytic leukemia;Chronic myeloid leukemia;Chronic myeloproliferative disorder;Clear cell sarcoma of tendon sheath;Colon cancer;Colorectal cancer, pediatric;Skin Cutaneous T-cell lymphoma;Endometrial carcinoma;Ependymoma, pediatric;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, pediatric;Ewing family of tumors;Extracranial germ cell tumors, pediatric;Extragonadal germ cell tumors;Extrahepatic bile duct carcinoma;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric (stomach) cancer;Gastric (stomach) cancer, pediatric;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, pediatric;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumor;Glioma, pediatric brainstem;Glioma, pediatric visual pathway and hypothalamic;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) carcinoma, adult (primary);Hepatocellular (liver) carcinoma, pediatric (primary); Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma in pregnancy; Hypopharyngeal cancer; Hypothalamic and visual pathway glioma, childhood; Intraocular melanoma; Islet cell carcinoma (pancreatic islet); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Laryngeal cancer, childhood; Leukemia, acute lymphoblastic, adult; Leukemia, acute lymphoblastic, childhood; Leukemia, acute myeloid, adult; Leukemia, acute myeloid, childhood; Leukemia, chronic lymphocytic; Leukemia, chronic myeloid; Leukemia, hairy cell; Lip and oral cavity cancer; Liver cancer, adult (primary); Liver cancer, childhood (primary); Lung cancer, non-small cell; Lung cancer, small cell; Lymphoblastic leukemia, adult acute;Lymphoblastic leukemia, acute, childhood; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin, adult; Lymphoma, Hodgkin, childhood; Lymphoma, Hodgkin during pregnancy; Lymphoma, non-Hodgkin, adult; Lymphoma, non-Hodgkin, childhood; Lymphoma, non-Hodgkin during pregnancy; Lymphoma, primary central nervous system; Macroglobulinemia, Waldenström; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma, childhood; Malignant thymoma; Medulloblastoma, childhood; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Primary Metastatic squamous cell neck cancer of unknown origin; Multiple endocrine neoplasia syndrome, children; Multiple myeloma / plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, acute, children; Myeloma, multiple; Myeloproliferative disorders, chronic; Nasal cavity and paranasal sinus cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, children; Neuroblastoma; Non-Hodgkin's lymphoma, adults; Non-Hodgkin's lymphoma, children; Non-Hodgkin's lymphoma in pregnancy; Non-small cell lung cancer; Oral cavity cancer, children; Oral cavity and lip cancer; Oropharyngeal cancer; Osteosarcoma / malignant fibrous histiocytoma of bone; Ovarian cancer, children; Ovarian epithelial cancer; Ovarian germ cell tumor; Ovarian low malignant potential tumor; Pancreatic cancer; Pancreatic Pancreatic cancer, pediatric;Pancreatic cancer, islet cell;Sinus and nasal cavity cancer;Parathyroid cancer;Penile cancer;Pheochromocytoma;Pineal and supratentorial primitive neuroectodermal tumor, pediatric;Pituitary tumor;Plasma cell neoplasm / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adult;Primary liver cancer, pediatric;Prostate cancer;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, pediatric;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, pediatric;Salivary gland cancer;Sarcoma, Ewing family of tumors;Sarcoma, pediatric Positive;Sarcoma (osteosarcoma) / Malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, pediatric;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, pediatric;Sezary syndrome;Skin cancer;Skin cancer, pediatric;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Small intestinal cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, pediatric;Squamous cell neck cancer of unknown primary, metastatic;Gastric (stomach) cancer;Gastric (stomach) cancer, pediatric;Supratentorial primitive neuroectodermal tumor, pediatric;T-cell lymphoma, skin;Testicular cancer;Thymoma, pediatric;Thymoma, malignant;Thyroid cancer;Thyroid cancer, pediatric;Transitional cell carcinoma of the renal pelvis and ureter;Childrenal trophoblastic tumor, gestational;Pediatric cancers of unknown primary site; rare cancers of childhood; ureteral and renal pelvis transitional cell carcinoma; urethral carcinoma; uterine sarcoma; vaginal carcinoma; visual pathway and hypothalamic glioma, pediatric; vulvar carcinoma; Waldenstrom's macroglobulinemia; and Wilms' tumor. Metastases of the above cancers can also be treated according to the methods described herein.

[0178] In one embodiment, the cancer is selected from solid tumors and leukemia. In another embodiment, the cancer is selected from leukemia, lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, MLL-fusion lymphoma, primary effusion leukemia, and multiple myeloma. In a further embodiment of the present application, the cancer is selected from leukemia, melanoma, lung cancer, bladder cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, neuroblastoma, and kidney cancer. In a further embodiment, the cancer is selected from leukemia, bladder cancer, prostate cancer, brain cancer, and neuroblastoma. In a further embodiment, the cancer is selected from bladder cancer, acute myeloid leukemia (AML), glioma, glioblastoma, and MYCN-amplified neuroblastoma.

[0179] In one embodiment, the disease, disorder, or condition mediated or treatable by inhibition of binding between the WDR5 protein and its binding partner is a disease, disorder, or condition associated with uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by the binding of WDR5 to its binding partner. In another embodiment, the uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by the binding of WDR5 to its binding partner is proliferative activity in a cell. Accordingly, the application also includes a method for inhibiting proliferative activity in a cell, comprising administering to a cell an effective amount of one or more compounds of the application. The application also includes the use of one or more compounds of the application for inhibiting proliferative activity in a cell, as well as the use of one or more compounds of the application for preparing a medicament for inhibiting proliferative activity in a cell. The application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell.

[0180] The present application also includes a method for inhibiting uncontrolled and / or abnormal cellular activity mediated directly or indirectly by the binding of WDR5 to its binding partner in a cell, either in a biological sample or in a subject, comprising administering to the cell an effective amount of one or more compounds of the application. The application also includes the use of one or more compounds of the application for inhibiting uncontrolled and / or abnormal cellular activity mediated directly or indirectly by the binding of WDR5 to its binding partner in a cell, as well as the use of one or more compounds of the application for the preparation of a medicament for inhibiting uncontrolled and / or abnormal cellular activity mediated directly or indirectly by the binding of WDR5 to its binding partner in a cell. The application further includes one or more compounds of the application for use in inhibiting uncontrolled and / or abnormal cellular activity mediated directly or indirectly by the binding of WDR5 to its binding partner in a cell.

[0181] In further embodiments, the present application also includes a method for treating a disease, disorder, or condition mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application in combination with another known agent useful for treating a disease, disorder, or condition mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner. The present application also includes the use of one or more compounds of the present application in combination with a known agent useful for treating a disease, disorder, or condition mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner for the treatment of a disease, disorder, or condition mediated by or treatable through inhibition of binding between WDR5 protein and its binding partner.

[0182] In a further embodiment, the disease, disorder, or condition mediated or treatable by inhibition of binding between the WDR5 protein and its binding partner is cancer, and one or more compounds of the present application are administered in combination with one or more additional cancer therapies, hi another embodiment, the additional cancer therapies are selected from radiation therapy, chemotherapy, targeted therapy, e.g., antibody therapy and small molecule therapy, e.g., tyrosine kinase inhibitors, immunotherapy, hormone therapy, and anti-angiogenic therapy.

[0183] Methods for preparing the compounds of the present application Scheme 1 shows one embodiment of a route to the compounds of the present application, in which a Suzuki or related coupling is performed on compound (A) to give intermediate (B). Subsequent coupling of (B) with a carboxylic acid or an appropriate acid halide gives the compounds of the present application. [ka] Scheme 1: a) R 3 B(OH)2 or boronic ester, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, μ-wave, 110 °C; b) R 2 C(O)OH, coupling agent or R 2 C(O)X, where X is a halide or amine.

[0184] In another embodiment, compounds of formula (I) are prepared by first coupling a carboxylic acid or acyl halide with an aniline (A), followed by a Suzuki or related coupling (Scheme 2). [ka] Scheme 2: a) R 2 C(O)OH, coupling agent or R 2 C(O)X, where X is a halide or amine; b) R 3 B(OH)2 or boronic ester, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, μ-wave, 110°C.

[0185] In some embodiments of the present application, compounds of formula (I) are prepared from nitroaryl or nitroheteroaryl compounds D (Q = Cl or Br; Z = F or Br). For example, nucleophilic aromatic substitution with various piperazines or amines provides intermediate E. In some embodiments, reduction of E under reducing conditions by various means, including catalytic hydrogenation and dissolving metal reduction (both in their various forms) [see House, HO, Modern Synthetic Reactions, 2nd Edition, WA Benjamin, Inc., Menlo Park, California, publication (1972)], provides compound F. Coupling of F with boronic acids or esters, for example, under Suzuki conditions [Tetrahedron 2002, 58:9633-9695; Organic Letters 2006, 8(9), 1787-1789], provides intermediate G. Related coupling reactions for the conversion of F to G or H to Formula I, as described in Scheme 3, include Heck (olefin) [J. Am. Chem. Soc. 1974 96(4):1133-1136]; Stille (organostannane) [Synthesis 1992 803-815]; Sonogashira (acetylene) [Tetrahedron Lett 1975 16(50):4467-4470], and Negishi (organozinc) [Aldrichimica Acta., 2005,38(3):71-78] coupling reactions. [ka] Scheme 3: a) piperazine or amine, base; b) Zn or Fe, alcohol solvent; c) R 3 B(OH)2 or boronic ester, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, μ-wave, 110 °C; d) R 2 C(O)OH, coupling agent or R 2 C(O)X, where X is a halide or amine.

[0186] In some embodiments, compounds of formula (I) are prepared by treatment of compounds of formula F with an amine (e.g., piperazine) to afford intermediate K (Scheme 4). In some embodiments, bromination of K with N-bromosuccinmide affords versatile intermediate L, which is converted to formula (I) according to Scheme 3. [ka] Scheme 4: a) Piperazine or amine, base; b) N-bromosuccinimide

[0187] In some embodiments of the application, compounds of formula (I), where R 2 A compound of formula (Ib) is prepared as shown in Scheme 5. Thus, in some embodiments, amide M is obtained by acylation of compound G (e.g., prepared by Scheme 3) with 6-chloro-4-(trifluoromethyl)nicotinic acid chloride (generated in situ from the corresponding acid and SOCl). Hydrolysis of M with sodium acetate in acetic acid under microwave conditions provides pyridone N. Coupling of N with a boronic acid or ester, e.g., under Suzuki conditions, provides a compound of formula (Ib). Alternatively, in some embodiments, Suzuki coupling intermediate O is acylated with 6-chloro-4-(trifluoromethyl)nicotinic acid chloride to provide Id, which is then hydrolyzed to compound Ib (Scheme 5). [ka] Scheme 5: a) R 2 C(O)OH, coupling agent or R 2 C(O)X, where X is a halide or amine; b) NaOAc, AcOH, microwave, 160°C; c) R 3 B(OH)2 or boronic ester, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, μ-wave, 110°C.

[0188] Scheme 6 illustrates another embodiment for the preparation of compounds of formula (Ib), wherein R in compounds of formula I 2 is trifluoromethylpyrimidone. In some embodiments, the aniline G is 6-methoxy-4-(trifluoromethyl)nicotinic acid [R a =Me] or 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid [R a =-CHCHTMS] (generated from the corresponding acid and alcohol, for example, as in Scheme 7) provides amide Q. In some embodiments, amide Q is then converted to a boronic ester R. In some embodiments, Suzuki coupling of R to various halides provides intermediate S. In some embodiments, subsequent deprotection of S provides compounds of the present application (Formula Ib). In some embodiments, compounds of Formula Ib are prepared by Suzuki coupling to Q, followed by deprotection (Scheme 6). [ka] Scheme 6: a) R 2 C(O)OH, coupling agent b) bipinacolatodiboron, Pd(dppf)2Cl2, NaOAc, dioxane, 110°C; c) R 3 B(OH)2 or boronic ester, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, μ-wave, 110 °C; d) R 3 - Halides or triflates, Pd(Amphos)Cl2, K3PO4, dioxane / H2O, microwave, 110°C; e) HCl or TFA; f) CsF or TBAF. [ka] Scheme 7: a) NaOMe, MeOH; b) NaH, TMS-EtOH

[0189] It should be understood that throughout the synthetic methods and processes described herein, suitable protecting groups will be added and subsequently removed, where appropriate, to the various reactants and intermediates in a manner readily understood by one skilled in the art. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It should also be understood that the conversion of a group or substituent to another group or substituent by chemical manipulation can be performed on any intermediate or final product along the synthetic route toward the final product, with the types of transformations possible being limited only by the inherent incompatibility of other functional groups possessed by the molecule at that stage with the conditions or reagents used in the transformation. Such inherent incompatibilities, and how to circumvent them by performing appropriate transformations and synthetic steps in a suitable order, will be readily understood by those skilled in the art. While exemplary transformations are provided herein, it should be understood that the described transformations are not limited solely to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks, such as "Advanced Organic Chemistry", March, 4th Edition, McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and will be readily understood by those skilled in the art.

[0190] Example The following non-limiting examples are illustrative of the present application:

[0191] A. General method Exemplary compounds of the present application were synthesized using methods described herein or other methods known in the art. Unless otherwise noted, reagents and solvents were obtained from commercial sources (e.g., Aldrich, Enamine, Combiblock, Bepharm, and J&W Pharma Lab).

[0192] Compounds and / or intermediates were characterized by high-performance liquid chromatography (HPLC) using a Waters ACQUITY UPLC system equipped with an SQ (single quadrupole) MS and a photodiode array (PDA) detector (Milford, MA). The analytical column was a reverse-phase Acqity UPLC BEH C18 (2.1 x 50 mm, 1.7 μm). Gradient elution was used (flow rate 0.4 mL / min), typically starting with mobile phases of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). Starting from 95% solvent A, the gradient increased to 5% in 1.8 min, held for 0.5 min, and returned to 95% in 0.5 min, allowing the column to equilibrate for 0.5 min. Compounds were detected by ultraviolet (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburgh, PA).

[0193] In some cases, purity was assessed by thin layer chromatography (TLC) using glass or plastic-backed silica gel plates, such as, for example, Baker-Flex silica gel IB2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well-known iodine vapor and various other staining techniques.

[0194] Compounds and / or intermediates were characterized by LCMS. General conditions were as follows: Low- and high-resolution mass spectra were acquired on LC / MS systems using electrospray ionization with a range of instruments configured as follows: low-resolution - Waters ACQUITY UPLC system with SQ (single quadrupole) MS; Waters ACQUITY UPLC H-Class system with 3100 (single quadrupole) MS; high-resolution - Waters ACQUITY UPLC II system equipped with Synapt Xevo QTof and Waters ACQUITY UPLC II system equipped with Synapt G2S QTof mass spectrometer with atmospheric pressure ion source. [M+H] indicates the protonated molecular ion of the chemical species.

[0195] Nuclear magnetic resonance (NMR) analyses were performed on a Bruker 500 MHz NMR spectrometer using ICON-NMR under TopSpin program control. Spectra were measured at 298 K and referenced to solvent chemical shifts unless otherwise noted.

[0196] B. Compound Synthesis The following compounds were prepared using one or more of the synthetic methods disclosed in Schemes 1-7.

[0197] Example 1: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide [ka] Step 1: Synthesis of 1-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine [ka] A microwave vial was charged with 1-bromo-4-chloro-5-fluoro-2-nitrobenzene (0.50 g, 1.965 mmol), palladium(II) acetate (0.044 g, 0.197 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 97% (0.114 g, 0.197 mmol), and cesium carbonate (0.960 g, 2.95 mmol). The vial was capped and evacuated and backfilled with nitrogen. Toluene (volume: 25 mL) and 1-methylpiperazine (0.196, 1.769 mmol) were added via syringe, and the reaction vial was evacuated and backfilled with nitrogen. The reaction was warmed to 40 °C overnight. LCMS indicated approximately 75% conversion and a ca. 3:1 ratio of the desired product to the ArF nucleophilic aromatic substitution (SNAr) rearrangement. The reaction was transferred to a round-bottom flask containing DCM and concentrated onto Celite. Purification by flash chromatography [0-10% MeOH / DCM + 1% NH4OH; 100 g column] afforded two inseparable products, 1-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine (0.428 g, 1.095 mmol, 55.7% yield) and 1-(5-bromo-2-chloro-4-nitrophenyl)-4-methylpiperazine. This mixture was used directly in the next step. LCMS [M+H] + 274 g / mol.

[0198] Step 2: Synthesis of 4-((2'-fluoro-4'-(4-methylpiperazin-1-yl))-5'-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine [ka] A mixture of 1-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine, 3-(4-morpholinomethyl)phenylboronic acid pinacol ester (0.498 g, 1.642 mmol), XPhos Pd G2 (0.017 g, 0.022 mmol), and XPhos (10.44 mg, 0.022 mmol) was charged to a vial. The vial was sealed with a cap and septum and evacuated and backfilled with nitrogen. 1,4-Dioxane (volume: 10 ml) and a 2 M aqueous solution of sodium carbonate monohydrate (ACS) (2.74 ml, 5.47 mmol) were added via syringe, and the vial was further evacuated and backfilled with nitrogen. The reaction was heated to 90 °C overnight in an aluminum block. LCMS indicated complete consumption of the starting material. The peak at 1.56 min was ionized for the mass of the target product. The reaction was cooled to room temperature and concentrated onto Celite. Purification by silica gel flash chromatography [1-10% MeOH / DCM + 1% NH4OH] afforded the desired 4-((2'-fluoro-4'-(4-methylpiperazin-1-yl)-5'-nitro-[1,1-biphenyl]-3-yl)methyl)morpholine (0.248 g, 0.598 mmol, 54.7% yield) as a yellow oil. LCMS [M+H] + 415 g / mol.

[0199] Step 3: Synthesis of 6-fluoro-4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine [ka] A solution of 4-((2'-fluoro-4'-(4-methylpiperazin-1-yl)-5'-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine (0.248 g, 0.598 mmol) in MeOH (volume: 10 ml) was hydrogenated at 1 atmosphere (balloon) of H2 (gas) in the presence of platinum(IV) oxide (0.014 g, 0.060 mmol). After 18 hours (overnight), LCMS showed the formation of two polar peaks, both of which were shown by MS to be the desired product. Celite was added to the reaction, and the mixture was filtered and eluted with MeOH. The filtrate was then concentrated onto Celite and purified by silica gel flash chromatography [1-10% MeOH / DCM + 1% NH4OH] to give 6-fluoro-4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)[1,1'-biphenyl]-3-amine (0.130 g, 0.338 mmol, 56.5% yield) as a blue foam, which was >90% desired product by NMR and LCMS. LCMS [M+H] + 385 g / mol.

[0200] Step 4: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide [ka] 4-Fluoro-3,5-dimethylbenzoic acid (0.016 g, 0.094 mmol) was activated with HATU (0.045 g, 0.117 mmol) and DIPEA (0.020 ml, 0.117 mmol) in N,N-dimethylformamide (DMF) (volume: 1 ml, ratio: 1.000) at room temperature. After 5 minutes, this solution was added to a solution of 6-fluoro-4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine (0.030 g, 0.078 mmol) in DMF (volume: 1 ml, ratio: 1.000) at room temperature. The reaction was briefly warmed (50 °C for 1 hour, then 70 °C for 1 hour). The reaction was then stirred overnight at room temperature and then concentrated onto Celite. This intermediate was purified using Biotage silica gel flash chromatography (reverse phase) [5–95% MeCN / water; 30 g C18 column] to give 4-fluoro-N-(6-fluoro-4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-3,5-dimethylbenzamide (0.009 g, 0.017 mmol, 21.57% yield) as a transparent film, which was pure by LCMS and NMR. 1 H NMR(500MHz,DMSO-d6)δ=9.49(s,1H),8.02(d,J=8.6Hz,1H),7.73(d,J=6.8Hz,2H),7.47-7.41(m,3H),7.34(d,J=6.8Hz,1H),7 .19(d,J=12.2Hz,1H),3.60-3.57(m,4H),3.54(s,2H),2.97-2.93(m,4H),2.38(br.s,4H),2.32(s,6H),2.24(s,3H).LCMS[M+H] + 535 g / mol.

[0201] Example 2: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide [ka] Diethyl chlorophosphate (0.045 mL, 0.312 mmol) was added to a solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (0.065 g, 0.312 mmol) in anhydrous pyridine (0.945 mL, 11.70 mmol) at room temperature under nitrogen. After stirring for 1 hour, this solution was added to a vial containing 6-fluoro-4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine (from Step 3(a): 0.030 g, 0.078 mmol) under nitrogen, and the reaction was heated at 70°C for 3 hours. The pyridine was removed under reduced pressure, and LCMS of the residue (dissolved in DCM, MeCN, and MeOH) showed complete conversion to the desired product. The mixture was loaded onto Celite and purified by flash chromatography [0.5–10% DCM / MeOH + 1% NH4OH] to give methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (0.024 g, 0.042 mmol, 53.6% yield) as a transparent film. 1 H NMR(500MHz,DMSO-d6)δ=9.53(s,1H),7.94(s,1H),7.76(d,J=8.4Hz,1H),7.46-7.42(m,2H),7.40-7.38(m,1H),7.32(d,J=7.3Hz,1 LCMS[M+H] + 574 g / mol.

[0202] In a similar manner, the following additional compounds of the present application were prepared using Schemes 1-7: The yields disclosed are for the final synthetic step leading to the compound of the present application.

[0203] Example 3: N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] Step 1. N-(5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] To a suspension of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (719 mg, 3.47 mmol) in anhydrous pyridine (4210 μL, 52.1 mmol) in a 10 mL microwave vial, diethyl chlorophosphate (514 μL, 3.56 mmol) was slowly added at room temperature under a N atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The suspension became a solution, then became a suspension again. To this mixture, 5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)aniline (250 mg, 0.868 mmol) was added, and the reaction was stirred at 70° C. for 3 hours. After completion of the reaction, the pyridine was removed under reduced pressure, and the residue was partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 minutes. The organic layer was separated and dried over anhydrous NaSO. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (0-100%, 89% CH₂Cl₂, 10% MeOH, 1% NH₄Ac / CH₂Cl₂) to give the desired compound. LCMS C8 [M+1] + =459.4

[0204] Step 2: N-(5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] In a 5 mL microwave vial, N-(5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (29.67 mg, 0.062 mmol), 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester (54.3 mg, 0.187 mmol), sodium carbonate, anhydrous (65.9 mg, 0.622 mmol), XPhos (5.93 mg, 0.012 mmol), and XPhos Pd G2 (9.78 mg, 0.012 mmol) were dissolved in water (1166 μL) and 1,4-dioxane (1943 μL) to give a white suspension. The suspension was stirred for 5 minutes, degassed, purged with N2, and microwaved at 120 °C for 60 minutes. The solvent was evaporated, and 15 ml of CHCl2 was added. The suspension was sonicated and extracted with water. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel flash column chromatography (0–100%, 89% CHCl2, 10% MeOH, 1% NHAc / CHCl2) to give the desired compound in 61% yield. 1 H NMR(500MHz,MeOD)δ8.55(s,2H),7.97(s,1H),7.91(d,J=8.2Hz,1H),7.11(d,J=12.0Hz,1H),6.9 2(s,1H),3.86-3.82(m,4H),3.78-3.74(m,4H),3.01(s,4H),2.66(s,4H),2.37(s,3H);LCMS[M+H] + 562.7.

[0205] Example 4: N-(4-fluoro-2-(4-methylpiperazin-1-yl)-5-(6-morpholinopyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] The title compound was prepared in 78% yield by a procedure similar to that described above for the preparation of Example 3, except 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine was used instead of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to afford the title compound in 78% yield. 1 H NMR(500MHz,MeOD)δ8.32(s,1H),7.97(s,1H),7.91(d,J=8.3Hz,1H),7.79(d,J=8.8Hz,1H),7.09(d,J=12.0Hz,1H),6.9 2(s,1H),6.91(d,J=9.1Hz,1H),3.83-3.80(m,4H),3.55-3.52(m,4H),3.03(s,4H),2.76(s,4H),2.45(s,3H);LCMS[M+H] + 561.6.

[0206] Example 5: N-(5-(benzo[d][1,3]dioxol-5-yl)-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] This example was prepared by a procedure similar to that described above for the preparation of Example 3, using 3,4-methylenedioxyphenylboronic acid instead of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to afford the title compound in 70% yield. 1 H NMR(500MHz,MeOD)δ7.96(s,1H),7.88(d,J=8.3Hz,1H),7.06(d,J=12.0Hz,1H),7.02(d,J=7.1Hz,2H),6.92(s, 1H),6.90(d,J=8.6Hz,1H),5.99(s,2H),3.02(t,J=4.9Hz,4H),2.73(s,4H),2.43(s,J=13.2Hz,3H);LCMS[M+H] + 519.5.

[0207] Example 6: (R)—N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] The title compound was prepared using (R)-4-(4-chloro-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine and 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to give the (R)-4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yl)morpholine intermediate, which was reduced to the corresponding amine by standard methods. Diethyl chlorophosphate (4 equivalents) was added to a solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (4 equivalents) in pyridine at room temperature under N. After stirring for 1 h, the activated acid solution was added to a vial containing (R)-4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-aminophenyl)pyrimidin-2-yl)morpholine (1 equiv.) under nitrogen and the reaction was heated to 70 °C for 3 h. The reaction mixture was concentrated onto Celite and subjected to flash chromatography [0.5-10% DCM / MeOH + 1% NH4OH] to give the title compound in 19% yield. 1 H NMR(500MHz,DMSO-d6)δ=9.43(br.s.,1H),8.53(s,2H),7.96(s,1H),7.78( d,J=8.4Hz,1H),7.08(d,J=12.2Hz,1H),6.70(s,1H),3.77-3.73(m,4H),3. 70-3.66(m,4H),3.08-2.95(m,2H),2.88-2.72(m,2H),2.41(t,J=10.6Hz,1 H),2.35-2.30(m,1H),2.25-2.18(m,4H),0.97(d,J=6.1Hz,3H);LCMS[M+H] + 576.

[0208] Example 7: (S)—N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] The title compound was prepared using (S)-4-(4-chloro-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine and 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to give the (S)-4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yl)morpholine intermediate, which was reduced to the corresponding amine by standard methods. Diethyl chlorophosphate (4 equivalents) was added to a solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (4 equivalents) in pyridine at room temperature under N. After stirring for 1 h, the solution of activated acid was added to a vial containing (S)-4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-aminophenyl)pyrimidin-2-yl)morpholine (1 equiv.) under nitrogen and the reaction was heated to 70 °C for 3 h. The reaction mixture was concentrated onto Celite and subjected to flash chromatography [0.5-10% DCM / MeOH + 1% NH4OH] to give the title compound in 15% yield. 1 H NMR(500MHz,DMSO-d6)δ=9.45(br.s.,1H),8.53(s,2H),7.95(s,1H),7.78(d,J=8.6 Hz,1H),7.08(d,J=12.2 Hz,1H),6.72(br.s.,1H),3.77-3.74(m,4H),3.69-3.66(m,4H),3.00(dd,J=11.0,17.4 Hz,2H),2.87-2.72(m,2H),2.44-2.30(m,3H),2.21(s,4H),0.97(d,J=6.1 Hz,3H);LCMS[M+H] + 576.4 .

[0209] Example 8: N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ka] Step 1: (2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine [ka] To a suspension of KCO (0.456 g, 3.30 mmol) in toluene (10 mL), 1-bromo-2,4-difluoro-5-nitrobenzene (1.497 g, 6.29 mmol) was added, and the reaction mixture was heated to 50 °C for 2 minutes. After that, a solution of (2R,6S)-1,2,6-trimethylpiperazine (0.806 g, 6.29 mmol) in toluene (3 mL) was added slowly over 3 minutes. The resulting mixture was stirred at 50 °C for 1 hour. After adding water (20 mL), it was extracted with EtOAc (30 mL x 2). The combined extracts were concentrated and dried under reduced pressure to give a thick orange-red oil that solidified into a yellow solid (2.166 g, 100% yield). LCMS [M+H] + =348.3.

[0210] Step 2: 4-(5-(2-fluoro-5-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidin-2-yl)morpholine [ka] To a 20 mL microwave vial charged with (2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine (1.04 g, 3 mmol), 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester (1.22 g, 4.2 mmol), and Pd(dppf)Cl (220 mg, 0.3 mmol, 10 mol%), dioxane (10 mL) was added, followed by a 1 M aqueous solution of KPO (5.0 mL, 5 mmol). The resulting mixture was heated at 110 °C by microwave irradiation for 2 h, diluted with HO (10 mL), and extracted with EtOA...

Claims

【Request 1】 【Chemistry 1】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt or solvate thereof.

2. The compound is 【Chemistry 2】 2. The compound of claim 1, 【Request 3】 【Chemistry 3】 【change】 【change】 or a pharma- ceutically acceptable salt or solvate thereof. 【Request 4】 【Chemical 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt or solvate thereof.

5. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or diluent.

6. A pharmaceutical composition for use in treating one or more diseases, disorders or conditions mediated by or treatable by inhibition of binding between WDR5 protein and its binding partner, comprising one or more compounds according to any one of claims 1 to 4 or a pharma- ceutical acceptable salt or solvate thereof.

7. The pharmaceutical composition according to claim 6, wherein the disease, disorder or condition mediated by or treatable by inhibition of the binding between WDR5 protein and its binding partner is a neoplastic disease.

8. The pharmaceutical composition of claim 7, wherein the neoplastic disease is cancer.

9. The pharmaceutical composition of claim 8, wherein the cancer is selected from solid cancers and leukemia.

10. 10. The pharmaceutical composition of claim 9, wherein the cancer is selected from leukemia, lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, MLL-effusion lymphoma, primary effusion leukemia and multiple myeloma.

11. 10. The pharmaceutical composition of claim 9, wherein the cancer is selected from leukemia, melanoma, lung cancer, bladder cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, neuroblastoma and kidney cancer.

12. The pharmaceutical composition of claim 8, wherein the cancer is selected from leukemia, bladder cancer, prostate cancer, brain cancer, and neuroblastoma.

13. The pharmaceutical composition of claim 8, wherein the cancer is selected from bladder cancer, acute myeloid leukemia (AML), glioma, glioblastoma, and MYCN-amplified neuroblastoma.

14. 【Chemical 5】 or a pharma- ceutically acceptable salt or solvate thereof.

15. 【Chemical 6】 or a pharma- ceutically acceptable salt or solvate thereof.

16. 【Chemical 7】 or a pharma- ceutically acceptable salt or solvate thereof.

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