Parte del contenido de esta aplicación no está disponible en este momento.
Si esta situación persiste, contáctenos aComentarios y contacto
1. (WO2017147700) INHIBITORS OF WDR5 PROTEIN-PROTEIN BINDING
Nota: Texto obtenido mediante procedimiento automático de reconocimiento óptico de caracteres.
Solo tiene valor jurídico la versión en formato PDF

TITLE: INHIBITORS OF WDR5 PROTEIN-PROTEIN BINDING

CROSS-REFERENCE TO RELATED APPLICTIONS

[0001] The present application claims the benefit of priority from United

States provisional patent application no. 62/301,673 filed on 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 comprising them and their use for the treatment of diseases, disorders and conditions mediated by binding between WDR5 and its binding partners including, but not limited to, MLLl.

BACKGROUND

[0003] Histones, the most basic units for packing DNA into nucleosomes and covalent modifications of histones, such as methylation, acetylation and phosphorylation, play a central role for regulation of gene transcription [Nat. Rev. Mol. Cell Biol. 2001, 2: 422-432; Cell 2007, 128: 693-705]. Epigenetics refers to the heritable changes that control how the genome is accessed in different cell types during embryonic development and cellular differentiation [Genes. Dev. 2009; 23: 781-3]. This capability permits specialization of function between cells without altering the DNA sequence.

[0004] It is now well recognized that misregulation of histone modifications plays a key 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]. Mixed Lineage Leukemia 1 (MLLl) protein is a Histone H3 Lysine 4 (H3K4) methyltransf erase and is frequently misregulated in a subset of acute leukemias [Trends Mol. Med., 2004, 10: 500-507, Cell. Stem. Cell, 2007, 1 :324-337]. MLLl itself has a weak H3K4 methyltransferase activity but its enzymatic activity is dramatically enhanced when MLLl is present in a core complex made up of MLLl, WD repeat domain 5 protein (WDR5), Absent, Small, or Homeotic-2-Like (ASH2L) and Retinoblastoma Binding Protein 5 (RbBP5). Recent studies have clearly shown that the binding between MLLl and WDR5 proteins is optimal for the activity of MLLl but dispensable for the activity of other MLL family members, including MLL2, MLL3 and MLL4 [Mol.

Cell, 2014, 53:247-261]. Hence, blocking the protein-protein binding of MLLl with WDR5 can specifically inhibit the activity of MLLl H3K4 methyltransferase activity, and such inhibition has potential for the treatment of human diseases such as a subset of acute leukemias whose development and progression depend upon MLLl activity.

[0005] WDR5 is a common subunit of all six mammalian histone H3K4 methyltransferases [Dev. Biol, 2010,339 (2):240-249]. WDR5 has334 amino acids and contains seven typical WD40 repeat domains, each approximately 40 amino acids in length [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 made up of a four-stranded antiparallel sheet. This structural property suggests that WDR5 has many exposed surfaces making it a useful adaptor to interact with other proteins. Further, pulldown assays indicate that WDR5 prefers to bind dimethylated histone H3K4 peptides [Nat. Struct. Mol. Biol, 2009, 16 (7):678-680].

[0006] Two recent studies suggested an important role of WDR5 in the MLLl complex. The WDR5 interacting (WIN) motif, made up of amino acid residues 3762-3773 next to the SET domain in MLLl protein, was independently discovered to mediate the binding of MLLl with WDR5 [J. Biol. Chem., 2008, 283(47):32158-32161 ; J. Biol. Chem., 2008,283(50):35258-35264] . The crystal structure of the WIN motif peptide with WDR5 shows that the WIN motif, which is the analogue of H3 N-terminal peptide, binds with WDR5 in the central depression of the β-propeller by adopting a 310-helical structure and inserting Arg3765 into the central channel. Hence, the binding between MLLl and WDR5 is mediated by a well-defined pocket in WDR5 and WIN motif (residues 3762-3773) in MLLl. Previous studies have demonstrated that a 3-residue peptide, i.e. Ac-A-R-A-NH2 (IQ = 0.12 mmol/L) has the same binding affinity as the 12-residue WIN peptide (IQ = 0.16 mmol/L) to WDR5 [J. Med. Chem., 2010, 53: 5179-5185; J. Am. Chem. Soc, 2013, 135: 669-682].

[0007] Because WDR5 is an essential component of the histone methylation, acetylation, and chromatin remodeling complexes, while not wishing to be limited by theory, WDR5 is believed to serve as an adaptor protein for complex assembly. However, it may also contribute to other physiological phenomena. WDR5 is an important component for assembly or stability of the virus-induced signaling adapter (VISA) associated complex, which plays a key role in virus-triggered induction of type I interferons (IFNs) and antiviral innate immune response [Proc. Natl. Acad. Sci. U S A., 2010, 107(2): 815-820]. Previous studies have demonstrated that VISA is located at the outer membrane of mitochondria. Interestingly, this study revealed that WDR5 was not only localized in the nucleus as believed before, but also abundantly localized in the cytoplasm. Viral infection caused translocation of WDR5 from the nucleus to the mitochondria located VISA complex, 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, specifically in virus-triggered signaling resulting in induction of type I IFNs [Proc. Natl. Acad. Sci. USA., 2010, 107(2): 815-820].

MLL1-WDR5 complex in Leukemogenesis

[0008] Leukemia is characterized by an abnormal increase of white blood cells in the blood or bone marrow. Among all types of cancers, the morbidity of leukemia is the highest for patients below 35 years old. Over 70% of infant leukemia patients bear a translocation involving chromosome 11, resulting in the fusion of the MLL1 gene with other genes [Nat. Rev. Cancer., 2007, 7(l l):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 cancers [Nat. Rev. Cancer., 2007,7(11):823-833]

[0009] MLL1 is the human homologue of Saccharomyces cerevisiae gene

Setl and the Drosophila gene Trx. The genes encode an enzyme to catalyze the methylation of H3K4 [Nat. Rev. Cancer., 2007, 7(l l):823-833]. Trimethylation of histone 3 at lysine 4 (H3K4) is a hallmark of active gene transcription, and alteration of this process often causes changes in gene expression partem. MLL1 translocation is also linked to altered transcription of important genes involved in stem cell maintenance and development and, thus, leads to leukemogenesis. The MLL1 gene was first discovered in leukemia patients in 1991 [Nat. Rev. Cancer., 2007, 7(11): 823-833]. cDNA of the MLL1 gene contains -12 kb nucleotides and encodes a peptide over 4000 amino acids in length. In the cell, the premature MLL1 protein is digested by taspase, which results in two peptides: a 300 kDa N-terminal fragment and a 170 kDa C-terminal fragment. The two cleaved peptides form a heterodimer, which is

complexed with other components, including WDR5, RBBP5, ASH2L and DPY30. In some leukemia patients, chromosomal translocation results in fusion of -4.2 kb DNA of the MLL1 N-terminal coding region with some other genes [Cancer. Cell., 2003, 4(3): 197-207].

[0010] The generation of MLL1 fusion protein is sufficient to induce leukemia, which has been demonstrated in animal models [Nat. Rev. Cancer., 2007, 7(l l):823-833]. The mechanisms of MLL1 fusion-mediated leukemia have been studied extensively in the past twenty years. The MLL/SET1 family members are most enzymatically active when part of the "core complex" (WRAD2), comprising the catalytic SET-domain-containing subunits bound to a sub-complex made up of the proteins WDR5, RbBP5, Ash2L and a homodimer of DPY-30. The necessity of MLL/SET1 members to bind WRAD2 for full activity is the basis of a particular drug development strategy, which seeks to disrupt the binding between the MLL/SET1 subunits and WDR5. Recent efforts to pharmacologically target the MLL1 catalytic activity has centered on attempts to disrupt the MLL1-WDR5 binding by means of Win-motif mimicking 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, as with most peptide based inhibitors, MLL1-WDR5 peptidic inhibitors exhibit poor cell-based activity and lack oral bioavailability due to poor cell-permeability and peptide chemical liability (e.g. susceptibility to peptidases).

Role of WDR5 in other cancers

Bladder Cancer

[0011] WDR5 also plays a critical role in embryonic stem cell self-renewal

[Cell. 2011; 145 (2): 183-97] and epithelial -mesenchymal transition [Mol. Cell, 2011; 43(5):811-22]. A recent study 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, though its expression pattern, role and mechanism in bladder cancer remained unclear. WDR5 is upregulated in bladder cancer tissues compared with normal tissues as determined by immunohistochemistry (IHC), and is correlated with advanced tumor stage and overall survival of bladder cancer patients. A recent study found that WDR5 is overexpressed in prostate cancer tissue 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] WDR5 silencing reduces cell growth in breast cancer and prostate cancer [Mol. Cell., 2014, 54 (4):613-25; Cell Rep., 2013 5 (2):302-13], but the detailed mechanism and role in vivo is still unknown. Through gain or loss of function, WDR5 was found to promote bladder cancer cell proliferation in vitro and tumor growth in vivo, and that silencing WDR5 mainly induces the G0/G1 phase cell cycle arrest. The cell cycle is regulated by cyclins and cyclin-dependent kinases. Cyclin El and Cyclin E2 regulate the Gl to S-phase transition, while Cyclin Bl regulates the G2 to M-phase transition. Moreover, 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 named KIS) is overexpressed in leukemia and promotes the Gl to S-phase transition [Leuk. Res., 2008; 32 (9): 1358-65]. Mechanistically, WDR5 knockdown inhibited cyclin El, cyclin E2 and UHMK1 leading to G0/G1 phase cell cycle arrest, which might disturb the effect of cyclin Bl downregulation on G2 to M-phase transition. Additional studies showed that knockdown of MLL1, a core component of the MLL/SET1 complexes, suppressed HeLa cell proliferation by reducing the expression of cyclin B and inducing the G2/M phase 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, but the role and mechanism are not the same as MLL1.

[0013] WDR5 is believed to play a role in cancer stem cells (CSCs). CSCs are a small subpopulation of cells in a tumor that can self-renew and differentiate into multiple lineages, and possess strong tumor-initiating capacity. CSCs have been widely identified in a number of malignancies, and the existence of CSCs in bladder cancer was found by Chan et al [Proc. Natl. Acad. Sci. USA., 2009; 106 (33): 14016- 21]. Several studies have found that sphere culture is an effective way to enrich cancer stem cells [Cell. 2007;131(6): 1109-23; Urol Oncol. 2012;30(3):314-8]. It was observed that WDR5 and pluripotency transcription factors were upregulated in UM- UC-3 and T24 spheres. Through gain or loss of function, it was demonstrated that WDR5 promoted UM-UC-3 and T24 cells self-renewal in vitro and upregulated the homeobox protein transcription factor Nanog. Emerging evidence shows that Nanog is overexpressed in poorly differentiated tumors and correlated with poor survival outcome of patients with various types of cancer, including bladder cancer [Nat. Genet, 2008; 40(5):499-507; Onco. Targets. Ther., 2013; 6: 1207-20]. Moreover, Nanog plays a role in CSCs self-renewal and targeting. Nanog has shown promising therapeutic potential in several types of cancer [Cell Stem Cell. 2011;9 (l):50-63; Oncogene. 2013;32(37):4397-405]. WDR5 directly activates Nanog by mediating its promoter H3K4me3 level. Taken together, recent findings suggest that WDR5 plays a role in self-renewal of bladder cancer cells by regulating Nanog.

[0014] Further studies have demonstrated that WDR5 silencing increased cell apoptosis and decreased bladder cancer cells resistance to cisplatin. Conversely, overexpression of WDR5 enhanced chemoresistance to cisplatin. Moreover, WDR5 directly regulates important inhibitors of apoptotic proteins, MCL1 [FEES Lett. 2010; 584(14):2981-9; Sci Rep. 2014 ;4:6098] and BIRC3 [Expert Opin Ther Targets.2009 ;13(11): 1333-45], by H3K4me3.

[0015] In summary, WDR5 is upregulated in bladder cancer, and promotes bladder cancer cell proliferation, self-renewal and chemoresistance via activating a series of oncogenes by H3K4me3. Therefore, WDR5 is 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 a short (30-kDa) CCAAT-enhancer binding protein-a (C/EBPa) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. Recent studies have shown that C/EBPa p30, but not the normal p42 isoform, preferentially interacts with WDR5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions are enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required WDR5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. Small-molecule inhibitors of WDR5-MLL binding selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells revealing the mechanism of p30-dependent transformation and establish the p30 cofactor WDR5 as a therapeutic target in CEBPA-mutant AML [Nat Chem Biol. 2015 ;11(8):571-8].

MYCN-amplified Neuroblastoma

[0017] MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, the relationship between WDR5 -mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells was investigated. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. WDR5 was shown to form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription[Ca«cer Res 2015; 75(23); 5143-54]. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, 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 growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion 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 tumorogenesis and as a novel therapeutic target for MYCN-amplified neuroblastomas [Cancer Res 2015; 75(23); 5143-54, Mol Cell. 2015 ;58(3):440-52.].

SUMMARY

[0018] The structural features as described in the background suggest that the

WDR5-MLL binding is a desirable drug target. Hence, agents that bind to the WDR5 protein and compete for binding with WDR5 -interacting partners can reverse the transcriptional activities of WDR5 containing complexes. Considering the challenges generally associated with inhibiting protein-protein interactions, along with the current need to treat WDR5-driven tumor types such as leukemia and bladder cancers, complementary approaches including virtual screening, focused library screening and traditional structure activity relationship (SAR) studies were conducted. These studies led to the identification of compounds which inhibit the WDR5 protein-protein binding. In addition, structure-activity relationship studies demonstrated that specific chemical features contribute to longer residence times for the binding of these compounds with WDR5. Studies indicate that longer residence times can be designed into WDR5 inhibitors and contribute to the ligand-induced anti-proliferative effects observed in hematologic and solid tumors.

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

[0020] Therefore, in one aspect, the present application includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:


(I)

wherein:

R1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, C3-iocycloalkyl, OR4, SR4, NR5R6, Ci-galkyleneOR4, Ci-6alkyleneSR4 and Ci-6alkyleneNR5R6, provided that R1 comprises at least one basic nitrogen atom;

R2 is selected from C6-ioaryl and heteroaryl, and R2 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR7, SR7 and NR8R9;

R3 is selected from Ce-io ryl, heteroaryl and heterocycloalkyl, and R3 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci_ efluoroalkyl, =0, =S, OR10, SR10, S02R10, NRnR12, R13, Ci-6alkyleneR13, Ci. salkenyleneR13, OCi-6alkyleneR13, SCi-6alkyleneR13,
Ci. salkyleneOR10, Ci-6alkyleneSR10,
SCi-6alkyleneNRnR12, OCi. salkyleneOR10, SCi-6alkyleneOR10, OCi-6alkyleneSR10, SCi-6alkyleneSR10, C(0)OR10, C(S)OR10, C(S)NRnR12 and C(0)NRnR12;

R4 is selected from H, Ci-6alkyl Ci-6fluoroalkyl, C(0)Ci-6alkyl and C(0)d. 6fluoroalkyl;

R5 and R6 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OCi-6alkyl, C(0)NHCi_ 6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, Ci-6alkyl OCi-6alkyl, Ci-6fiuoroalkyl, OCi-efluoroalkyl, C(0)Ci-6alkyl, C(0)Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)NHCi-6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci-ealkyleneOCi-ealkyl, Ci-salkyleneCs-ioaryl, Ci. 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl; R7 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6fluoroalkyl and C(0)Ci_ ealkyl;

R8 and R9 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci_ 6fluoroalkyl and C(0)Ci-6alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, CN, Ci-6alkyl OCi-6alkyl, Ci-6fluoroalkyl and OCi-6fluoroalkyl;

R10 is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3.iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted or substituted with one or more substituents selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16;

R11 and R12 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(O)C3-i0cycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C(0)OCi-6alkyl, C(0)OCi-6fluoroalkyl, C(0)OC6-ioaryl, C(0)OC3-iocycloalkyl, C(0)Oheteroaryl, C(0)Oheterocycloalkyl, C(0)NHCi-6alkyl, C(0)NHCi-6fluoroalkyl, C(O)NHC6-i0aryl, C(0)NHC3- locycloalkyl, C(0)NHheteroaryl, C(0)NHheterocycloalkyl, S02Ci-6alkyl, S02d. 6fluoroalkyl, S02C6-ioaryl, S02C3-iocycloalkyl, S02heteroaryl, S02heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R11 and R12 are independently unsubstituted or substituted with one or more substituents selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-galkyleneSR14 and Ci-6alkyleneNR15R16, or

R11 and R12 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3.iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci_ 6alkyleneNR15R16;

R13 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3- locycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R13 is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR14, SR14, NR15R16, Ci-galkyl, C(0)R , C(0)OR , C(0)NR13R , S(0)Ci-6alkyl, S02Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-galkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16,

R14 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl and Ci-6alkyleneheterocycloalkyl, and R14 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-galkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi_ salkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci_ salkyleneNiCi-galky iCi-galkyl);

R15 and R16 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci_ 6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R15 and R16 is unsubstituted or substituted with one or more substituents independently selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R15 and R16 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

X1 and X2 are each independently selected from CR17 and N;

R17 is selected from H, F, Ci-6alkyl and Ci-6fiuoroalkyl;

A is F, and

all alkyl and alkylene groups are optionally fluorosubstituted.

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

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

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

[0024] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration 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.

DRAWINGS

[0025] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0026] Figure 1 illustrates WDR5 as an adaptor protein in multiple complexes and related biological processes.

DETAILED DESCRIPTION

I. Definitions

[0027] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0028] The term "compound of the application" or "compound of the present application" and the like as used herein refers to a compound of Formula I, including compounds of la, lb, Ic and Id, and pharmaceutically acceptable salts and/or solvates thereof.

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

[0030] The term "and/or" as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that "at least one of or "one or more" of the listed items is used or present. The term "and/or" with respect to pharmaceutically acceptable salts and/or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a salt of a solvate of a compound of the application.

[0031] As used in the present application, the singular forms "a", "an" and

"the" include plural references unless the content clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present certain aspects with one compound, or two or more additional compounds.

[0032] In embodiments comprising an "additional" or "second" component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A "third" component is different from the other, first, and second components, and further enumerated or "additional" components are similarly different.

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

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

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

[0036] The term "suitable" as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art.

[0037] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than

20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included 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 which 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 varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0040] The present description refers to a number of 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 mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0042] The expression "proceed to a sufficient extent" as used herein with reference to the reactions or process steps disclosed herein means that the reactions or process steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater 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 that has a lone pair of electrons available to participate in an interaction with a hydrogen atom. In an embodiment, the interaction is a hydrogen bond, an ionic bond or a covalent bond. In general, the basic nitrogen atom will be either a primary, secondary or tertiary alkyl amine nitrogen atom, either in a linear, branched or cyclic group. In some embodiments, the pKa of the conjugate acid of the basic nitrogen atom will be greater than about 8-10.

[0044] The term "alkyl" as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix "Cnl-n2". For example, the term Ci.i0alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0045] The term "alkylene", whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix "Cni-n2". For example, the term C2-6alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0046] The term "alkenyl" as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix "Cni-n2". For example, the term C2-6alkenyl means 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 wherein one or more, including all of the hydrogen atoms are replaced by a fluorine atom. In an embodiment, the fluoroalkyl comprises at least one -CHF2 group. In another embodiment, the fluoroalkyl comprises at least one -CF3 group.

[0048] The term "fluorosubstituted" as used herein refers to a chemical group wherein one or more, including all of the hydrogen atoms, are replaced by a fluorine atom.

[0049] The term "cycloalkyl," as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing a number of carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix "Cni-n2 "· For example, the term C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

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

[0051] The term "heterocycloalkyl" as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing 3 to 20 atoms, suitably 3 to 10 atoms, and at least one non- aromatic, ring in which one or more of the atoms are a heteromoiety selected from O, S, S(O), S02, N, NH and NCi-6alkyl, suitably O, S, N, NH and NCi-6alkyl. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds) and contain one or more than one ring (i.e. are polycyclic). When a heterocycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond. When a heterocycloalkyl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.

[0052] A first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms there between.

[0053] The term "heteroaryl" as used herein refers to cyclic groups containing from 5 to 20 atoms, suitably 5 to 10 atoms, at least one aromatic ring and at least one a heteromoiety selected from O, S, S(O), S02, N, NH and NCi-6alkyl, suitably O, S, N, NH and NCi-6alkyl. Heteroaryl groups contain one or more than one ring (i.e. are polycyclic). When a heteroaryl group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond. When a heteroaryl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.

[0054] The term "available", as in "available hydrogen atoms" or "available atoms" refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

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

[0056] The term "amine" or "amino," as used herein, whether it is used alone or as part of another group, refers to groups of the general formula NRR', wherein R and R' are each independently selected from hydrogen and an alkyl group, such as Ci_

6alkyl.

[0057] The term "atm" as used herein refers to atmosphere.

[0058] The term "MS" as used herein refers to mass spectrometry.

[0059] The term "aq." as used herein refers to aqueous.

[0060] DCM as used herein refers to dichloromethane.

[0061] DIPEA as used herein refers to Ν,Ν-diisopropyl ethylamine

[0062] DMF as used herein refers to dimethylformamide.

[0063] DMSO as used herein refers to dimethylsulfoxide.

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

[0065] HATU as used herein refers to l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate.

[0066] MeOH as used herein refers to methanol.

[0067] MeCN as used herein refers to acetonitrile.

[0068] HC1 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-butyl ammonium fluoride.

[0071] CsF as used herein is cesium fluoride.

[0072] μwave as used herein refers to a microwave reaction vessel.

[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" and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999 and in 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 suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications. In an embodiment, the subject is a mammal. In another embodiment, the subject is human.

[0077] The term "pharmaceutically acceptable" means compatible with the treatment of subjects, for example humans.

[0078] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

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

[0080] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic

compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono-or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0081] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine,

dicyclohexylamine, choline, and caffeine. [See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19]. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0082] The term "solvate" as used herein means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0083] The term "treating" or "treatment" as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. "Treating" and "treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

"Treating" and "treatment" as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or altematively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or altematively comprise a series of administrations. For example, the compounds of the application are administered at least once a week. However, in another embodiment, the compounds are administered to the

subject from about one time per two weeks, three weeks or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application, and/or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.

[0084] "Palliating" a disease, disorder or condition means that the extent and/or undesirable clinical manifestations of a disease, disorder or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0085] The term "prevention" or "prophylaxis", or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition or manifesting a symptom associated with a disease, disorder or condition.

[0086] The "disease", "disorder" or "condition" as used herein refers to a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, in particular MLLl, and in particular using a WDR5 protein inhibitor, such as a compound of the application herein described.

[0087] The term "mediated or treatable by inhibition of binding between

WDR5 protein and its binding partners" as used herein means that the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes WDR5 binding, in particular, increased WDR5 binding, to its binding partners, such as MLLl . Such biological basis includes, for example, WDR5 and/or MLLl gene overexpression or WDR5 and/or MLLl protein over-accumulation or over-expression of proteins that are products of or precursors to WDR5-mediated and/or MLLl gene expression. In a

refined context, "mediated or treatable by inhibition of binding between WDR5 protein and its binding partners" refers to an effect mediated through inhibition of binding between WDR5 and MLL1. In a broader context, "mediated or treatable by inhibition of binding between WDR5 protein and its binding partners" can include the large number of diseases that are caused by aberrant methylation of histone 3 lysine 4 (H3K4) residues, as results from aberrant WDR5 and/or MLL1 activity. As used herein, WDR5 refers to the protein identified as GenBank Accession number NM_017588 [J. Biol. Chem. 2001, 276 (49), 46515-46522] and isoforms that include this sequence, and shorter versions. Similarly, the other WDR5 proteins are characterized and described in any of the protein databases. As used herein, MLL1 refers to the protein identified as GenBank Accession number NM_005933 [Proc. Natl. Acad. Sci. U.S.A. 1991, 88 (23), 10735-10739; DNA Cell Biol. 1995, 14 (6), 475-483] and isoforms that include this sequence, and shorter versions. Similarly, the 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, such as two proteins, that leads to a functional effect.

[0089] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the application that is effective, at dosages and for periods of time necessary to achieve the desired result. For example in the context of treating a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, an effective amount is an amount that, for example, increases said inhibition compared to the inhibition without administration of the one or more compounds. In an embodiment, effective amounts vary 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 will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled 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 that have the capacity for autonomous growth 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 growth and/or division of cells in a subject having a neoplastic disorder. Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ) or malignant (i.e. cancer). Exemplary neoplastic disorders include the so-called solid tumours and liquid tumours, including but not limited to carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders, (e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders), metastatic tumors and other cancers.

[0092] The term "cancer" as used herein refers to cellular-proliferative disease states.

II. Compounds and Compositions of the Application

[0093] The present application includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:


(I)

wherein:

R1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, C3-iocycloalkyl, OR4, SR4, NR5R6, Ci-galkyleneOR4, Ci-6alkyleneSR4 and Ci-6alkyleneNR5R6, provided that R1 comprises at least one basic nitrogen atom;

R2 is selected from C6-ioaryl and heteroaryl, and R2 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR7, SR7 and NR8R9;

R3 is selected from Ce-io ryl, heteroaryl and heterocycloalkyl, and R3 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci_ efluoroalkyl, =0, =S, OR10, SR10, S02R10, NRnR12, R13, Ci-6alkyleneR13, Ci. salkenyleneR13, OCi-6alkyleneR13, SCi-6alkyleneR13,
Ci. salkyleneOR10, Ci-6alkyleneSR10,
SCi-6alkyleneNRnR12, OCi. salkyleneOR10, SCi-6alkyleneOR10, OCi-6alkyleneSR10, SCi-6alkyleneSR10, C(0)OR10, C(S)OR10, C(S)NRnR12 and C(0)NRnR12;

R4 is selected from H, Ci-6alkyl C^fluoroalkyl, C(0)Ci-6alkyl and C(0)d. 6fluoroalkyl;

R5 and R6 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OCi-6alkyl, C(0)NHCi_ 6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci-ealkyleneOCi-ealkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, Ci-6alkyl OCi-6alkyl, Ci-6fiuoroalkyl, OCi-efluoroalkyl, C(0)Ci-6alkyl, C(0)Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)NHCi-6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci-ealkyleneOCi-ealkyl, Ci-ealkyleneCe-ioaryl, Ci. 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl;

R7 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6fluoroalkyl and C(0)Ci-ealkyl;

R8 and R9 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6fluoroalkyl and C(0)Ci-6alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or

substituted with one or more substituents selected from halo, OH, CN, Ci-6alkyl OCi-6alkyl, Ci-6fluoroalkyl and OCi-6fluoroalkyl;

R10 is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted or substituted with one or more substituents selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16;

R11 and R12 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(O)C3-i0cycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C(0)OCi-6alkyl, C(0)OCi-6fluoroalkyl, C(0)OC6-ioaryl, C(0)OC3-iocycloalkyl, C(0)Oheteroaryl, C(0)Oheterocycloalkyl, C(0)NHCi-6alkyl, C(0)NHCi-6fluoroalkyl, C(O)NHC6-i0aryl, C(0)NHC3- locycloalkyl, C(0)NHheteroaryl, C(0)NHheterocycloalkyl, S02Ci-6alkyl, S02d. 6fluoroalkyl, S02C6-ioaryl, S02C3-iocycloalkyl, S02heteroaryl, S02heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R11 and R12 are independently unsubstituted or substituted with one or more substituents selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16, or

R11 and R12 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR , Ci-6alkyleneOR , Ci-6alkyleneSR and Ci_ 6alkyleneNR15R16;

R13 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3- locycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R13 is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-galkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16,

R14 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl and Ci-6alkyleneheterocycloalkyl, and R14 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-galkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi_ 6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci_ salkyleneNiCi-galky iCi-galkyl);

R15 and R16 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci_ 6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R15 and R16 is unsubstituted or substituted with one or more substituents independently selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3- locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R15 and R16 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

X1 and X2 are each independently selected from CR17 and N;

R17 is selected from H, F, Ci-6alkyl and Ci-6fiuoroalkyl;

A is F, and

all alkyl and alkylene groups are optionally fluorosubstituted.

[0094] The present application also includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:


(I)

wherein:

R1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, OR4, SR4, NR5R6, Ci_ 6alkyleneOR4, Ci-6alkyleneSR4 and Ci-6alkyleneNR5R6, provided that R1 comprises at least one basic nitrogen atom;

R2 is selected from C6-ioaryl and heteroaryl, and R2 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR7, SR7 and NR8R9;

R3 is selected from C6-ioaryl, heteroaryl and heterocycloalkyl, and R3 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci_ sfiuoroalkyl, OR10, SR10, NRnR12, R13, Ci-6alkyleneR13, OCi-6alkyleneR13, SCi. salkyleneR13, Ci-6alkyleneNRnR12, Ci-6alkyleneOR10, Ci-6alkyleneSR10, OCi. 6alkyleneNRnR12, SCi-6alkyleneNRnR12, OCi-6alkyleneOR10, SCi-6alkyleneOR10, OCi-6alkyleneSR10, SCi-6alkyleneSR10, C(0)OR10, C(S)OR10, C(S)NRnR12 and C(0)NRnR12;

R4 is selected from H, d.6alkyl Ci-6fluoroalkyl, C(0)Ci-6alkyl and C(0)d. 6fluoroalkyl;

R5 and R6 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl, C(0)Ci-6alkyl and C(0)Ci-6fluoroalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, Ci-galkyl OCi-6alkyl, Ci-6fluoroalkyl, OC^fluoroalkyl, C(0)Ci-6alkyl and C(0)Ci_ 6fluoroalkyl;

R7 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6fluoroalkyl and C(0)Ci_ 6alkyl;

R8 and R9 are independently selected from H, Ci-6alkyl, Ci-6fiuoroalkyl, C(0)Ci. 6fluoroalkyl and C(0)Ci-6alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, Ci-6alkyl OCi-6alkyl, Ci-6fluoroalkyl and OCi-6fluoroalkyl;

R10 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted or substituted with one or more substituents selected from halo, OR , SR14, NR15R16, Ci-galkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci. 6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci_ salkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16;

R11 and R12 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6- loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R11 and R12 are independently unsubstituted or substituted with one or more substituents selected from halo, OR14, SR14, NR15R16, Ci-galkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-galkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16, or

R11 and R12 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents independently selected from halo, OR14, SR14, NR15R16, Ci-6alkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR14, Ci-6alkyleneOR14, Ci-6alkyleneSR14 and Ci_ 6alkyleneNR15R16;

R13 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-i0cycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R13 is unsubstituted or substituted with one or more substituents independently selected from halo, OR14, SR14, NR15R16, Ci_ salkyl, C(0)R14, C(0)OR14, C(0)NR15R16, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR14, Ci-galkyleneOR14, Ci-6alkyleneSR14 and Ci-6alkyleneNR15R16,

R14 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl and Ci-6alkyleneheterocycloalkyl, and R14 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi.6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci. 6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)d. 6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci_ 6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

R15 and R16 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci_ 6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R15 and R16 is unsubstituted or substituted with one or more substituents independently selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R15 and R16 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-sfiuoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, NCCi-salkylXCi-salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi_ 6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci_ 6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

X1 and X2 are each independently selected from CR17 and N;

selected froni H, Ci-6alkyl and Ci-6fluoroalkyl;

A is F; and

all alkyl and alkylene groups are optionally fluorosubstituted.

[0095] In some embodiments, R is a heterocycloalkyl that is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci_ 6fluoroalkyl, NR5R6 and Ci-6alkyleneNR5R6, provided that R1 comprises at least one basic nitrogen atom. In some embodiments, R1 is a heterocycloalkyl that is substituted with one or two substituents selected from halo, Ci-6alkyl and NR5R6, provided that R1 comprises at least one basic nitrogen atom. In some embodiments, R1 is a heterocycloalkyl that is substituted with one or two substituents selected from Ci-6alkyl and NR5R6, provided that R1 comprises at least one basic nitrogen atom. In some embodiments, R1 is a Cs-eheterocyclalkyl comprising one or two nitrogen atoms at least one of which is basic.

[0096] In some embodiments, R1 is selected from:


In some embodiments, R1 is selected from:


In some embodiments, R1 is selected from:

In some embodiments, R1 is selected from:

[00100] In some embodiments, R1 is selected from:


[00101] R1 is selected from:


[00102] In some embodiments, R2 is selected from C6-ioaryl and heteroaryl, and

R2 is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, OR7, SR7 and NR8R9. In some embodiments, R2 is selected from C6-ioaryl and heteroaryl, and R2 is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, =0 and NR8R9. In some embodiments, R2 is selected from C6-ioaryl and heteroaryl, and R2 is unsubstituted or substituted with one or two substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl and =0. . In some embodiments, R2 is selected from phenyl and Ce-heteroaryl, and R2 is substituted with one to three substituents selected from F, CF2H, CF3 and =0.

[00103] In some embodiments, R is selected from:


[00104] In some embodiments, R2 is selected from


or a tautomer thereof.

[00105] In some embodiments, R2 is selected from:


tautomer thereof.

[00106] In an embodiment, the tautomer of the R2 group is
or


[00107] In some embodiments, R2 is selected from:


tautomer thereof.

[00108] In some embodiments, R is selected from:

[
00109] In some embodiments,

[00110] In some embodiments, R3 is selected from C6-ioaryl, heteroaryl and heterocycloalkyl, and R3 is substituted with one, two or three substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OR10, NRnR12, R13, Ci-6alkyleneR13, OCi. salkyleneR13, Ci-6alkyleneNRnR12, Ci-6alkyleneOR10, OCi-6alkyleneNRnR12, OCi. salkyleneOR10, C(0)OR10 and C(0)NRnR12. In some embodiments, R3 is selected from C6-ioaryl, heteroaryl and heterocycloalkyl, and R3 is substituted with one or two substituents selected from halo, CN, Ci-6alkyl, Ci.6fluoroalkyl, OR10, NRnR12, R13, Ci-6alkyleneR13, OCi-6alkyleneR13,
Ci-6alkyleneOR10, OCi. salkyleneNR^R1" and OCi-6alkyleneORlu. In some embodiments, R is selected from C6-ioaryl, heteroaryl and heterocycloalkyl, and R3 is unsubstituted or substituted with one or two substituents selected from halo, CN, C1-6alkyl, OR10, NRnR12, R13 and OCi-6alkyleneR13. In some embodiments, R3 is heteroaryl, and R3 is substituted with one substituent selected from halo, CN, Ci-6alkyl, OR10, NRnR12, R13 and OCi. 6alkyleneR13. In some embodiments, R3 is heteroaryl, and R3 is substituted with one substituent selected from R13. In some embodiments, R3 is phenyl. In some embodiments, R3 is selected from monocyclic Cs-eheterocycloalkyl and monocyclic Cs. 6heteroaryl. In some embodiments, R3 is selected from 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-tetrahydropyridinyl, piperazinyl, mo holinyl, thiomo holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl. In some embodiments, R3 is selected from phenyl, pyridinyl, pyrimidinyl and dihydropyridinyl.

[00111] In some embodiments, R5 and R6 are independently selected from Η,

Ci-6alkyl and heterocycloalkyl. In some embodiments, R5 and R6 are independently selected from Η and Ci-6alkyl. In some embodiments, R5 and R6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one, two or three substituents selected from halo and Ci-6alkyl. In some embodiments, R5 and R6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.

[00112] In some embodiments, R10 is selected from Η, Ci-6alkyl, Ci_

6fiuoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci_

6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci_

6alkyleneheterocycloalkyl. In some embodiments, R10 is selected from Η, Ci-6alkyl, Ci_

6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, Ci-ealkyleneCs-iocycloalkyl and Ci. 6alkyleneheterocycloalkyl. In some embodiments, R is selected from H, Ci-6alkyl, Ci_ 6fluoroalkyl, heterocycloalkyl and Ci-6alkyleneC3-iocycloalkyl. In some embodiments, R10 is selected from Ci-6alkyl and Ci-6fluoroalkyl. In some embodiments, R10 is an unsubstituted or substituted monocyclic heterocycloalkyl selected from 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, 1,2,3,6-tetrahydropyridinyl, piperazinyl, mo holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl In some embodiments, R10 is morpholinyl.

[00113] In some embodiments, R11 and R12 are each independently selected from

Η, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci_ 6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl. In some embodiments, R11 and R12 are each independently selected from Η, Ci-ioalkyl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl. In some embodiments, R11 and R12 are each independently selected from Η, Ci-ioalkyl and C3-iocycloalkyl. In some embodiments, R11 and R12 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.

[00114] In some embodiments, R13 is selected from C(0)Ci-6alkyl, C3-locycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl. In some embodiments, R13 is selected from C3-iocycloalkyl and heterocycloalkyl. In some embodiments, R13 is heterocycloalkyl. In some embodiments, R13 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, 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-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl,

4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl. In some embodiments, R is morpholinyl.

[00115] In some embodiments, X1 and X2 are each independently selected from CR17 and N, in which R17 is selected from H and Ci-6alkyl. In some embodiments, both of X and X are CR , in which R is H. In some embodiments, one of X and X2 is CR17 and the other of X1 and X2 is N, in which R17 is H.

[00116] 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-l-yl)-5-[3-(mo holin-4-ylmethyl)phenyl]phenyl]- 6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-mo holin-4-ylpyrirnidin-5-yl)phenyl]-6- oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(6-mo holin-4-ylpyridin-3-yl)phenyl]-6- oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(l ,3-benzodioxol-5-yl)-4-fluoro-2-(4-methylpiperazin- 1 -yl)phenyl] -6-oxo-4- (trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-[(3R)-3,4-dimethylpiperazin-l-yl]-4-fluoro-5-(2-mo holin-4-ylpyrimidin-5- yl)phenyl]-6-oxo-4-(mfluoromethyl)-lH^yriine-3-carboxamide;

N-[2-[(3S)-3,4-dimethylpiperazin-l-yl]-4-fluoro-5-(2-moφholin-4-ylpyrimidin-5- yl)phenyl]-6-oxo-4-(mfluoromethyl)-lH^yriine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrirmώn-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(mfluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2^yrrolidin-l-ylpyrimidin-5-yl)phenyl]-6- oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-l- yl)phenyl]-6-oxo-4-(mfluoromethyl)-lH^yriine-3-carboxamide;

N-[5-[2-(cyclohexylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-ethoxypyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-methylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclohexylamino)pyridin-3-yl]-4-fluoro-2-(4-me1hylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 -(2-hydroxypyrimidin-5 -yl)-2-(4-methylpiperazin- 1 -yl)phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[2-(2,2,2-trifluoroe1hoxy)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-pyrimidin-5-ylphenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2,4-dime1hoxypyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N- [4-fluoro-2-(4-methylpiperazin- 1 -yl)-5 -(2-morpholin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo- 1 H-pyridine-3 -carboxamide;

N-[2-[3-(dimethylamino)pyrrolidin-l-yl]-4-fluoro-5-(2-moφholin-4-ylpyrimiώ yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(l,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -3-methylbenzamide;

6-acetamido-N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-

trimethylpiperazin- 1 -yl] phenyl] -4-(tafluoromethyl)pyridine-3 -carboxamide;

4- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,5-dimethylbenzamide;

N-[4-fluoΓO-5-(4-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[6-(oxan-4-yloxy)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2-me lpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-pyridin-3-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5^yridin-4-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] -4-fluoro-5-(2-mo holin-4-ylpyrimidin- 5- yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-[(3S)-3-(dimethylamino)pynOlidin^

5- yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(dimethylamino)pyrimidin-5-yl] -4-fluoro-2-(4-methylpiperazin- 1 -yl)phenyl] - 6- oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[6-(mo holin-4-ylmethyl)pyridin-3-

yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -3 -(trifluoromethyl)- lH-pyrazole-4-carboxamide;


yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;

N-(3 '-((cyclopentylamino)methyl)-6-fluoro-4-(4-methylpiperazin- 1 -yl)- [ 1 , 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;


yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;

N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-mo holinopyridin-4-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;

N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(5-(moφholinomethyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide;

N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,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)-l,6-dihydropyridine- 3-carboxamide;

(R)-N-(4-(3 ,4-dimethylpiperazin- 1 -yl)-6-fluoro-3 '-(moφholinomethyl)- [ 1 , 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;


3-yl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide;

N-(6-fluoro-3 '-(moφholinomethyl)-4-((3R,5 S)-3,4,5 -trimethylpiperazin- 1 -yl)- [ 1 , Γ-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;

N-(4-(3-(dimethylamino)pyrrolidin- 1 -yl)-6-fluoro-3 '-(moφholinomethyl)- [ 1 , 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide;

N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-moφholin-4-ylpyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

2 difluorome l)-N-(5 2 (2S,6R)-2,6-dime lmo holino) yrimidin-5-yl)-2-((S)-3,4-dime1hylpiperazin-l-yl)-4-fluorophenyl)-4-fluorobenzamide;

N-[5-(l,3-benzodioxol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -4-methoxy-6-oxo- 1 H-pyridine-3 -carboxamide;

N-[5-[2-(cyclopropylmethoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-[(cyclohexylamino)methyl]phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3-cWoro-4-moφholin-4-ylphenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[5-(3,4-dihydro-2H-l,5-benzodioxepin-7-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2,3-dihydro-l,4-benzodioxin-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(4-methyl-2,3-dihydro-l,4-benzoxazin-7-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-acetamidopyrimidin-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-phenyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-

carboxamide;

N-[4-fluoro-5-(2-moφholin-4-yl yrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethyl i erazin- 1- yl]phenyl]benzamide;

4- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3-methoxybenzamide;

3,5-dichloro-N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridazine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]furan-2-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]pyridine-3-carboxamide;

N-[4-fluoro-5 2-moφholin-4-ylpyridin-4-yl)-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(3-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrirmdin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -2-methoxybenzamide;

2- c^lloro-4-fluoro-N-[4-fluoro-5-(2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

5- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrirnidin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[5-chloro-6-(2-methylpropoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[3-chloro-4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]-5-(l,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yljphenyl] -3 -(tafluoromethyl)- 1 H-pyrazole-4-carboxamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-3,5-dimethylbenzamide;

N-[5-(3-chloro-5-cyano-4-hydroxyphenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(5-cyano-6-phenylmethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(4-cyanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3-cyanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6- oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(5,6-dime1hoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -1,3 -benzodioxole-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -4-methoxybenzamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(3-fluoro-5-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

2-chloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

2- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3-methoxybenzamide;

3,4-difluoro-N-[4-fluoro-5-(2-mo holin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(4-pyrrolidin-l-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3- acetanlido-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l- yl]phenyl]-l-methylindazole-3-carboxamide;

N-[4-fluoro-5-(4-moφholin-4-yl henyl)-2-[(3R)-3,4-dimethyl i erazin-l-yl] henyl]-1 -methylindazole-3 -carboxamide;

N-[4-fluoro-5 3 [methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[3-[(4-fluoropiperidin-l-yl)methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-(3,4,6,7,9,9a-hexahydro-lH-pyrazino[2, 1 -c] [ 1 ,4] oxazin-8-yl)-4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)phe yl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methylpyrazole-4-carboxamide;

N-[4-fluoro-5-(4-moφholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-1 -methylpyrazole-4-carboxamide;

N-[5-(5-cyano-6-hydroxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphe yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[5-[3-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3 dime lamino)-N-[4-fluoro-5 2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -1,3 -oxazole-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(4-moφholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]- l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(2-propan-2-yloxypyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trime1hylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[5 -(6-cyanopyridin-3 -yl)-4-fluoro-2-[(3R,5 S)-3,4,5 -trimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(6-cyano-5-methylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-cyanopyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-methoxy-6-(trifluoromethyl)pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-methoxy-6-methylpyridin-4-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-cyano-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-methoxypyridine-3-carboxamide;

3-chloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

2,6-dichloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

3-chloro-2-fluoro-N-[4-fluoro-5-(2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(2-moφholin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

tert-butyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carbonyl]amino]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-[4- (trifluoromethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-[4-(tafluoromethoxy)phenyl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-phenyl-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 4-cWorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 6-me lpyridazin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(2-methylpropyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin^-yl]-5 1 3,3,3-trifluoropropyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-

carboxamide;

N-[4-fluoro-5 1-^yridin-3-ylme1hyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin -yl]-5 1 thiophen-3-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[5-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-piperazin-l-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazm yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3-cωoro-5-fluoro-N-[4-fluoro-5 2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

3.5- difluoro-N-[4-fluoro-5 2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-5-yl]-2-[(3S,5R)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]-5 1 l,3-tliiazol-2-ylme1hyl)- 3.6- dihydro-2H-pyridin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 -[ 1 -[(2-methyl- 1 ,3 -oxazol-5 -yl)methyl] -3 ,6-dihy dro-2H-pyridin-4-yl] -2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-

pyridine-3-carboxamide;

N-[4-fluoro-5-[ 1 -[(4-moφholin-4-yl henyl)methyl] -3,6-dihydro-2H-pyridin-4-yl] -2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-3,6-dihydro-2H^yridin^

4-yl]-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(oxan-4-ylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3,5-dichloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] phenyl] benzamide;

3,5-dichloro-N-[4-fluoro-5-(4-moφholin-4-ylphenyl)-2-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] phenyl] benzamide;

N-[5-(5-cyano-6-moφholin-4-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(5-methyl-6-mo holin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]-5 5 trifluoromethyl)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[5-(tert-butylcarbamoyl)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3-chloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-

trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide;

3- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide;

N-[4-fluoro-5-(4-moφholin-4-ylphenyl)-2-[(3R)-3-(dimethylan^ino)pyn·olidin-l-yljphenyl] - 1 H-pyrazole-4-carboxamide;

N-[4-fluoro-5-(5-methylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(5-carbamoylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin -yl]-5 5 trifluoromethyl)pyridin-3-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-methyl-l,3-thiazole-2-carboxamide;

2-[(dimethylarrino)methyl]-N-[4-fluoro^

3,4-dimethylpiperazin- 1 -yl] phenyl] -1,3 -thiazole-4-carboxamide;

4- chloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] - lH-pyrazole-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dime1hylamino)pyrrolidi^ 1 -yl] phenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrirnidin-5^

1 -yl] phenyl] -3 -(trifluoromethyl)- lH-pyrazole-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -3 -(trifluoromethyl)benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1- yl]phenyl]-4-(trifluoromethyl)pyrimidine-5-carboxamide;

N-[4-fluoro-5-(2-moφholin-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-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide;

3- fluoro-N-[4-fluoro-5-(2-moφholin-4-yl yrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-methoxybenzamide;

3,5-dichloro-N-[4-fluoro-5-(4-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methylpyrazole-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-lH-pyrazole-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-2-methyl-l,3-thiazole-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-2-methyl-l,3-thiazole-5-carboxamide;

N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-2-methyl-4-(trifluoromethyl)-l,3-thiazole-5-carboxamide;

3,5-dichloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- 1 H-pyridine-3-carboxamide;

4- fluoro-N-[4-fluoro-5-[2 4-me1hyl-l,4-diazepan-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide;

N-[4-fluoΓO-5-(4-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-(5-cyanopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(5-chloropyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2-cyclohexyloxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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^yrrolidin-l-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -3 -(trifluoromethyl)thiophene-2-carboxamide;

3,5-dichloro-4-fluoro-N-[4-fluoro-5 2-moφholin-4-ylpyrin^idin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzamide;

2,3-dichloro-N-[4-fluoro-5-(2-moφholin-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)- 1 H-pyridine-3-carboxamide;

N-[5-(5-ethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(2-moφholin-4-ylpyrin^idin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]- 4-(difluoromethyl)- 1 -methyl-6-oxopyridine-3 -carboxamide;

N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)- 1 -methyl-6-oxopyridine-3 -carboxamide;

N-[5-[6-(dimethylarrdno)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpipera^ yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 5-cyano-6 dime larnino)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(dimethylamino)-5-fluoropyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[5-(5-chloro-6-moφholin-4-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

2 difluoromethyl)-N-(2-((S)-3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-((S)-2-methylmoφholino)pyrimidin-5-yl)phenyl)-4-fluorobenzamide;

N-[4-fluoro-5 -(2-moφholin-4-ylpyrimidin-5 -yl)-2-(3 ,3 ,4-trimethylpiperazin- 1 -yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide;

N-[4-fluoro-5 2-moφholin-4-ylpyridin-4-yl)-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5 4^yrrolidin-l-ylphenyl)-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fl^

yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

2,3-difluoro-N-[4-fluoro-5 2-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

2-chloro-4-fluoro-N-[4-fluoro-5-(2-mo holin-4-yl yrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

N-[5-(l-cyclopentyl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(l-butan-2-yl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5^iperidin-4-yl-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3- (dimethylarrino)pyrrolidin-l-yl] phenyl] -6^

carboxamide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2^ropan-2-yloxypyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3- carboxamide;

N-[4-fluoro-5 1 l-methylpiperidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(2,2-dimethylpropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 l-pyrirnidin-2-yl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-5-yl]-2-[(3S,5R)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphe 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-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-(l-methylsulfonyl-2,5-dihydropyrrol-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-(l-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-

carboxamide;

ethyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

2-methylpropyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-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,5 S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(6-fluoropyridin-3-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2 4-(dimethylamino)piperidin^^

yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-[4-[2-(dimethylan^ino)ethyl]piperazin-l-yl]-4-fluoro-5-(2-mo holin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[2-[2-[(dimethylan^ino)methyl]mo holin-4-yl]-4-fluoro-5-(2-mo holi^ ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-(6^yrrolidin-l-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(5-cyano-6-pyrrolidin-l-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(2,2-difluoro-l,3-benzodioxol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

3-οωοΓθ-4-ΑυοΓθ-Ν-[4-ΑυοΓθ-5-(2^οφΗο1ίη-4^^ήηιίά-η-5^1)-2-[(3Κ,58)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

3-chloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-methoxybenzamide;

3-οωοΓθ-2,4-ώΑυοΓθ-Ν-[4-ΑυοΓθ-5-(2^οφΗο1ίη-4^1ρ^ηιίώη-5^1)-2-[(3Κ,58)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzamide;

N-[4-fluoro-5-(l-methyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(2-moφholin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[5-(6-cyano-4-methylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-pyridin-2-yl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-me lpyrirnidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrirnidin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 1 5-chloropyrirnidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

ethyl 2-[4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridin-l-yl]pyrimidine-4-carboxylate;

N-[4-fluoro-2-[3-(methylan^ino)pyrrolidin-l-yl]-5-(2-moφholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[2-[3-[(dimethylamino)methyl]pyrrolidin- 1 -yl] -4-fluoro-5-(2-mc^holin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-(4-methylpiperazin-l-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-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3-hydroxy-5-(trifluoromethyl)benzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -3 -hydroxybenzamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -3 -hydroxy quinoline-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dime1hylamino)pyrroliώ^ 1 -yl] phenyl] - 1 -methyl-3 -(trifluoromethyl)pyrazole-4-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide;

N-[5-[l-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(pyrrolidine-l-carbonyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 -[ 1 -(4-methylpiperazine- 1 -carbonyl)-3 ,6-dihy dro-2H-pyridin-4-yl] -2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

phenyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

N-[4-fluoro-5-[l-[(2R,6S)-2,6-dimethyloxan-4-yl]-3,6-dihydro-2H-pyridin-4-yl]-2- [(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-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-mo holin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-hydroxybenzamide;

N-[5-[2-(cyclobutylmethoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(2,2-dimethylpropoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(diethylamino)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpipera^ 1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

3- fluoro-N-[4-fluoro-5-(2-moφholin-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-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] benzamide;

2- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-(trifluoromethyl)benzamide;

4- fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-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-l-yl]-5-(2-moφholin-4-ylpyrimidin-5 -yl)phenyl] benzamide;

N-[4-fluoro-5-[6-(4-methylpiperazin-l-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-l-yl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-2-[3-[methyl(propyl)amino]pyrrolidin-l-yl]-5-(2-moφholin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

3,5-dichloro-N-[4-fluoro-2-[3-[methyl ropyl)amino]pyn·olidin-l-yl]-5-(2-mo holin-4-ylpyrimidin-5-yl)phenyl]benzamide;

N-[5-[l-[2-(dime lamino)acetyl]-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-[4-[5-[2-fluoro-5-[[6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]pyrimidin-2-yl]piperazin-l-yl]-4-oxobutanoic acid;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-(dime1hylan^ino)-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-(dime1hylamino)-4-fluoropyrrolidin- 1 -yl] phenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3 -carboxamide;

N-[4-fluoro-2-moφholin-4-yl-5-(2-piperazin-l-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,4R)-3-(dime1hylan^ino)-4-fluoropyrrolidin- 1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,4R)-3-(dime1hylamino)-

4-fluoropyn-olidin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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)- 1 H-pyridine-3-carboxamide; tert-butyl 4-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-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- 1 H-pyridine-3-carboxamide;

l-ethyl-N-[4-fluoro-5-(2-mo holin-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-l-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

2,3-dichloro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

N-[4-fluoro-2-[(3R)-3,4-dime lpiperazin-l-yl]-5-[2-(2,2,6,6-tetramethylmoφholin-4-yl)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-[2-(2,2,6,6-tetramethylmo holin-4-yl)pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)-lH-pyrazole-3-carboxamide;

tert-butyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carbonyl]amino]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yl]phenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

tert-butyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carbonyl]amino]-4- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate; tert-butyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate;

tert-butyl 5-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]armno]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3,6-ihydro-2H pyridine- 1 -carboxylate;

tert-butyl 3-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate;

tert-butyl 3-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate;

N-[4-fluoro-2 (3R,5S)-3,4,5-trime lpiperazin^-yl]-5 l,2,3,64etrahydropyridin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carboxarnide;

N-[5 2,5-dihydro-lH-pyrrol-3-yl)-4-fluoro-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carboxarnide;

N-[5 8-azabicyclo[3 ]oct-2-en-3-yl)-4-fluoro-2 (3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

4 difluorome l)-N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

N-[5 2-butan-2-yloxypyriin-4-yl)-4-fluoro-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyriine-3-carboxarnide;

N-[4-fluoro-5 2-moφholin-4-ylpyrirniώn-5-yl)-2 (3R,4R)-3 dime lan^ino)-4-methoxypyrrolidin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(l-pyrirnidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-pyrimidin-2-yl-2,5-dihydropyrrol-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 8-pyrirnidin-2-yl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

N-[4-fluoΓO-2-[(3R)-3,4-dimethylpipeΓazin-l-yl]-5-[2-[(3R)-3-methylmoφholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide;

N-[4-fluoro-5-[2-[(3R)-3-methylmo holin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2-moφholin-4-yl ,4,5,6 etrahydropyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3S)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methylmoφholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide;

N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2-moφholin-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-moφholin-4-ylpyrimidin-5-yl)-2-[(lR,4R)-5-methyl-2,5-diazabicy clo[2.2.1 ]heptan-2-yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2 (3R,4R)-3 e l(me l)an^ino]- 4-fluoropyn-olidin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- [e1hyl(methyl)amino]pyrrolidin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine- 3- carboxamide;

N-[4-fluoro-5 2-moφholin-4-yl yrimidin-5-yl)-2 (3R,4R)-3 e l(me l)amino]- 4- fluoropyrrolidin- 1 -yl] phenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3 -carboxamide;

N-[4-fluoro-2 (3R)-3,4-dime lpiperazin-l-yl]-5-[2-[(2R)-2-propan-2-ylmoφholin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide;

N-[4-fluoro-5-[2-[(2R)-2-propan-2-ylmoφholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(2,2-dimethylmo holin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[5-[2-(2,2-dimethylmoφholin-4-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-7-(trifluoromethyl)-[l,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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphenyl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmoφholin-4-yl]pyrimidin-5-yl]-2-[(3R,5R)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-(3-ΑυοΓθ-4^οφΗο1ίη-4^1 Η^1)-2-[(3Κ,5Κ)-3,4,5-ίήηΐ6^1 ί 6Γ3ζίη-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2 (3R,4R)-3 e l(me l)an^ino]-4-methoxypyrrolidin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-5-yl]-2-[(3S,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 me l-[(3R)-oxolan-3-yl]amino]pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-[me l-[(3R)-oxolan-3-yl]amino]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-[l-(6-methoxypyrimidin-4-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(5-fluoropyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-fonnylpyrirnidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 1 dime lcarbamoyl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

ethyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

N-[4-fluoro-5-[l-(pyrrolidine-l-carbonyl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-me lpyrirnidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

4-fluoro-N-[4-fluoro-5-[2 4-me lpiperazin-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[5 2 dime lamino)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-l-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-me1hylpiperazin-l-yl)pyrimidin-5-yl]-2-[(3R,5R)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4- (difluorome l)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin- 5- yl] -2-[(3R)-3,4-dimethylpiperazin- 1 -yl]phenyl] -1 -methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridazin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

4- (difluorome l)-N-[4-fluoro-5-[2-[(2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin- 5- yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-(difluorome l)-N-[4-fluoro-5-[2-[(2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5R)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-[2-[(2R)-2-methylmo holin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methylmo holin-4- yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R)-2-methylmo holin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 l^yrirnidin-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-l-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(4-pyrimidin-2-ylpiperazin^

yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[5-(hydroxymethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin-5-yl]-2-[(3S)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-lH^yridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methyln ^holin-4-yl] pyrimidin-5 -yl] phenyl] -6-oxo- lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH^yridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methylmoφholin-4-yl] pyrimidin-5 -yl] phenyl] -6-oxo- lH-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)- lH-pyridine-3 -carboxamide;

4-fluoro-N-[4-fluoro-5-[2-(4-methyl-l,4-diazepan-l-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(2-piperazin-l-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(6-moφholin-4-yl yridin-3-yl)-2-[(3R)-3,4-dimethyl i erazin-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- 1 H-pyridine-3-carboxamide;

N-[5-[l-(5-cyanopyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-[5-[(dimethylamino)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl^ fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[5-(moφholin-4-ylmethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin- 4-yl]-2 (3R,5S)-3,4,5-trime lpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[5-[(4-methylpiperazin-l-yl)methyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4- (trifluoromethyl)-lH-pyridine-3-carboxamide;

2-methylpropyl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine- 1 -carboxylate;

N-[4-fluoro-5 1 5-fonnylpyrirnidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(MuoΓomethyl)-N-[4-fluoΓO-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxarnide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxarnide;

N-[4-fluoro-5-[l-[5-(hydroxymethyl)pyrimidin-2-yl]-3,6-dihydro-2H-pyridin-5-yl]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-[5-[(dimethylarrino)methyl]pyri

fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-[1-[5-^οφ^1ίη-4^^6&^

5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[5-[(4-methylpiperazin-l-yl)methyl]pyrimidin-2-yl]-3,6-dihydro-2^ pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4- (trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3S)-3 dime lamino)pyrrolidin-l-yl]-5-[2-[(2R,6S)-2,6-dimethylmo holin-4-yl]pyrimidin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[^[(21^6S)-2,6-dinie lmor^

[ethyl(methyl)amino]pyrrolidin-l-yl]ph^

3- carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(diethylamino)pyrrolidin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrin^idin-5-yl)-2-[(3R)-3-[methyl(propan-2-y^aminolpyn-olidin-l-ylJphenylJ-e-oxo^-^rifluoromethy^-lH-pyridine-S-carboxamide;

N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmoφholin-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-dimethylmoφholin-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-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3R)- 3,4-dime1hylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide;

N-[4-fluoro-5 2 4-hydroxy-4-methylpiperidin-l-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5 2 4½droxy-4-methylpiperidin-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2 (3S)-3 dime lamino)pyrrolidin-l-yl]-5-[2-[(2R,6S)-2,6-dimethylmo holin-4-yl]pyrin^idin-5-yl]phenyl]-l-methyl-6-oxo-4- (trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-5-yl]-2-[(3S)-3-[ethyl(methyl)amino] pyrrolidin- 1 -yljphenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(diethylamino)pyrrolidm^ 1 -yl] phenyl] - 1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3 -carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrin^idin-5-yl)-2-[(3R)-3-[methyl(propan-2-y^aminolpyn-olidin-l-yllphenyll-l-methyl-e-oxo^-^fluoromethy^pyridine-S-carboxamide;

4-fluoro-N-[4-fluoro-5-[2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin-5-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl]phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-[2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluorome1hyl)benzamide;

4-fluoro-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluorome1hyl)benzamide;

N-[4-fluoro-2 (3R)-3,4-dime lpiperazin-l-yl]-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3 -yl] phenyl] -6-oxo-4-(tafluoromethyl)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(4-cyclopropylpiperazin-l-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-moφholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-methoxypyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(6-methoxypyrimidin-4-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-me lpyrirnidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 1 5-fluoropyrimidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(pyrrolidine-l-carbonyl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(pyrazine-2-carbonyl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

2-methylpropyl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate;

N-[4-fluoro-5 1 5-fonnylpyrirnidin-2-yl)-2,5-dihydropyrrol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-methylpyrazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-

yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 4-cyano-l,3-thiazol-2-yl)-4-fluoro-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 5-cyano-l,3-thiazol-2-yl)-4-fluoro-2 (3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-moφholin-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-dime lpiperazin-l-yl]-5-[2-[(2R)-2-methylmo holin-4-yl]pyrimidin-5-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R)-2-me lmo holin-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-l-yl]-5-[2-[(2R)-2-methylmoφholin-4-yl] pyrimidin-5 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-[2-[(2R)-2-me1hylmoφholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide;

N-[5-[2-(4-cyclopropylpiperazin-l-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-l-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-l-yl]-5-[2-[(2R)-2-

N-[5-[l-[5-[(dimethylaniino)methyl]pyrirnidin-2-yl]-2,5-dihydropyn-ol-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl]phenyl] -6-oxo-4-(tafluoromethyl)- 1H-pyridine-3-carboxamide;

N-[4-fluoro-5-[ 1 -[5-(moφholin-4-ylmethyl)pyrimidin-2-yl] -2,5-dihydropyrrol-3-yl] -2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-[5-[(4-methylpiperazin-l-yl)methyl]pyrimidin-2-yl]-2,5-dihydropyrrol-3 -yl] -2-[(3R,5 S)-3 ,4,5 -trimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methylmc^holin-4-yl] pyrimidin-5 -yl] phenyl] - 1 -methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin- 5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-2,3,3a,4,6,6a-hexahy dro- 1 H-pyrrolo [2,3 -c] pyrrol -5-yl]phenyl] -6-oxo-4-(tafluoromethyl)- 1H-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-piperazin- 1 -ylpyrirnidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxarnide;

4-fluoro-N-[4-fluoro-5-[2-(4^ropan-2-ylpiperazin-l-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-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)berizarnide;

N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-l-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-l-yl]-5-[2-[(3R)-3-methylmo holin-4-yl]pyrirmdin-5-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxainide;

N-[4-fluoro-5-[2-[(3R)-3-methylmo holin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-

trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

(1-methylcyclobutyl) 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine- 1 -carboxylate;

(1-methylcyclobutyl) 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine- 1 -carboxylate;

(1-methylcyclobutyl) 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate;

N-[4-fluoro-5-(6-moφholin-4-ylpyriώn-2-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 -(6-moφholin-4-ylpyrazin-2-yl)-2-[(3R,5 S)-3 ,4,5 -trimethylpiperazin- 1 -yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluorome l)-N-[4-fluoro-5-[2-[(3R)-3-me lmoφholin-4-yl]pyrimidin-5-yl]-2- [(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-l-propyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(mfluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3aR,6aR)-l-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]phenyl]-6-oxo-4-(mfluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(3-fluoro-4-moφholin-4-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,4,5-tetramethylpiperazin-4-ium- 1 -yl]phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-methylmorpholin-4-yl] pyrimidin-5 -yl] phenyl] - 1 -methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2- [(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiazole-4-carboxamide;

N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-4-carboxamide;

N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiazole-4-carboxamide;

N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-4-carboxamide;

N-[4-fluoro-5-[4-(moφholine-4-carbonyl)-l,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 4 4-me lpiperazine-l-carbonyl)-l,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

(3-methyloxetan-3-yl) 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine- 1 -carboxylate;

(3-methyloxetan-3-yl) 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine- 1 -carboxylate;

(3-methyloxetan-3-yl) 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate;

Ν-[4-ΑυοΓθ-5-[5-(ηιοφ1ιο1ίη-4^1ηΐ6 1)ύιίορ1ΐ6η-2^1]-2-[(3Κ,58)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-thiophen-2-ylphenyl]-6-o 4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-thiophen-3-ylphenyl]-6-ox 4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-[5-(ηιοφ1ιο1ίη-4^1ηΐ6 1)ύιίορ1ΐ6η-3^1]-2-[(3Κ,58)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-5-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiaz^ carboxamide;

N-(cyclopropylmethyl)-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-5-carboxamide;

N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(tafluoro

carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiaz^ carboxamide;

N-cyclohexyl-2-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]arruno]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,^ thiazole-5-carboxamide;

N-[4-fluoro-5-[5-(moφholine-4-carbonyl)-l,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH^yridine-3-

carboxamide;

N-[4-fluoro-5 5 4-me lpiperazine-l-carbonyl) ,3-thiazol-2-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

5-amino-4-fluoro-N-[4-fluoro-5 2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[5-[l-(6-cyclopropylpyridazin-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(6-ethylpyridazin-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]phenyl]-6-oxo-lHφyridine-3-carboxan^ide;

4 difluorome l)-N-[4-fluoro-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH^yridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-yl]-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]phenyl]-6-oxo-lHφyridine-3-carboxan^ide;

4 difluorome l)-N-[4-fluoro-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH^yridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 6 (2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

5-amino-4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrin^idin-5-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5 2-moφholin-4-yl yrimidin-5-yl)-2-[(3aR,6aR)-l-ethyl-2,3,3a,4,6,6a-hexahydropyn-oloP^-cJpyrrol-S-ylJphenylJ-e-oxo^-^fluoromethy^-lH-pyridine-S-carboxamide;

4 difluorome l)-N-[4-fluoro-5 6 (2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl] -2-[(3 S)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- lH-pyridine-3 -carboxamide;

4 difluorome l)-N-[4-fluoro-5 6 (2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3S)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-yl]-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]phenyl]-l-me1hyl-6-oxopyridine-3-carboxan^ide;

4-(difluoromethyl)-N-[4-fluoro-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]-2- [(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5-[6-[(2R,6S)-2,6-dimethylmoφholin-4-yl]pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]phenyl]-l-me1hyl-6-oxopyridine-3-carboxan^ide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-[methyl(2,2,2-trifluoroethyl)amino] pyrrolidin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

4-(difluorome l)-N-[4-fluoro-5-[2-[(3R)-3-me lmoφholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxarnide;

N-(cyclopropylmethyl)-4-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l,3-thiazole-2-carboxamide;

N-(cyclopropylmethyl)-4-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-

carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-2-carboxamide;

N-cyclohexyl-4-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiazole-2-carboxamide;

N-cyclohexyl-4-[2-fluoro-5-[[l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-2-carboxamide;

N-[4-fluoro-5-[2-(moφholine-4-carbonyl)-l,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-me lpiperazine-l-carbonyl)-l,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-l-ylphenyl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(6-piperazin-l-ylpyridin-3-yl)-2-[(3R)-3,4-dimethylpiperazin-1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-(cyclopropylmethyl)-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiazole-2-carboxamide;

N-(cyclopropylmethyl)-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-N-methyl-l,3-thiazole-2-carboxamide;

N-cyclohexyl-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-l,3-thiazole-2-carboxamide;

N-cyclohexyl-4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-N-methyl-l,3- thiazole-2-carboxamide;

N-[4-fluoro-5-[2-(moφholine-4-carbonyl)-l,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 4-me lpiperazine-l-carbonyl) ,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[2-(cyclohexylamino)pyrimidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-(methylamino)pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiper^ 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

N-[5-(2-cyanopyrimidin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 2 dime lamino)pyrimidin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[4-(methylamino)piperidin-l-yl]-5-(2-moφholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5-[6-[(2R)-2-methylmoφholin-4-yl]pyridin-3-yl]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-2 (3S)-3,4-dimethylpiper^

yl]pyrimidin-5-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

4-fluoro-N-[4-fluoro-5-[2 (2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(2-piperazin-l-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-

trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

4-fluoro-N-[4-fluoro-5-(6-moφholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-(6-piperazin-l-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(4-piperazin-l-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

2-fluoro-5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

2-fluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-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-l-yl)pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-fluoro-2-(trifluoromethyl)benzamide;

N-[5-[2-(2,2-dimethylmo holin-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-dimethylmo holin-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-l-yl]pyrimidin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-fluoro-2-(trifluoromethyl)benzamide;

N-[2-(4-cyclo ro yl i erazin-l-yl)-4-fluoro-5-(2-moφholin-4-yl yrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(5-fluoro-6-oxo-lH-pyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

benzyl N-[5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]pyridin-3-yl]carbamate;

N-[4-fluoro-5-(5-fluoro-l-methyl-6-oxopyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[ 1 -(4-methoxybenzoyl)-3,6-dihydro-2H-pyridin-4-yl] -2-[(3R,5 S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-oxo-l,3-dihydropyrrolo[2,3-b]pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 l-me l-2-oxopyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-methyl-6-oxopyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 1 cyclohexanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

tert-butyl N-[l-[2-[(3,5-dicWorobenzoyl)amino]-5-fluoro-4-(2-moφholin-4-ylpyrimidin-5 -yl)phenyl] pyrrolidin-3 -yl] -N-methylcarbamate;

3,5-dichloro-N-[4-fluoro-2-[3-[3-methoxypropyl(methyl)amino]pyrrolidin-l-yl]-5-(2-moφholin-4-ylpyrimidin-5-yl)phenyl]benzan^ide;

N-[4-fluoro-2-[3-[3-methoxypropyl(methyl)amino]pyrrolidin-l-yl]-5-(2-moφholin-4-ylpyrimidin-5 -yl)phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-[ 1 -(pyrazine-2-carbonyl)-3,6-dihydro-2H-pyridin-4-yl] -2-[(3R,5 S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(mfluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- [methyl(methylsulfonyl)amino]pyrrolidin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- [methyl(methylsulfonyl)amino]pyrrolidin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-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-moφholin-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-moφholin-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-moφholin-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-moφholin-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-l-yl]phenyl]-6-oxo-4-(mfluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-(methanesulfonamido)pyrirnidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(5-cyanopyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-

3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-methylsulfonyl-3,6-dihydro-2H-pyridin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(l-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-(2^οφηο1ίη-4^1ρ^ι^

[cyclopropylmethyl(methyl)amino]pyrro^^

lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-2 (3R)-3,4-dime lpiperazin-l-yl]-5-[2-[(2R)-2-methylmo holin-4-yl]pyrimidin-4-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide;

N-[4-fluoro-5 2 (2R)-2-me lmo holin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-

carboxamide;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

N-[5-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 3-fluoro-4 methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 4-fluoro-3 methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-(4-moφholin-4-ylpyrimidin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

propan-2-yl 3-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,5-dihydropyrrole-l-carboxylate; propan-2-yl 5-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]- 4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

propan-2-yl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]- 4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[4-fluoro-3-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-[4-fluoro-3-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-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-dime lpiper^

yl]pyrimidin-5-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxami

N-[4-fluoro-5-(6-fluoropyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[6-(trifluoromethyl)pyridin-2-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-5-[2 (2R)-2-me lmoφholin-4-yl]pyrimidin-5-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,5-dimethylbenzamide;

4-(Difluoromethyl)-N-(4-fluoro-5 -(1 -(pyrrolidine- 1 -carbonyl)-2,5 -dihydro- 1 H-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-me1hylpiperidin-l-yl)pyrimidin-5-yl]-2-[(3R)-3,4-dime1hylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)berizarnide;

4-fluoro-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[5-[l-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-yl-l,3-thiazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorornethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-yl-l,3-t^liazol-4-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

N-[4-fluoro-5-(2-moφholin-4-yl-l,3-t^liazol-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

N-[4-fluoro-5-(2-moφholin-4-yl-l,3-thiazol-5-yl)-2-[(3R,5S)-3,4,5-

trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(MuoΓomethyl)-N-[4-fluoΓO-5-(2-moφholin-4-yl-l,3-1hiazol-4-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4-(MuoΓomethyl)-N-[4-fluoΓO-5-(2-moφholin-4-yl-l,3-1hiazol-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5-(2-moφholin-4-yl-l,3-thiazol-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5-(2-moφholin-4-yl-l,3-thiazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

2,4-difluoro-5-[2-fluoro-5-[[4-fluoro-2-(ta^

3,4,5-trimethylpiperazin-l-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide;

2,4-difluoro-5 2-fluoro-5 [4-fluoro-2 trifluorome l)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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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-l-yl]phenyl]-6-oxo- 1 H-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(3R)-3-methylrt ^holin-4-yl] pyrimidin-5 -yl] phenyl] -6-oxo- lH-pyridine-3-carboxamide

(S)-4-(Sifluoromethyl)-N-(2-(3,4-dimethylp^

1 -carbonyl)-2,5-dihydro- lH-pyrrol-3-yl)phenyl)-6-oxo- 1 ,6-dihydropyridine-3-carboxamide;

1-Methylcyclobutyl 3-(5-(4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxamido)-2-fluoro-4-((3S,5R)-3,4,5 rimethylpiperazin-l-yl)phenyl)-2,5-dihydro-lH-pyrrole-1 -carboxylate;

1-Methylcyclobutyl (S)-3-(5-(4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3- carboxamido)-4-(3,4-dimethylpiperazin-l-yl)-2-fluorophenyl)-2,5-dihydro-lH-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)- lH-pyridine-3 -carboxamide;

N-[5-(5-carbamoyl-2,4-difluorophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trime1hylpiperazin-1 -yl] phenyl] -4-(difluoromethyl)-6-oxo- 1 H-pyridine-3-carboxamide;

2,4-difluoro-5 2-fluoro-5 [4-fluoro-2 trifluorome l)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzamide;

2,4-difluoro-5 2-fluoro-5 [4-fluoro-2 trifluorome l)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

4-fluoro-N-[4-fluoro-5-[2-(4-hydroxy-4-me1hylpiperidin-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluorome1hyl)benzamide;

3,3-Difluorocyclobutyl 3-(5-(4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxamido)-2-fluoro-4-((3S,5R)-3,4,5 rimethylpiperazin-l-yl)phenyl)-2,5-dihydro-lH-pyrrole-1 -carboxylate;

3,3-Difluorocyclobutyl (S)-3-(5-(4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxamido)-4-(3,4-dimethylpiperazin-l-yl)-2-fluorophenyl)-2,5-dihydro-lH-pyrrole- 1 -carboxylate;

(S)-N-(5-(l-(2-cyanopyrimidin-5-yl)-l,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-me lmo holin-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-l-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-[l-(4-cyano-l,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3- carboxamide;

N-[4-fluoro-5-[l-(l,3-oxazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-tamethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(tri

4-(difluoromethyl)-N-[4-fluoro-5-(l-pyrimidin-2-yl-3,6-dihydro-2H-pyridin-5-yl)-2 [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-[l-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 1 5-fonnylpyrimidin-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-[l-(6-methoxypyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

ethyl 5-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5 S)-3,4,5-trimethylpiperazin-l -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

4-fluoro-N-[4-fluoro-5-(l-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-[l-(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-lH-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

N-[5-(4-carbamoyl-3-fluorophenyl)-4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-5-[3-fluoro-4-(methylcarbamoyl)phenyl]-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

2 difluorome l)-4-fluoro-N-[4-fluoro-5 2-mo holin-4-ylpyrin^idin-5-yl)-2-[(3R)- 3,4-dimethylpiperazin- 1 -yl] phenyl] benzamide;

2 difluorome l)-4-fluoro-N-[4-fluoro-5 2-mo holin-4-ylpyrin^idin-4-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] benzamide;

2,6-difluoro-4 2-fluoro-5 [4-fluoro-2 trifluorome l)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzamide;

2,6-difluoro-4 2-fluoro-5 [4-fluoro-2 trifluorome l)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-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)- lH-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- 1 H-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(3R)-3-methylmoφholin-4-yl] pyrimidin-5 -yl] phenyl] -2-(trifluoromethyl)benzamide;

N-[4-fluoro-5-[2-(4-propan-2-ylpiperazin-l-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-dimethylmo holin-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-moφholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

2,3-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluorome l)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-N-(2,4,4-trimethylpentan-2-yl)benzamide;

2,3-difluoro-4-[2-fluoro-5-[[4-fluoro-2-(trifluorome l)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-(trifluorome l)benzoyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzamide;

2,3-difluoro-4 2-fluoro-5 [4-fluoro-2 trifluorome l)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]benzamide;

N-[5-[2,3-Muoro-4-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-4-fluoro-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-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)- lH-pyridine-3 -carboxamide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(6-moφholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-5-(6-moφholin-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)-lH-pyridine-3-carbonyl]amino]- 4-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-2,3,6,7-tetrahydroazepine-l-carboxylate;

N-[4-fluoro-5-(l-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-(3-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 l,3-benzothiazol-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 l,3-benzothiazol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5 l,3-benzothiazol-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4 difluoromethyl)-N-[4-fluoro-5-(l-methylbenzimidazol-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] - 1 -methyl-6-oxopyridine-3 -carboxamide;

4-(difluorome l)-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 l,3-benzothiazol-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[5 l,3-benzothiazol-5-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[5 l,3-benzothiazol-6-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide;

N-[5 1-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

N-[5-[ 1 -(5-cyano- 1 ,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl] -4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-(difluoromethyl)-6-oxo- lH-pyridine-3 -carboxamide;

N-[5-[l-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

N-[5-[l-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-(difluoromethyl)-6-oxo- lH-pyridine-3 -carboxamide;

N-[5-[l-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-fluoro-2-(tafluoromethyl)benzamide;

N-[5-[ 1 -(5-cyano- 1 ,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl] -4-fluoro-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -4-fluoro-2-(tafluoromethyl)benzamide;

N-[4-fluoro-5-[2-[(2R)-2-methylmo holin-4-yl]pyrimidin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-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-me lmo holin-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)- lH-pyridine-3 -carboxamide;

N-[5-[l-(5-cyano-l,3-1hiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmo holin-4-yl]pyrimidin-4-yl]-2-[(3S,5R)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-[(2R,6S)-2,6-dimethylmo holin-4-yl]pyrimidin-4-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- 1 H-pyridine-3-carboxamide;

(1-methylcyclobutyl) 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,3,6,7-tetrahy droazepine- 1 -carboxylate;

N-[5-[ 1 -(5-cyano- 1 ,3-thiazol-2-yl)-2,3,6,7-tetrahydroazepin-4-yl] -4-fluoro-2-[(3R,5 S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[l-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-5-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

(3,3-difluorocyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

(3,3-difluorocyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-lH-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-lH-pyridine-3-carbonyl]arruno]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

(3,3-difluorocyclobutyl) 5-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl] amino] -2-fluoro-4-[(3R)-3,4-dimethylpiperazin- 1 -yljphenyl] -3,6-dihydro-2H-pyridine- 1 -carboxylate;

(3,3-difluorocyclobutyl) 5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)berizoyl]arnino]-4-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -3 ,6-dihy dro-2H-pyridine- 1 -carboxylate;

(3,3-difluorocyclobutyl) 4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)berizoyl]arnino]-4-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -3 ,6-dihy dro-2H-pyridine- 1 -carboxylate;

N-[5-[l-(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- lH-pyridine-3 -carboxamide;

N-[5-[l-(2-cyanopyrimidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-(cyclohexylcarbamoyl)-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-[(2,2-dimethylcyclohexyl)carbamoyl]-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-(cyclopropylmethylcarbamoyl)-3,5-difluorophenyl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[2-(moφholin-4-ylmethyl)-l,3-thiazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5-[l-(2-moφholin-4-ylethyl) yrazol-4-yl]-2-[(3R)-3,4-dimethyl i erazin-1 -yl] phenyl] -6-oxo-4-(trifluoromethyl)- lH-pyridine-3 -carboxamide;

4 difluorome l)-N-[4-fluoro-5-[l-(2-moφholin-4-ylethyl)pyrazol-4-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] - 1 -methyl-6-oxopyridine-3 -carboxamide;

N-[4-fluoro-5-[l-(2-moφholin-4-ylethyl)pyrazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorornethyl)-lH-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-[l-(2-moφholin-4-yle1hyl)pyrazol-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-5-(2-moφholin-4-ylpyrimidin-4-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

N-[4-fluoro-5-(6-moφholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxarnide;

4-(difluorome l)-N-[4-fluoro-5-(2-moφholin-4-ylpyrin^idin-4-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

4-(difluoromethyl)-N-[4-fluoro-5-(6-moφholin-4-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin- 1 -yl] phenyl] -6-oxo- 1 H-pyridine-3-carboxamide;

2-(difluoromethyl)-4-fluoro-N-[4-fluoro-5-(2-mo holin-4-ylpyrin^idin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]benzarnide;

propan-2-yl 4-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]arnino]-2-fluoro- 4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,3,6,7-tetrahydroazepine-l-carboxylate;

propan-2-yl 4-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]arnino]-2-fluoro-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate; propan-2-yl 5 -[5-[ [4-(difluoromethyl)-6-oxo- 1 H-pyridine-3 -carbonyl] amino] -2-fluoro- 4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

propan-2-yl 5 -[5-[ [4-(difluoromethyl)-6-oxo- 1 H-pyridine-3 -carbonyl] amino] -2-fluoro-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

propan-2-yl 4-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

propan-2-yl 5-[2-fluoro-5-[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]-4-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate;

(1-methylcyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,3,6,7-tetrahy droazepine- 1 -carboxylate;

(3,3-difluorocyclobutyl) 4-[5-[[4-(difluoromethyl)-6-oxo-lH-pyridine-3-carbonyl]amino]-2-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2,3,6,7-tetrahy droazepine- 1 -carboxylate;

N-[5-[ 1 -(5-cyano- 1 ,3-thiazol-2-yl)-2,3,6,7-tetrahydroazepin-4-yl] -4-fluoro-2-[(3R,5 S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-6-oxo-lH-pyridine-3-carboxamide;

N-[5-[4-(cyclohexylcarbamoyl)-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-[cyclopropylmethyl(methyl)carbamoyl]-3-fluorophenyl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-[(4,4-difluorocyclohexyl)carbamoyl]-3-fluorophenyl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[5-[4-(cyclopropylmethylcarbamoyl)-3-fluorophenyl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-fluoro-N-[4-fluoro-2-[(3R)-3,4-dimethylpiperazin-l-yl]-5-[2-[(2R)-2-

4-fluoro-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-yl]-5-[2-[(3R)-3-

4-fluoro-N-[4-fluoro-2-[(3S)-3,4-dimethylpiperazin-l-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-dime lmoφholin-4-yl]pyrin^idin-4-yl]-2-[(3R)-3,4-dimethylpiperazin- 1 -yljphenyl] -2-(trifluoromethyl)benzamide;

N-[5-[l-(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- lH-pyridine-3 -carboxamide;

4-((1ίΑυοΓοηΐ6 1)-Ν-[4-ΑυοΓθ-5-[4-(ηιοφ^1ίη-4^1ηΐ6 1)-1,3-ύιί3ζο1-2^1]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

N-[4-fluoro-5-(6-piperazin-l-ylpyridin-2-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmo holin-4-yl]pyrirnidin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin- 4-yl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2 (2R,6S)-2,6-dime lmoφholin-4-yl]pyrin^idin- 4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 difluorome l)-N-[4-fluoro-5 2-moφholin-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-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

4-((Ηί1υοΓοηΐ6 1)-Ν-[4-ΑυοΓθ-5-[5-(ηιοφ^1ίη-4^1ηΐ6 1)-1,3-ύιί3ζο1-2^1]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

4 ώΑυοΓοηΐ6 1)-Ν-[4-ΑυοΓθ-5-[2-(ηιοφ1ιο1ίη-4^1ηΐ6 1)-1,3-ί1ιί3ζο1-4^1]-2- [(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-[4-(ηιοφ1ιο1ίη-4^1ηΐ6 1)-1,3-ύιί3ζο1-2^1]-2-[(3Κ,58)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluorome1hyl)-lH-pyridine-3-carboxamide;

Ν-[4-ΑυοΓθ-5-[5-(ηιοφ1ιο1ίη-4^1ηΐ6 1)-1,3-ύιί3ζο1-2^1]-2-[(3Κ,58)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide;

2 difluorome l)-N-(5 2 (2S,6R)-2,6-dime lmo holino)pyrimidin-5-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-fluorobenzamide;

2-(difluoromethyl)-4-fluoro-N-(4-fluoro-5-(2-((S)-2-methylmoφholino)pyrimidin-5 yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)benzamide; and

2- (difluoromethyl)-4-fluoro-N-(4-fluoro-5-(2-((R)-2-methylmoφholino)pyrimidin-5^ yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)benzamide,

3- (difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmo holino)pyrimidin-5-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-5-fluoropicolinamide;

3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)picolinamide;

(S)-3-(difluoromethyl)-N-(2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-moφholinopyrimidin-4-yl)phenyl)-5-fluoropicolinamide;

3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-((R)-2-methylmo holino)pyrimidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)picolinamide;

3-(difluoromethyl)-N-(5-(2-((2S,6R)-2,6-dimethylmo holino)pyrimidin-4-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-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-l-yl)phenyl)-5-fluoropicolinamide; and

3-(difluoromethyl)-5-fluoro-N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)picolinamide;

or a pharmaceutically acceptable salt and/or solvate thereof.

117] In some embodiments, the compound of Formula I is selected from,:

104

106

or a pharmaceutically acceptable salt and/or solvate thereof

[00118] In some embodiments, the compound of Formula I is selected from,:

108

or a pharmaceutically acceptable salt and/or solvate thereof.

[00119] In some embodiments, the compound of Formula I is selected from, a pharmaceutically acceptable salt and/or solvate thereof:


[00120] The present application also includes a compound of Formula (la) or a pharmaceutically acceptable salt and/or solvate thereof:

(la)

wherein:

R18 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, C3-iocycloalkyl, OR21, SR21, NR22R23, Ci-galkyleneOR21, Ci-6alkyleneSR21 and Ci-6alkyleneNR22R23, provided that R18 comprises at least one basic nitrogen atom;;

R19 is selected from C6-ioaryl and heteroaryl, and R19 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR24, SR24 and NR25R26;

R20 is selected from H, halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OR27, SR27, S02R27, NR28R29, R30, Ci-6alkyleneR30, Ci-6alkenyleneR30, OCi-6alkyleneR30, SCi-6alkyleneR30, Ci-6alkyleneNR28R29, Ci-6alkyleneOR27, Ci-6alkyleneSR27, OCi-6alkyleneNR28R29, SCi-6alkyleneNR28R29, OCi-6alkyleneOR27, SCi-6alkyleneOR27, OCi-6alkyleneSR27, SCi-6alkyleneSR27, C(0)OR27, C(S)OR27, C(S)NR28R29 and C(0)NR28R29;

R21 is selected from H, Ci-6alkyl Ci-6fluoroalkyl, C(0)Ci-6alkyl and C(0)Ci_ 6fluoroalkyl;

R22 and R23 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OCi-6alkyl, C(0)NHCi_

6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneC6-ioaryl,

Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl, or R22 and R23 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, Ci-6alkyl OCi-6alkyl, Ci-6fiuoroalkyl, OCi-sfiuoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)NHCi-6alkyl, S02Ci-6alkyl, S02HNCi-6alkyl, Ci.6alkyleneOCi-6alkyl, Ci-ealkyleneCe-ioaryl, Ci. 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl and Ci-6alkyleneC3-6cycloalkyl;

R24 is selected froni H, Ci-6alkyl, Ci-6fluoroalkyl and C(0)Ci-6alkyl;

R25 and R26 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl and C(0)Ci_ 6alkyl, or R25 and R26 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, CN, Ci-6alkyl OCi-6alkyl, Ci-6fiuoroalkyl and OCi-6fluoroalkyl;

R27 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-ealkyleneCe-ioaryl, Ci-6alkyleneheteroaryl and Ci_6alkyleneheterocycloalkyl, and is unsubstituted

31 31 32 33 or substituted with one or more substituents selected from halo, OR , SR , NR R , Ci-6alkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-galkyleneOR31, Ci-6alkyleneSR31 and Ci-6alkyleneNR32R33;

R28 and R29 are each independently selected from H, Ci.i0alkyl, Ci.iofluoroalkyl, C(0)Ci-6alkyl, C(O)C6-i0aryl, C(0)C3-iocycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C(0)OCi-6alkyl, C(0)OCi-6fluoroalkyl, C(O)OC6-i0aryl, C(O)OC3-i0cycloalkyl, C(0)Oheteroaryl, C(0)Oheterocycloalkyl, C(0)NHCi-6alkyl, C(0)NHCi-6fluoroalkyl, C(O)NHC6-i0aryl, C(0)NHC3-iocycloalkyl,

C(0)NHheteroaryl, C(0)NHheterocycloalkyl, S02Ci-6alkyl, S02Ci-6fluoroalkyl, S02C6-ioaryl, S02C3-iocycloalkyl, S02heteroaryl, S02heterocycloalkyl, C3-locycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R28 and R29 are independently unsubstituted or substituted with one or more substituents selected from halo, CN, OR31, SR31, NR32R33, Ci-6alkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-6alkyleneOR31, Ci-galkyleneSR31 and Ci-6alkyleneNR32R33, or

R and R together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR31, SR31, NR32R33, C1-6alkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR31, Ci-6alkyleneOR31, Ci-6alkyleneSR31 and Ci_ 6alkyleneNR32R33;

R30 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3- locycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R30 is unsubstituted or substituted with

31 31 32 33 one or more substituents independently selected from halo, CN, OR , SR , NR R , Ci-galkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-galkyleneOR31, Ci-6alkyleneSR31 and Ci-6alkyleneNR32R33,

R31 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3.iocycloalkyl and Ci. 6alkyleneheterocycloalkyl, and R31 is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci-ealkyleneNi i-ealkylXCi-ealkyl);

R32 and R33 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci_ 6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R15 and R16 is unsubstituted or substituted with one or more substituents independently selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-6fluoroalkyl, SCi. salkyl, SC^fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_ 6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci_ 6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R32 and R33 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

X3 and X4 are each independently selected from CR34 and N;

R34 is selected from H, Ci-6alkyl and Ci-6fluoroalkyl;

A2 is F; and

alkyl and alkylene groups are optionally fluorosubstituted.

[00121] The present application also includes a compound of Formula (la) or a pharmaceutically acceptable salt and/or solvate thereof:


(la)

wherein:

R18 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci.6fluoroalkyl, OR21, SR21, NR22R23, Ci-6alkyleneOR21, Ci-6alkyleneSR21 and Ci-6alkyleneNR22R23, provided that R1 comprises at least one basic nitrogen atom;

R19 is selected from C6-ioaryl and heteroaryl, and R19 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR24, SR24 and NR25R26;

R20 is selected from H, halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OR27, SR27, NR28R29, R30, Ci-6alkyleneR30, OCi-6alkyleneR30, SCi-6alkyleneR30, Ci-6alkyleneNR28R29, Ci. salkyleneOR27, Ci-6alkyleneSR27, OCi-6alkyleneNR28R29, SCi-6alkyleneNR28R29, OCi. salkyleneOR27, SCi-6alkyleneOR27, OCi-6alkyleneSR27, SCi-6alkyleneSR27, C(0)OR27, C(S)OR27, C(S)NR28R29 and C(0)NR28R29;

R21 is selected from H, Ci-6alkyl Ci.6fluoroalkyl, C(0)Ci-6alkyl and C(0)d. 6fluoroalkyl;

R22 and R23 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl, C(0)Ci-6alkyl and C(0)Ci-6fluoroalkyl, or R22 and R23 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, Ci-galkyl OCi-6alkyl, Ci-6fluoroalkyl, OC^fluoroalkyl, C(0)Ci-6alkyl and C(0)d. 6fluoroalkyl;

R24 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl and C(0)Ci-6alkyl;

R25 and R26 are independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl and C(0)Ci_ 6alkyl, or R25 and R26 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, OH, Ci-6alkyl OCi-6alkyl, Ci-6fiuoroalkyl and OCi-6fluoroalkyl;

R27 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted 31 31 32 33 or substituted with one or more substituents selected from halo, OR , SR , NR R , Ci-galkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-galkyleneOR31, Ci-6alkyleneSR31 and Ci-6alkyleneNR32R33;

R28 and R29 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3. locycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci_ 6alkyleneheterocycloalkyl, and each of R28 and R29 are independently unsubstituted or

31 31 32 33 substituted with one or more substituents selected from halo, OR , SR , NR R , Ci_ salkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-galkyleneOR31, Ci-6alkyleneSR31 and Ci-6alkyleneNR32R33, or

R28 and R29 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents independently selected from halo, OR31, SR31, NR32R33, Ci-6alkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR31, Ci-6alkyleneOR31, Ci-6alkyleneSR31 and Ci_ 6alkyleneNR32R33;

R30 is selected from C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R30 is unsubstituted or substituted with one or more substituents independently selected from halo, OR31, SR31, NR32R33, Ci-6alkyl, C(0)R31, C(0)OR31, C(0)NR32R33, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR31, Ci-6alkyleneOR31, Ci-galkyleneSR31 and Ci-6alkyleneNR32R33,

R31 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci_ 6alkyleneheterocycloalkyl, and R31 is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-efluoroalkyl, SCi-6alkyl, SC^fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(d. 6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

R32 and R33 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci_ 6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R15 and R16 is unsubstituted or substituted with one or more substituents independently selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-6fluoroalkyl, SCi. salkyl, SC^fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_ 6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci_ 6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R32 and R33 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or more substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-sfiuoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, NCCi-salkylXCi-salkyl), C(0)Ci-6alkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(d. 6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl);

X3 and X4 are each independently selected from CR34 and N;

R is selected from H, Ci-6alkyl and Ci-6fluoroalkyl;

A2 is F; and

alkyl and alkylene groups are optionally fluorosubstituted.

[00122] In some embodiments, R18 is a heterocycloalkyl that is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci_ efluoroalkyl, NR22R23 and Ci-6alkyleneNR22R23, provided that R18 comprises at least one basic nitrogen atom. In some embodiments, R18 is a heterocycloalkyl that is substituted with one or two substituents selected from halo, Ci-6alkyl and NR22R23, provided that R18 comprises at least one basic nitrogen atom. In some embodiments, R18 is a heterocycloalkyl that is substituted with one, two or three substituents selected from

22 23 18

Ci-6alkyl and NR R , provided that R comprises at least one basic nitrogen atom. In some embodiments, R18 is a Cs-eheterocyclalkyl comprising one or two nitrogen atoms at least one of which is basic.

[00123] In some embodiments, R18 is selected from:

In some embodiments, R is selected from:

In some embodiments, R is selected from:


R18 is selected from:


[00128] In some embodiments, R is selected from C6-ioaryl and heteroaryl, and R19 is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci-6fluoroalkyl, =0, OR24, SR24 and NR25R26. In some embodiments, R19 is selected from C6-ioaryl and heteroaryl, and R19 is unsubstituted or substituted with one, two or three substituents selected from halo, Ci-6alkyl, Ci-6-fluoroalkyl, =0 and NR25R26. In some embodiments, R19 is selected from C6-ioaryl and heteroaryl, and R19 is unsubstituted or substituted with one or two substituents selected from halo, Ci-6alkyl, Ci-6fiuoroalkyl and =0. In some embodiments, R is selected from phenyl and C6-heteroaryl, and R19 is substituted with one to three substituents selected from F, CF2H, CF3 and =0.

[00129] In some embodiments, R is


tautomer thereof. The tautomer of this R group is

[00130] In some embodiments, R is selected from


tautomer thereof.

[00131] In some embodiments, R is

[00132] In some embodiments, R is selected from H, halo, CN, Ci-6alkyl, Ci_ efluoroalkyl, OR27, NR28R29, R30, Ci-6alkyleneR30, OCi-6alkyleneR30, Ci. 6alkyleneNR28R29, Ci-6alkyleneOR27, OCi-6alkyleneNR28R29, OCi-6alkyleneOR27, C(0)OR27 and C(0)NR28R29. In some embodiments, R20 is selected from H, halo, CN, Ci-galkyl, Ci-6fluoroalkyl, OR27, NR28R29, R30, Ci-6alkyleneR30, OCi-6alkyleneR30, Ci. 6alkyleneNR28R29, Ci-6alkyleneOR27, OCi-6alkyleneNR28R29 and OCi-6alkyleneOR27. In some embodiments, R20 is selected from H, CN, Ci-6alkyl, OR27, NR28R29, R30, Ci. 6alkyleneRJU and OCi-6alkyleneRJu. In some embodiments, wherein R is selected from Ci-galkyl and R30.

[00133] In some embodiments, R22 and R23 are independently selected from H,

Ci-6alkyl and heterocycloalkyl. In some embodiments, R22 and R23 are independently selected from H and Ci-6alkyl.

[00134] In some embodiments, R22 and R23 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted or substituted with one or two substituents selected from halo and Ci-6alkyl. In some embodiments, R22 and R23 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.

[00135] In some embodiments, R27 is selected from H, Ci-6alkyl, Ci_

6fluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci_ 6alkyleneheterocycloalkyl. In some embodiments, R27 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC3-iocycloalkyl and Ci_ 6alkyleneheterocycloalkyl. In some embodiments, R27 is selected from H, Ci-6alkyl, Ci-6fluoroalkyl, heterocycloalkyl and Ci-6alkyleneC3-iocycloalkyl. In some embodiments, R27 is selected from Ci-6alkyl, Ci-6fluoroalkyl and heterocycloalkyl. In some embodiments, R27 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, piperazinyl, morpholinyl, thiomo holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl.

[00136] In some embodiments, R28 and R29 are each independently selected from

Η, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci_ 6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl. In some embodiments, R28 and R29 are each independently selected from Η, Ci-ioalkyl, C3-iocycloalkyl, heterocycloalkyl, Ci_ 6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl. In some embodiments, R28 and R29 are each independently selected from Η, Ci-ioalkyl and C3-iocycloalkyl.

[00137] In some embodiments, R28 and R29 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.

[00138] In some embodiments, R30 is selected from C(0)Ci-6alkyl, C3-locycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl. In some embodiments, R30 is selected from C3-iocycloalkyl and heterocycloalkyl. In some embodiments, R30 is heterocycloalkyl. In some embodiments R30 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, 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-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl.

[00139] In some embodiments, X3 and X4 are each independently selected from

CR34 and N, in which R34 is selected from Η and Ci-6alkyl. In some embodiments, X3 and X4 are CR34, in which R34 is H. In some embodiments, X1 and X2 is CR34 and the other of X1 and X2 is N, in which R34 is H. In some embodiments, both of X3 and X4 are N.

[00140] The present application also include a compound of Formula (lb) or a pharmaceutically acceptable salt and/or solvate thereof:


(lb)

wherein:

R35 is selected from phenyl, Cs-eheteroaryl and Cs-eheterocycloalkyl, and R35 is substituted with one substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR40, SR40, S02R40, NR41R42, R43, Ci-6alkyleneR43, Ci-6alkenyleneR43, OCi_ salkyleneR43, SCi-6alkyleneR43, Ci-6alkyleneNR41R42, Ci-6alkyleneOR40, Ci. salkyleneSR40, OCi-6alkyleneNR41R42, SCi-6alkyleneNR41R42, OCi-6alkyleneOR40, SCi. salkyleneOR40, OCi-6alkyleneSR40, SCi-6alkyleneSR40, C(0)OR40, C(S)OR40, C(S)NR41R42 and C(0)NR41R42;

R36 is selected from CF2H and CF3;

R37 is selected from H and CH3;

R38 and R39 are independently selected from H and CH3

R40 is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted or substituted with one to three substituents selected from halo, CN, OR44, SR44, NR45R46, Ci-6alkyl, C(0)R44, C(0)OR44, C(0)NR45R46, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneR , Ci-6alkyleneOR , Ci-6alkyleneSR and Ci-6alkyleneNR45R46;

R41 and R42 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(O)C3-i0cycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C(0)OCi-6alkyl, C(0)OCi-6fluoroalkyl, C(0)OC6-ioaryl, C(0)OC3-iocycloalkyl, C(0)Oheteroaryl, C(0)Oheterocycloalkyl, C(0)NHCi-6alkyl, C(0)NHCi-6fluoroalkyl, C(O)NHC6-i0aryl, C(0)NHC3- locycloalkyl, C(0)NHheteroaryl, C(0)NHheterocycloalkyl, S02Ci-6alkyl, S02Ci. 6fluoroalkyl, S02C6-ioaryl, S02C3-iocycloalkyl, S02heteroaryl, S02heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R41 and R42 are independently unsubstituted or substituted with one to three substituents selected from halo, CN, OR44, SR44, NR45R46, Ci-6alkyl, C(0)R44, C(0)OR44, C(0)NR45R46, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci_ 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR44, Ci-6alkyleneOR44, Ci-6alkyleneSR44 and Ci-6alkyleneNR45R46, or

R41 and R42 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycle that is unsubstituted or substituted with one to three substituents independently selected from halo, CN, OR44, SR44, NR45R46, Ci-6alkyl, C(0)R44, C(0)OR44, C(0)NR45R46, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneR44, Ci-6alkyleneOR44, Ci-6alkyleneSR44 and Ci_ 6alkyleneNR45R46;

R43 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3- locycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R43 is unsubstituted or substituted with one to three substituents independently selected from halo, CN, OR44, SR44, NR45R46, Ci-galkyl, C(0)R44, C(0)OR44, C(0)NR45R46, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR44, Ci-6alkyleneOR44, Ci-6alkyleneSR44 and Ci-6alkyleneNR45R46;

R is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl and Ci-6alkyleneheterocycloalkyl, and R44 is unsubstituted or substituted with one to three substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-galkyl, OC^fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi_ salkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci_

6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH,
Ci-6alkyleneNH2, and Ci. salkyleneNiCi-galky iCi-galkyl);

R45 and R46 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci_ 6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R45 and R46 is unsubstituted or substituted with one to three substituents independently selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R45 and R46 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycle that is unsubstituted or substituted with one to three substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3. locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl).

[00141] In some embodiments, R35 is selected from phenyl, pyrimidinyl, pyridinyl, dihydropyridine, pyrrolyl and dihydropyrrolyl, each of which is substituted with one substituent selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, =0, =S, OR40, SR40, S02R40, NR41R42, R43, Ci-6alkyleneR43, Ci-6alkenyleneR43, OCi-6alkyleneR43, SCi. salkyleneR43, Ci-6alkyleneNR41R42, Ci-6alkyleneOR40, Ci-6alkyleneSR40, OCi. 6alkyleneNR41R42, SCi-6alkyleneNR41R42, OCi-6alkyleneOR40, SCi-6alkyleneOR40, OCi. salkyleneSR40, SCi-6alkyleneSR40, C(0)OR40, C(S)OR40, C(S)NR41R42 and C(0)NR41R42.

[00142] In some embodiments, R35 is substituted with one substitutent selected from Ci-galkyl, Ci-6fluoroalkyl, OR40, NR41R42, R43, Ci-6alkyleneR43, OCi-6alkyleneR43, Ci-6alkyleneNR41R42, Ci-6alkyleneOR40, OCi-6alkyleneNR41R42, OCi-6alkyleneOR40, C(0)OR40 and C(0)NR41R42.

[00143] In some embodiments, R35 is substituted with R43 or Ci-6alkyleneR43 wherein R43 is selected from C5-6cycloalkyl, C5-6heterocycloalkyl, C5-6heteroaryl and phenyl, and R43 is unsubstituted or substituted with one to three substituents independently selected from halo and Ci-6alkyl. In some embodiments, R43 is Ce-heterocycloalkyl. In some embodiments, R43 is selected from piperazinyl, morpholinyl, thiomo holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl. In some embodiments, R43 is mo holinyl, optionally substituted with one or two Me.

[00144] In some embodiments, R35 is selected from:


, wherein R is the subsituent.

5] In some embodiments, the compound of Formula lb is selected from:





or a pharmaceutically acceptable salt and/or solvate thereof.

[00146] The present application also include a compound of Formula (Ic) or a pharmaceutically acceptable salt and/or solvate thereof:


(Ic)

wherein:

R47 is selected from phenyl, Cs-eheteroaryl and Cs-eheterocycloalkyl, and R47 is substituted with one substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, =0, =S, OR53, SR53, S02R53, NR54R55, R56, Ci-6alkyleneR56, Ci-6alkenyleneR56, OCi. salkyleneR56, SCi-6alkyleneR56, Ci-6alkyleneNR54R55, Ci-6alkyleneOR53, Ci. salkyleneSR53, OCi-6alkyleneNR54R55, SCi-6alkyleneNR54R55, OCi-6alkyleneOR53, SCi. salkyleneOR53, OCi-6alkyleneSR53, SCi-6alkyleneSR53, C(0)OR53, C(S)OR53, C(S)NR54R55 and C(0)NR54R55;

R48, R49 and R50 are independently selected from H, F, CF3 and CF2H, provided that at least one of R48, R49 and R50 is not H;

R51 and R52 are independently selected from H and CH3

RM is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and is unsubstituted or substituted with one to three substituents selected from;

R54 and R55 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3-iocycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C(0)OCi-6alkyl, C(0)OCi-6fluoroalkyl, C(0)OC6-ioaryl, C(0)OC3-iocycloalkyl, C(0)Oheteroaryl, C(0)Oheterocycloalkyl, C(0)NHCi-6alkyl, C(0)NHCi-6fluoroalkyl, C(O)NHC6-i0aryl, C(0)NHC3- locycloalkyl, C(0)NHheteroaryl, C(0)NHheterocycloalkyl, S02Ci-6alkyl, S02Ci. 6fluoroalkyl, S02C6-ioaryl, S02C3-iocycloalkyl, S02heteroaryl, S02heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci-6alkyleneC3.iocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneheteroaryl and Ci-6alkyleneheterocycloalkyl, and each of R54 and R55 are independently unsubstituted or substituted with one to three substituents selected from halo, CN, OR57, SR57, NR58R58, Ci-6alkyl, C(0)R57, C(0)OR57, C(0)NR58R59, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3- locycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci.6alkyleneC3.iocycloalkyl, Ci. 6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR57, Ci-6alkyleneOR57, Ci-galkyleneSR57 and Ci-6alkyleneNR58R59, or

R54 and R55 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycle that is unsubstituted or substituted with one to three substituents independently selected from halo, CN, OR57, SR57, NR58R58, Ci-6alkyl, C(0)R57, C(0)OR57, C(0)NR58R59, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR57, Ci_ salkyleneOR57, Ci-6alkyleneSR57 and Ci-6alkyleneNR58R59;

R56 is selected from C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(O)C6-i0aryl, C(0)C3- locycloalkyl, C(0)heteroaryl, C(0)heterocycloalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and R56 is unsubstituted or substituted with one to three substituents independently selected halo, CN, OR57, SR57, NR58R58, Ci_ 6alkyl, C(0)R57, C(0)OR57, C(0)NR58R59, S(0)Ci-6alkyl, S02Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3. locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneR , Ci-galkyleneOR57, Ci-6alkyleneSR57 and Ci-6alkyleneNR58R59;

R57 is selected from H, Ci-6alkyl, Ci.6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl and Ci-6alkyleneheterocycloalkyl, and R57 is unsubstituted or substituted with one to three substituents selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-galkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci-6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi_ salkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci-6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-loaryl, Ci-6alkyleneC3.iocycloalkyl, Ci-6alkyleneheteroaryl, Ci.

6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci-6alkyleneNHCi-6alkyl and Ci_ salkyleneNiCi-galky iCi-galkyl);

R58 and R59 are each independently selected from H, Ci-6alkyl, Ci-6fluoroalkyl, C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci. 6alkyleneC6-ioaryl, Ci-6alkyleneC3-iocycloalkyl and Ci-6alkyleneheterocycloalkyl and each of R58 and R59 is unsubstituted or substituted with one to three substituents independently selected from halo, CN, Ci-6alkyl, Ci-6fluoroalkyl, OH, SH, OCi-6alkyl, OCi-gfluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci.6alkyl)(Ci. salkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2, C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Ci-6alkyl), S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH,
Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci. 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl), or

R58 and R59 together with the nitrogen atom to which they are attached form a 3-6 membered heterocycle that is unsubstituted or substituted with one to three substituents selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, OH, SH, OCi-6alkyl, OCi-6fluoroalkyl, SCi-6alkyl, SCi-6fluoroalkyl, NH2, NHCi-6alkyl, N(Ci-6alkyl)(Ci. 6alkyl), C(0)Ci-6alkyl, C(0)Ci-6fluoroalkyl, C(0)OH, C(0)OCi-6alkyl, C(0)NH2,

C(0)NHCi-6alkyl, C(0)N(Ci.6alkyl)(Cwalkyl)5 S02Ci-6alkyl, S(0)Ci-6alkyl, C6-i0aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci-6alkyleneC6-ioaryl, Ci-6alkyleneC3-locycloalkyl, Ci-6alkyleneheteroaryl, Ci-6alkyleneheterocycloalkyl, Ci-6alkyleneOH, Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneSH, Ci-6alkyleneSCi-6alkyl, Ci-6alkyleneNH2, Ci_ 6alkyleneNHCi-6alkyl and Ci-6alkyleneN(Ci-6alkyl)(Ci-6alkyl).

[00147] In some embodiments, R47 is selected from phenyl, pyrimidinyl, pyridinyl, dihydropyridine, pyrrolyl and dihydropyrrolyl, each of which is substituted with one substituent selected from halo, CN, Ci-6alkyl, Ci-6fiuoroalkyl, =0, =S, OR53, SR53, S02R53, NR54R55, R56, Ci-6alkyleneR56, Ci-6alkenyleneR56, OCi-6alkyleneR56, SCi. salkyleneR56, Ci-6alkyleneNR54R55, Ci-6alkyleneOR53, Ci-6alkyleneSR53, OCi. 6alkyleneNR54R55, SCi-6alkyleneNR54R55, OCi-6alkyleneOR53, SCi-6alkyleneOR53, OCi. salkyleneSR53, SCi-6alkyleneSR53, C(0)OR53, C(S)OR53, C(S)NR54R55 and C(0)NR54R55.

[00148] In some embodiments, R47 is substituted with one substituent selected from Ci-galkyl, Ci-6fluoroalkyl, OR53, NR54R55, R56, Ci-6alkyleneR56, OCi-6alkyleneR56, Ci-6alkyleneNR54R55, Ci-6alkyleneOR53, OCi-6alkyleneNR54R55, OCi-6alkyleneOR53, C(0)OR53 and C(0)NR54R55.

[00149] In some embodiments, R47 is substituted with R56 or Ci-6alkyleneR56 wherein R56 is selected from C5-6cycloalkyl, Cs-eheterocycloalkyl, Cs-eheteroaryl and phenyl, and R56 is unsubstituted or substituted with one to three substituents independently selected from halo and Ci-6alkyl. In some embodiments, R56 is Ce-heterocycloalkyl. In some embodiments, R56 is selected from piperazinyl, morpholinyl, thiomo holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl. In some embodiments, R56 is mo holinyl, optionally substituted with one or two Me.

[00150] In some embodiments, R47 is selected from:


wherein R is the subsituent.

[00151] In some embodiments, R48, R49 and R50 are located on the phenyl ring as follows:


wherein R is selected from CF3 and CF2H and R and R3U are independently selected from H and F. In some embodiments, both R and R50 are F. In some embodiments, R49 is F and R50 is H.

[00152] In some embodiments, the compound of Formula Ic is selected from:


, or a pharmaceutically acceptable salt and/or solvate thereof. [00153] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of nay of the diseases, disorders or conditions described herein.

[00154] The compounds of the application are 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, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[00155] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[00156] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient 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, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); 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 sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried com starch.

[00157] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented 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 application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[00158] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[00159] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH's of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[00160] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00161] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably 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 (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[00162] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[00163] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[00164] In some embodiments a compound of the application is coupled with 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, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[00165] A compound of the application including pharmaceutically acceptable salts and/or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to

about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[00166] A compound of the application is either used alone or in combination with other known agents useful for treating diseases, disorders or conditions that are mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, and those that are treatable with a WDR5 inhibitor, such as the compounds disclosed herein. When used in combination with other agents useful in treating diseases, disorders or conditions mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, it is an embodiment that a compound of the application is administered contemporaneously with those agents. As used herein, "contemporaneous administration" of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In an embodiment, a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, 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.

[00167] The dosage of a compound of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some

embodiments, a compound of the application is administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the compound of the application from about 0.01 μg/cc to about 1000 μg/cc, or about 0.1 μg/cc to about 100 μg/cc. As a representative example, oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from 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 will be administered. For oral administration, a representative amount is from 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 suppository form, a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg. In an embodiment of the application, compositions are formulated for oral administration and the one or more compounds are suitably in the form of tablets 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 embodiments 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 daily doses.

[00168] In the above, the term "a compound" also includes embodiments wherein one or more compounds are referenced.

III. Methods and Uses of the Application

Therapeutic Methods and Uses

[00169] The compounds of the application have been shown to be inhibitors of the binding of WDR5 to MLL1.

[00170] Accordingly, the present application includes a method for inhibition of binding of WDR5 to its binding partners in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell. The application also includes a use of one or more compounds of the application for inhibition of binding of WDR5 to its binding partners in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of binding of WDR5 to its binding partners in a cell. The application further includes one or more compounds of the application for use to inhibit binding of WDR5 to its binding partners in a cell.

[00171] It is an embodiment of the present application, in all aspects, 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, consisting 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].

[00172] As the compounds of the application have been shown to be capable of inhibiting the binding of WDR5 to its binding partners, the compounds of the application are useful for treating diseases, disorders or conditions mediated or treatable by inhibition of binding between WDR5 protein and its binding partners. Therefore the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.

[00173] The present application also includes a method of treating a disease, disorder or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partners comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.

[00174] The present application also includes a use of one or more compounds of the application for treating a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners as well as a use of one or more compounds of the application for the preparation of a medicament for treating of a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners. The application further includes one or more compounds of the application for use in treating a disease,

disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners.

[00175] In an embodiment, the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners 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 application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder. The application further includes one or more compounds of the application for use in treating a neoplastic disorder. In an embodiment, the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment.

[00176] In another embodiment of the present application, the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners 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 application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer. The application further includes one or more compounds of the application for use in treating cancer. In an embodiment, the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.

[00177] In an embodiment, the cancer is selected from, but not limited to:

Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone

Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); 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 Myelogenous; 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, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; 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, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter,

Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.

[00178] In an embodiment, the cancer is selected from solid cancer and leukemias. In another embodiment, the cancer is selected from leukaemia, lymphoma, non-Hodgkin's lymphoma, Burkitt 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), gliomas, glioblastomas and MYCN-amplified neuroblastoma.

[00179] In an embodiment, the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by a binding of WDR5 to its binding partners. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by binding of WDR5 to its binding partners is proliferative activity in a cell. Accordingly, the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell. The present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of 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.

[00180] The present application also includes a method of inhibiting uncontrolled and/or abnormal cellular activities mediated directly or indirectly by binding of WDR5 to its binding partners in a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application to the cell. The application also includes a use of one or more compounds of the application for inhibition of uncontrolled and/or abnormal cellular activities mediated directly or indirectly by binding of WDR5 to its binding partners in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of uncontrolled and/or abnormal cellular activities mediated directly or indirectly binding of WDR5 to its binding partners in a cell. The application further includes one or more compounds of the application for use in inhibiting uncontrolled and/or abnormal cellular activities mediated directly or indirectly by binding of WDR5 to its binding partners in a cell.

[00181] In further embodiments, the present application also includes a method of treating a disease, disorder or condition that is mediated or treatable by inhibition of binding between WDR5 protein and its binding partners comprising administering a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners to a subject in need thereof. The present application also includes a use of one or more compounds of the application in combination with a known agent useful for treatment of a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners, for treatment of a disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners.

[00182] In a further embodiment, the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments. In another embodiment, the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.

Methods of Preparing the Compounds of the Application

[00183] Scheme 1 illustrates one embodiment of a route to compounds of the application in which Suzuki or related coupling is performed on compounds (A) to afford intermediates (B). Subsequent coupling of (B) with a carboxylic acid or appropriate or acid halide provides compounds of the application.

Compounds of Formula (I)

(A) (B)

Scheme 1: a) R3B(OH)2 or boronate ester, Pd(Amphos)Cl2, K3PO4, dioxane/H20, μwave, 110°C; b) R2C(0)OH, coupling agent or R2C(0)X, wherein X is a halide, amine.

[00184] In an alternate embodiment, compounds of Formula (I) are prepared by first coupling the carboxylic acid or acyl halides with aniline (A) followed by Suzuki or related coupling (Scheme 2).

Compounds of Formula (I)

(A) (B)

Scheme 2: a) R2C(0)OH, coupling agent or R2C(0)X, wherein X is a halide amine; b) R3B(OH)2 or boronate ester, Pd(Amphos)Cl2, K3P04, dioxane H20, μwave, 110°C.

[00185] In some embodiments of the application, compounds of Formula (I) are prepared from the nitroaryl or nitroheteroaryl compounds D (Q = CI or Br; Z = F or Br). Nucleophilic aromatic substitution with, for example, various piperazines or amines provide intermediate E. In some embodiments, reduction of E under reductive conditions by various means, including catalytic hydrogenation and dissolving metal reductions both in their various forms [see House, H.O., Modern Synthetic Reactions, Second Edition, W.A. Benjamin, Inc., Menlo Park, California, publication (1972)] affords compounds F. Coupling of F with boronic acids or esters, for example under the Suzuki conditions [Tetrahedron 2002, 58:9633-9695; Organic Letters 2006, 8(9), 1787-1789] affords intermediate G. Related coupling reactions for the conversion of F to G or H to Formula I as described in Scheme 3 include the 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.

Scheme 3: a) piperazine or amine, base; b) Zn or Fe, alcohol solvent; c) R3B(OH)2 or boronate ester, Pd(Amphos)Cl2, K3P04, dioxane H20, μwave, 110°C; d) R2C(0)OH, coupling agent or R2C(0)X, where X is a halide, amine.

[00186] In some embodiments compounds of Formula (I) are prepared by treatment of compounds of Formula F with amines (e.g. piperazines) to afford the intermediate K (Scheme 4). In some embodiments, bromination of K with N-bromosuccinmide provides the versatile intermediate L which is transformed into Formula (I) according to Scheme 3.


Scheme 4: a) piperazine or amines, base; b) N-bromosuccinimide.

[00187] In some embodiments of the application, compounds of Formula (I) wherein R2 = 2-chloro-4-trifluoromethylpyridine or trifluoromethylpyrimidone are prepared as shown in Scheme 5. Therefore, in some embodiments, acylation of compounds G (prepared, for example, via Scheme 3) with the 6-chloro-4-(trifluoromethyl)nicotinic acid chloride (generated in situ from the corresponding acid and SOCl2] gives amide M. Hydroylsis of M with sodium acetate in acetic acid under microwave conditions provides pyridone N. Coupling of N with boronic acids or esters, for example, under the Suzuki conditions deliver compounds of Formula (lb). Alternatively, in some embodiments, the Suzuki coupled intermediate O is acylated with the 6-chloro-4-(trifluoromethyl)nicotinic acid chloride to give Id which is subsequently hydrolysed to compounds lb (Scheme 5).


(O) (1d) (1b)

Scheme 5: a) R2C(0)OH, coupling agent or R2C(0)X, X is a halide, amine; b) NaOAc, AcOH, μwave, 160°C; c) R3B(OH)2 or boronate ester, Pd(Amphos)Cl2, K3PO4, dioxane/H20, μwave, 110°C.

[00188] Scheme 6 illustrates another embodiment for the preparation of compounds of Formula (lb), wherein R2 in the compounds of Formula I is trifluoromethyl pyrimidone. In some embodiments, acylation of aniline G with the 6-methoxy-4-(trifluoromethyl)nicotinic acid [Ra = Me] or 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid [Ra = -CH2CH2TMS] (generated from the corresponding acid and the alcohol, for example, as in Scheme 7) gives amide Q. In some embodiments, the amide Q is then transformed into the boronate ester R. In some embodiments, the Suzuki coupling of R to a variety halides affords intermediates S. In some embodiments, subsequent deprotection of S provides compounds of the present application (Formula lb). In some embodiments, compounds of Formula lb are prepared via Suzuki coupling to Q followed by deprotection (Scheme 6).

ds of b)

(S)

Scheme 6: a) R2C(0)OH, coupling agent; b) bipinacolatodiboron, Pd (dppf)2Cl2, NaOAc, dioxane, 110°C; c) R3B(OH)2 or boronate ester, Pd(Amphos)Cl2, K3P04, dioxane/H20, μwave, 110°C; d) R3-halide or triflate, Pd(Amphos)Cl2, K3P04, dioxane/H20, μwave, 110°C; e) HC1 or TFA; f) CsF or TBAF.


Scheme 7: a) NaOMe, MeOH; b) NaH, TMS-EtOH

[00189] Throughout the synthetic methods and processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be 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 is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only 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" R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4th ed. 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 column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

EXAMPLES

[00190] The following non-limiting examples are illustrative of the present application:

A. General Methods

[00191] Exemplary compounds of the application were synthesized using the methods described herein, or other methods, which are known in the art. Unless otherwise noted, reagents and solvents were obtained from commercial suppliers (e.g. Aldrich, Enamine, Combiblock, Bepharm, and J& W PharmLab).

[00192] The compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters ACQUITY UPLC system with a SQ (single quadrupole) MS and a photodiode array (PDA) detector (Milford, MA). The analytical columns were reversed phase Acqity UPLC BEH CI 8

(2.1 X 50 mm, 1.7 μηι). A gradient elution was used (flow 0.4 mL/min), typically starting with mobile phase 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). A gradient starting at 95% solvent A going to 5% in 1.8 min., holding for 0.5 min., going back to 95% in 0.5 min. and equilibrating the column for 0.5 min. Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA).

[00193] In some instances, 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 other various staining techniques.

[00194] The 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 methods from a range of instruments of the following configurations: Low resolution - Waters ACQUITY UPLC system with a SQ (single quadrupole) MS; Waters ACQUITY UPLC H-Class system with a 3100 (single quadrupole) MS. High resolution - Waters ACQUITY UPLC II system equipped with a Synapt Xevo QTof and Waters ACQUITY UPLC II system equipped with a Synapt G2S QTof mass spectrometer with an atmospheric pressure ionization source. [M+HJ refers to the protonated molecular ion of the chemical species.

[00195] Nuclear magnetic resonance (NMR) analysis was performed on a

Bruker 500MHz NMR spectrometer using ICON-NMR, under TopSpin program control. Spectra were measured at 298K, unless indicated otherwise and were referenced relative to the solvent chemical shift.

B. Synthesis of Compounds

[00196] The following compounds were prepared using one or more of the synthetic methods disclosed in Schemes 1 to 7:

Example 1: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide

Step 1: Synthesis of l-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine


[00197] A microwave vial was charged with l-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, evacuated and backfilled with nitrogen. Toluene (volume: 25 ml) and 1 -methylpiperazine (0.196 ml, 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 about 75% conversion and -3: 1 for the desired product versus the nucleophilic aromatic substitution (SNAr) displacement of the ArF. The reaction was transferred to a round bottom flask with DCM and then concentrated onto celite. Purification by flash chromatography [0-10% MeOH/DCM + 1% NH4OH; 100 g column] afforded an inseparable mixture of the two products l-(4-chloro-5-fluoro-2-nitrophenyl)-4-methylpiperazine (0.428 g, 1.095 mmol, 55.7% yield) and l-(5-bromo- 2- chloro-4-nitrophenyl)-4-methylpiperazine. The mixture was used directly in the next step. LCMS [M+H]+ 274 g/mol.

Step 2: Synthesis of 4-((2'-fluoro-4'-(4-methylpiperazin-l-yl)-5'-nitro-[ 1, l '-biphenyl] - 3- yl)methyl)morpholine


[00198] A vial was charged with the mixture obtained in l-(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). The vial was sealed with a cap and septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (volume: 10 ml) and a 2M aq. solution of sodium carbonate monohydrate (ACS) (2.74 ml, 5.47 mmol) were added via syringe and the vial was evacuated and backfilled with nitrogen an additional time. The reaction was heated at 90°C in an aluminum block overnight. LCMS indicated complete consumption of the starting material(s). The peak at 1.56 minutes 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 + l% NH4OH;] afforded the desired4-((2'-fluoro-4'-(4-methylpiperazin-l-yl)-5'-nitro-[l,Γ-biphenyl]-3-yl)methyl)mo holine (0.248 g, 0.598 mmol, 54.7% yield) as a yellow oil. LCMS [M+H]+ 415 g/mol.

Step 3: Synthesis of 6-fluoro-4-(4-methylpiperazin-l-yl)-3'-(morpholinomethyl)-[l, l '-biphenylJ-3-amine


[00199] A solution of 4-((2'-fluoro-4'-(4-methylpiperazin-l-yl)-5'-nitro-[l,r-biphenyl]-3-yl)methyl)mo holine (0.248 g, 0.598 mmol) in MeOH) (volume: 10 ml) was hydrogenated in the presence of platinum(IV) oxide (0.014 g, 0.060 mmol) at 1 atm (balloon) of H2 (g). After 18 h (overnight), LCMS indicated formation of two polar peaks, both indicating the desired product by MS. Celite was added to the reaction and the mixture was filtered eluting with MeOH. The filtrate was then concentrated onto celite and purified by silica gel flash chromatography [1-10% MeOH/DCM + 1% NH4OH] to afford 6-fluoro-4-(4-methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (0.130 g, 0.338 mmol, 56.5% yield) as a blue foam that was >90% the desired product by NMR and LCMS. LCMS [M+H]+ 385 g/mol.

Step 4: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide


[00200] 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, the solution was added to a solution of 6-fluoro-4-(4-methylpiperazin-l-yl)-3'-(moφholinomethyl)-[l, -biphenyl]-3-amine (0.030 g, 0.078 mmol) in DMF (volume: 1 ml, ratio: 1.000) at room temperature. The reaction was warmed briefly (at 50°C for lh and then at 70°C for lh). The reaction was then stirred at room temperature overnight and then concentrated onto celite. The intermediate was purified by silica gel flash chromatography (reverse phase) on the Biotage [5-95% MeCN/Water; 30 g CI 8 column] to afford 4-fluoro-N-(6-fluoro-4-(4-methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-yl)-3,5-dimethylbenzamide (0.009 g, 0.017 mmol, 21.57% yield) as a clear film that was pure by LCMS and NMR. ¾ NMR (500 MHz, DMSO-d6) δ = 9.49 (s, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.73 (d, J=6.8 Hz, 2H), 7.47 - 7.41 (m, 3H), 7.34 (d, J=6.8 Hz, 1H), 7.19 (d, J=12.2 Hz, 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.

Example 2: Synthesis of 4-fluoro-N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-3,5-dimethylbenzamide


[00201] 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 pyridine, anhydrous (0.945 ml, 11.70 mmol) at room temperature under nitrogen. After stirring for lh, this solution was added to a vial containing 6-fluoro-4-(4-methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (step 3 from (a): 0.030 g, 0.078 mmol) under nitrogen and the reaction was heated to 70°C for 3 hours. The pyridine was removed under reduced pressure and LCMS of the residue (dissolved in DCM, MeCN and MeOH) indicated complete conversion to the desired product. The mixture was loaded onto celite purified by flash chromatography [0.5-10% DCM/MeOH + 1% NH4OH] to methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l,Γ-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (0.024 g, 0.042 mmol, 53.6% yield) as a clear film. ¾ NMR (500 MHz, DMSO-d6) δ = 9.53 (s, 1H), 7.94 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.40 - 7.38 (m, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.08 (d, J=12.5 Hz, 1H), 6.81 (s, 1H), 3.60 - 3.57 (m, 4H), 3.53 (s, 2H), 2.93 (br. s., 4H), 2.38 (br. s., 4H), 2.24 (s, 3H); LCMS [M+H]+ 574 g/mol.

[00202] In a like manner, the following additional compounds of the application were prepared using schemes 1-7 and the yields disclosed are for the final synthetic step to afford the compounds of the present application:

Example 3: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide

Step 1. N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l -yl)phenyl)-6-oxo-4- ( trifluoromethyl)-!, 6-dihydropyridine-3-carboxamide


[00203] In a 10 ml microwave vial to a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (719 mg, 3.47 mmol) in anhydrous pyridine (4210 μΐ, 52.1 mmol) was slowly added diethyl chlorophosphate (514 μΐ, 3.56 mmol) at RT in an atmosphere of N2. The reaction mixture was stirred at RT for 2 h. The suspension turned into a solution and then into a suspension again. To this mixture, 5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)aniline (250 mg, 0.868 mmol) was added and the reaction was heated at 70 °C for 3 h. After completion of the reaction, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2SC>4. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound. LCMS C8 [M+l]+ = 459.4

Step 2: N-( 5-bromo-4-fluoro-2-(4-methylpiperazin-l -yl)phenyl)-6-oxo-4-(rifluoromethyl) -1 , 6-dihydropyridine-3-carboxamide

[00204] In a 5 niL microwave vial N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,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 μΐ) and 1,4-dioxane (1943 μΐ) to give a white suspension. The suspension was stirred for 5 min, degassed, purged with N2, and micro waved for 60 min at 120 °C. The solvent was evaporated and 15 ml of CH2CI2 were added. The suspension was sonicated and extracted from water. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2CI2, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound in 61% yield. XH NMR (500 MHz, MeOD) δ 8.55 (s, 2H), 7.97 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 6.92 (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.

Example 4: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(6-morpholinopyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00205] The title compound was prepared in 78% yield similar to the sequence described above for the preparation of Example 3 except using 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine in place of 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester to provide the title compound in 78% yield. 1H NMR (500 MHz, MeOD) δ 8.32 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 6.91 (d, J = 9.1 Hz, 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.

Example 5: N-(5-(benzo[d] [l, 3]dioxol-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00206] This example was prepared similar to the sequence described above for the preparation of Example 3 using 3,4-methylenedioxyphenylboronic acid in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to provide the title compound in 70% yield. XH NMR (500 MHz, MeOD) δ 7.96 (s, 1H), 7.88 (d, J = 8.3

Hz, 1H), 7.06 (d, J = 12.0 Hz, 1H), 7.02 (d, J = 7.1 Hz, 2H), 6.92 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 5.99 (s, 2H), 3.02 (t, J = 4.9 Hz, 4H), 2.73 (s, 4H), 2.43 (s, J = 13.2 Hz, 3H); LCMS [M+H]+ 519.5.

Example 6: (R)-N-(2-(3, 4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholmopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00207] The title compound was prepared using (i?)-4-(4-chloro-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine and 2-(4-moφholino)pyrimidine-5-boronic acid pinacol ester to give the (i?)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-nitro henyl) yrimidin-2-yl)mo holine intermediate, which was reduced to the corresponding amine using standard methods. Diethyl chlorophosphate (4 equiv.) was added to a solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (4 equiv.) in pyridine at room temperature under N2. After stirring for 1 h, the solution of activated acid was added to a vial containing (i?)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-aminophenyl)pyrirnidin-2-yl)mo holine (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% NH40H] to afford the title compound in 19% yield. ¾ NMR (500MHz, DMSO-de) δ = 9.43 (br. s., 1H), 8.53 (s, 2H), 7.96 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.08 (d, J=12.2 Hz, 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=10.6 Hz, 1H), 2.35 - 2.30 (m, 1H), 2.25 - 2.18 (m, 4H), 0.97 (d, J=6.1 Hz, 3H); LCMS [M+H]+ 576.

Example 7: (S)-N-(2-(3, 4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholmopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00208] The title compound was prepared using (5)-4-(4-chloro-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine and 2-(4^ο ηο1ίηο^ήΓώ(ϋη6-5-οοΓοηίΰ acid pinacol ester to give the (5)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yl)mo holine intermediate, which was reduced to the corresponding amine using standard methods. Diethyl chlorophosphate (4 equiv.) was added to a solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (4 equiv.) in pyridine at room temperature under N2. After stirring for 1 h, the solution of activated acid was added to a vial containing (S)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-arninophenyl)pyrirnidin-2-yl)moφholine (1 equivalent) 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% NH40H] to afford the title compound in 15% yield. ¾ NMR (500MHz, DMSO-de) 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 .

Example 8: N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


Step 1: (2S, 6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2, 6-trimethylpiperazine


[00209] To a suspension of K2CO3 (0.456 g, 3.30 mmol) in toluene (10 mL) was added l-bromo-2,4-difluoro-5 -nitrobenzene (1.497 g, 6.29 mmol) and the reaction mixture was heated at 50 °C for 2 min before a solution of (2R,6S)- 1,2,6-trimethylpiperazine (0.806 g, 6.29 mmol) in toluene (3 mL) was slowly added over 3 min. The resulting mixture was stirred at 50 °C for 1 h. After adding water (20 mL), it was extracted with EtOAc (30 mL x 2) and the combined extracts were concentrated and dried under vacuum to give a dark orange red oil which solidified to a yellow solid (2.166 g, 100% yield). LCMS [M + H]+= 348.3.

Step 2: 4-(5-(2-fluoro-5-nitro-4-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)pyrimidin-2-yl)morpholine


[00210] To a 20 mL microwave vial charged with (2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2,6-trimethylpiperazine (1.04 g, 3 mmol), 2-(4^ο ηο1ίηο^ηηη^ίη6-5-boronic acid pinacol ester (1.22 g, 4.2 mmol), and Pd(dppf)Cl2 (220 mg, 0.3 mmol, 10 mol%) was added dioxane (10 mL), followed by 1 M aq K3PO4 (5.0 mL, 5 mmol). The resulting mixture was irradiated in microwave at 110 oC for 2 h, diluted with H20 (10 mL) and extracted with EtOAc (30 mL x 2). The combined extracts were concentrated and purified by Biotage SNAP KP-Sil and 100 g column (EtO Ac/hex 0-100% then MeOH/DCM 0-15%) to give the crude nitro. LCMS [M+H]+ = 431.3.


Step 3: 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline

[00211] To a solution of 4-(5-(2-fluoro-5-nitro-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)pyrimidin-2-yl)mo holine (1.081 g) in 1 : 1 MeOH/THF (30 mL) at ambient temperature was added a suspension of Raney -Nickel (129 mg, 0.5 mmol) in MeOH (2 mL), followed by hydrazine monohydrate (0.44 mL, 9 mmol) dropwise over 1 min. After addition, the reaction mixture was stirred at rt for 15 min. Additional MeOH (5 mL) and THF (5 mL) was added and the mixture was heated at 60 °C. Additional Raney-Nickel (129 mg, 0.5 mmol) in MeOH (2 mL) was added, followed by hydrazine monohydrate (0.44 mL, 9 mmol). The reaction mixture was heated at 60 °C for 30 min. The mixture was allowed to cool, passed through celite and rinsed with MeOH (30 mL x 2) and DCM (20 mL). The filtrate was concentrated to about 30 mL of volume. The resulting precipitate was collected by suction filtration to give the title compound as a grey solid. LC-MS [MH]+ 401.3.


Step 4: N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide

[00212] To a 25 mL round bottomed flask charged with 6-chloro-4- (trifluoromethyl)nicotinic acid (406 mg, 1.8 mmol) was added thionyl chloride (2.18 mL, 30 mmol). The resulting suspension was heated at 80 °C for 1 h. The mixture was evaporated to give a light yellow oil which was treated with DCM (10 mL), 4-fluoro-5-(2-mo holinopyrirnidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (601 mg, 1.5 mmol) and Et3N (0.63 mL, 4.5 mmol). The resulting mixture was stirred at ambient temperature for 1 h. After quenching with sat. aq NaHCCb (20 mL), the mixture was extracted with DCM (30 mL x 2) and the combined extracts were evaporated and dried to give the chloro intermediate as a light brown foam. The resulting chloropyridine intermediate was taken up in HOAc H20 (10 mL/3 mL) and NaOAc (246 mg, 3 mmol) was added in a 20 mL microwave vial. The mixture was irradiated in a microwave apparatus at 160 °C for 6 h. LCMS showed completion of the reaction. After removal of HO Ac using a Rotovap at (bath heated to 60 °C), the residue was diluted with DCM (30 mL), basified with sat. NaHC03 (20 mL) and extracted with DCM (50 mL x 2). The combined extracts were concentrated and purified by Biotage SNAP KP-Sil using a 50g column. Fractions showing clean product were combined concentrated and dried to give the title compound as an off-white solid (460 mg, 51% yield). H NMR (500MHz, MeOD-d4) δ = 8.58 - 8.55 (m, 2H), 7.98 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.10 (d, J=12.1 Hz, 1H), 6.93 (s, 1H), 3.89 - 3.82 (m, 4H), 3.81 - 3.75 (m, 4H), 3.08 (d, J=11.2 Hz, 2H), 2.67 - 2.52 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); 19F NMR (471MHz, METHANOLS) δ = -63.80, -120.73; LCMS [MH]+ 590.32.

[00213] Example 9: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-(pyrrolidin-l-yl)pyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00214] The title compound was prepared similar to the sequence described above for the preparation of Example 3 using 2-(pyrrolidin-l-yl)pyrimidine-5-boronic acid pinacol ester in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester to give the title compound in 66% yield. H NMR (500 MHz, MeOD) δ 8.51 (s, 2H), 7.97 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 3.60 (t, J = 6.7 Hz, 4H), 3.02 (t, J = 5.0 Hz, 4H), 2.69 (s, J = 2.2 Hz, 4H), 2.40 (s, 3H), 2.05 -2.03 (m, 4H); LCMS [M+H]+ 546.38.

Example 10: N-(5-(2-(cyclopropylamino)pyrimidm-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00215] The title compound was prepared in 33% yield similar to the sequence described above for the preparation of Example 3 using 2-cyclopropylaminopyrimidine-5-boronic acid, pinacol ester in place of 2-(4^ο ηο1ίηο^ΓίΓ^ίηβ-5^θΓοηίΰ acid

pinacol ester. XH NMR (500 MHz, MeOD-d4) δ 8.47 (s, 2H), 8.03 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 11.7 Hz, 1H), 6.93 (s, 1H), 3.22 (s, 4H), 2.91 (s, 3H), 1.32 (dd, J= 9.0, 6.1 Hz, 4H); LCMS [M+H]+ 532.5.

Example 11: N-(5-(2-(cyclohexylamino)pyrimidm-5-yl)-4-fluoro-2-(4-methylpiperazm-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00216] The title compound was prepared in 29% yield similar to the sequence described above for the preparation of Example 3 using 2-(cyclohexylamino)pyrimidine-5-boronic acid, pinacol ester in place of 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester. H NMR (500 MHz, MeOD) δ 8.45 (s, 2H), 7.97 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 11.9 Hz, 1H), 6.92 (s, 1H), 3.86 - 3.75 (m, 1H), 3.01 (s, 4H), 2.69 (s, 4H), 2.39 (s, 3H), 2.02 (dd, J = 11.9, 2.2 Hz, 2H), 1.80 (dd, J = 10.5, 2.8 Hz, 2H), 1.68 (d, J = 12.9 Hz, 2H), 1.43 (d, J = 12.8 Hz, 2H), 1.31 (d, J= 13.4 Hz, 2H); LCMS [M+H]+ 574.4.

Example 12: N-(5-(2-ethoxypyrimidin-5-yl)-4-fluoro-2-( 4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluorometh l)-l,6-dihydropyridine-3-carboxamide


[00217] The title compound was prepared in 68% yield similar to the sequence described above for the preparation of Example 3 using 2-ethoxypyrimidine-5-boronic acid in place of 2-(4-mo holino)pyrimidine-5 -boronic acid pinacol ester. H NMR (500 MHz, MeOD) δ 8.74 (s, 2H), 7.98 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.03 (s, 4H), 2.68 (s, 4H), 2.39 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); LCMS [M+H]+ 520.9.

Example 13: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-methylpyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00218] The title compound was prepared in 50% yield similar to the sequence described above for the preparation of Example 3 using 2-methylpyrimidin-5-ylboronic acid pinacol ester in place of 2-(4-morpholino)pyrimidine-5 -boronic acid pinacol ester. XH NMR (500 MHz, MeOD-d4) δ 8.89 (s, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.98 (s, 1H), 7.17 (d, J = 12.1 Hz, 1H), 6.93 (s, 1H), 3.06 (t, J = 4.2 Hz, 4H), 2.75 (s, 3H), 2.72 (s, 4H), 2.41 (s, 3H); LCMS [M+H]+ 491.2.

Example 14: N-(5-(6-(cyclohexylamino)pyridin-3-yl)-4-fluoro-2-(4-methylpiperazin-1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide

[00219] The title compound was prepared in 99% yield similar to the sequence described above for the preparation of Example 3 using 6-(cyclohexylamino)pyridine-3-boronic acid pinacol ester in place of 2-(4-mo holino)pyrimidine-5 -boronic acid pinacol ester. l NMR (500 MHz, MeOD-d4) (major rotamer) δ 8.11 (s, IH), 7.97 (s, IH), 7.88 (d, J = 8.2 Hz, IH), 7.62 (d, J = 8.9 Hz, IH), 7.08 (d, J = 12.0 Hz, IH), 6.92 (s, IH), 6.59 (d, J = 8.8 Hz, IH), 3.71 - 3.63 (m, IH), 3.03 (s, 4H), 2.77 (s, 4H), 2.46 (s, 3H), 2.03 (dd, J = 12.4, 2.7 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.45 (td, J = 12.4, 3.3 Hz, 2H), 1.32 - 1.22 (m, 4H); LCMS [M+H]+ 573.4 g/mol.

Example 15: N-(4-fluoro-5-(2-hydroxypyrimidin-5-yl)-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00220] The title compound was isolated in 4% yield as a side product from the chromatographic purification of Example 12. lU NMR (500 MHz, MeOD-d4) δ 8.53 (s, 2H), 7.99 (s, IH), 7.91 (d, J= 8.3 Hz, IH), 7.17 (d, J= 12.0 Hz, IH), 6.93 (s, IH), 3.11 (s, 4H), 3.03 (s, 4H), 2.66 (s, 3H); LCMS [M+H]+ 493.3.

Example 16: N-(5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide

[00221] The title compound was prepared in 41% yield similar to the sequence described above for the preparation of Example 3 using 2-cyanopyrimidine-5-boronic acid pinacol ester in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester. XH NMR (500 MHz, MeOD-d4) δ 9.14 (s, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.20 (d, J = 12.3 Hz, 1H), 6.93 (s, 1H), 3.11 - 3.07 (m, 4H), 2.74 (s, 4H), 2.43 (s, 3H); LCMS [M+H]+ 501.8 g/mol.

Example 17: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-(2,2,2-Mfluoroethoxy)pyrimidin-5-yl)phenyl)-6 >xo-4-(Mfluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00222] The title compound was prepared in 81% yield similar to the sequence described above for the preparation of Example 3 using 2-(2,2,2-trifluoroethoxy)pyrimidine-5-boronic acid, pinacol ester in place of 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester. H NMR (500 MHz, MeOD-d4) δ 8.82 (s, 2H), 7.97 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 5.01 (q, J = 8.6 Hz, 2H), 3.06 - 3.02 (m, 4H), 2.70 (s, 4H), 2.40 (s, 3H); LCMS [M+H]+ 574.8.

Example 18: N-(4-fluoro-2-(4-methylpiperazin-l -yl)-5-(pyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide

[00223] The title compound was prepared in 78% yield similar to the sequence described above for the preparation of Example 3 using 5-pyrimidine boronic acid pinacol ester in place of 2-(4-morpholino)pyrimidine-5 -boronic acid pinacol ester. H NMR (500 MHz, MeOD-d4) δ 9.15 (s, 1H), 9.00 (s, 2H), 8.01 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.18 (d, J = 12.1 Hz, 1H), 6.92 (s, 1H), 3.06 (t, J = 4.4 Hz, 4H), 2.69 (s, 4H), 2.40 (s, 3H); LCMS [M+H]+ 476.9.

Example 19: N-(5-(2, 4-dimethoxypyrimidin-5-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00224] The title compound was prepared in 73% yield similar to the sequence described above for the preparation of Example 3 using 2,4-dimethoxypyrimidine-5-boronic acid, pinacol ester in place
acid pinacol ester. ¾ NMR (500 MHz, MeOD-cU) δ 8.22 (s, 1H), 7.95 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.92 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.03 (s, 4H), 2.71 (s, 4H), 2.41 (s, 3H); LCMS [M+H]+ 537.3.

Example 20: 4-(difluoromethyl)-N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-l, 6-dihydropyridine-3-carboxamide

[00225] In a 5 ml microwave vessel to a suspension of 4-(difluoromethyl)-6-hydroxynicotinic acid (60.9 mg, 0.322 mmol) in anhydrous pyridine (391 μΐ, 4.83 mmol) was added slowly diethyl chlorophosphate (47.7 μΐ, 0.330 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred for 2 h. The suspension turned homogeneous and then a precipitate formed. To this mixture, 4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-mo holinopyrirnidin-5-yl)aniline (30 mg, 0.081 mmol) was added and the reaction was heated at 70 °C for 3 h. After completion, the pyridine was removed in vacuo and the residue partitioned between EtOAc (3 mL) and saturated aqueous NaHC03 (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2S04. The solvent was evaporated in vacuo yielding the crude product. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% DCM, 10% MeOH, 1% NH4Ac/DCM) to afford the desired compound in 72% yield. ¾ NMR (500 MHz, MeOD-cU) δ 8.55 (d, J = 1.1 Hz, 2H), 8.03 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 55.0 Hz, 1H), 7.10 (d, J = 12.1 Hz, 1H), 6.81 (s, 1H), 3.85 - 3.82 (m, 4H), 3.77 - 3.75 (m, 4H), 3.02 (s, 4H), 2.67 (s, 4H), 2.38 (s, 3H); LCMS [M+H]+ 544.4.

Example 21: N-[2-[3-(dimethylamino)pyrrolidin-l-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

Step 1 : l-(5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine


[00226] A suspension of 3-(dimethylamino)pyrrolidine (0.40 mL, 3.1 mmol) and

K2C03 (0.22 g, 1.6 mmol) in toluene (4 mL) was warmed to 45 °C. After 10 minutes 2,4-difluoro-1 -nitrobenzene (0.35 mL, 3.1 mmol) was added dropwise. The reaction was maintained at 45 °C for 1 h. The reaction was concentrated onto celite and flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded l-(5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.33 g, 41 %). LCMS [M+H]+: 254.0.

Step 2: l-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine


[00227] A solution of l-(5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine

(0.325 g, 1.3 mmol) and NBS (0.22 g, 1.3 mmol) in acetic acid (10 mL) was heated at

105 °C for 2 h. The reaction was cooled to room temperature and poured into water. The mixture was carefully neutralised with Na2C03 (2M Aq.) and the resultant was extracted exhaustively with DCM. The combined extracts were dried over magnesium sulfate,

filtered and concentrated to dryness. Flash chromatography [1-10% DCM/MeOH + 1% NH40H] afforded the title compound (0.184 g, 43 %). LCMS [M+H]+: 332.2.

Step 3: l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine


[00228] A 30 mL vial was charged with a mixture of l-(4-bromo-5-fiuoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.092 g, 0.277 mmol), 2-(4-Mo holino)pyrimidine-5-boronic acid pinacol ester (0.113 g, 0.388 mmol), XPhos Pd G2 (4.36 mg, 5.54 μηιοΐ) and XPhos (2.64 mg, 5.54 μηιοΐ). The vial was sealed with a cap/septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (4 ml) and 2M Aq sodium carbonate (0.692 ml, 1.385 mmol) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated in an aluminum block overnight at 95 °C. LCMS [BJW-5015-0054-01; more polar method] indicated clean conversion to the desired product. The reaction mixture was loaded onto celite and purified by flash [0.5-10% MeOH/DCM + 1% NH4OH] to afford l-(5-fluoro-4-(2-moφholinopyrilnidin-5-yl)-2-nitrophenyl)-N,N-dimethylpylτolidin-3-amine (0.271 mmol, 98 % yield) as a yellow film that was >95% pure by LCMS. LCMS [M+H]+: 417.3.

Step 4. l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine


[00229] A mixture of l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.113 g, 0.271 mmol), iron (0.076 g, 1.357 mmol) and acetic acid (3 ml) was heated to 85 °C for 1 h. The reaction mixture was cooled, diluted with DCM, and decanted by pipette to a round bottom flask. LCMS indicated complete consumption of the starting nitro compound. Concentration onto celite followed by flash [0.1-10% MeOH/DCM + 1% NH4OH] afforded l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (0.204 mmol, 75 % yield) [BJW-5015-0056-02] as a yellow foam that was -92% pure by LCMS. LCMS [M+H]+ = 387.3

Step 5: N-[2-[3-(dimethylamino)pyrrolidin-l-ylJ-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00230] Diethyl chlorophosphate (0.118 ml, 0.818 mmol) was added to a stirring solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (0.169 g, 0.818 mmol) in pyridine (Py) (2 ml) at room temperature. After stirring for 45 minutes the solution of activated acid was added to a stirring solution of l-(2-amino-5-fiuoro-4-(2-

mo holino yrimidin-5-yl) henyl)-N,N-dimethyl yrrolidin-3-amine (0.079 g, 0.204 mmol) also in pyridine (2 ml) at room temperature. The reaction was heated to 75 °C for ~5 h. LCMS indicated complete conversion to the desired product along with the excess nicotinic acid. The reaction was concentrated onto celite and purified by flash RP on the biotage [5-95% MeCN/water - no modifier] to afford N-(2-(3-(dimetiiylainino)pyrrolidin-l-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (0.064 mmol, 32 % yield) as a tan solid.1H-NMR (500 MHz, DMSO-d6) δ = 12.56 (br. s., 1H), 9.82 (s, 1H), 8.51 (s, 2H), 7.96 (br. s., 1H), 7.32 (d, J=7.5 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=13.3 Hz, 1H), 3.76 - 3.67 (m, 8H), 3.41 - 3.38 (m, 2H), 3.26 - 3.22 (m, J=8.6, 8.6 Hz, 1H), 2.64 (br. s., 2H), 2.19 - 2.13 (m, 6H), 2.07 (br. s., 1H),1.74 - 1.67 (m, 1H); LCMS [M+H]+ 576.5.

Example 22: N-[5-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1 : N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00231] To a solution of 4-(1iifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid (800 mg, 2.60 mmol) in pyridine (6.0 mL) was added slowly diethyl chlorophosphate (0.384 ml, 2.65 mmol) at rt in an atmosphere of argon, and the reaction mixture was stirred at rt for about 1 h. The clear solution became cloudy/suspension. To this was then added 5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)aniline (150 mg, 0.521 mmol) in one lot, and the reaction mixture was heated to 90°C under argon atmosphere. The reaction was complete in 2 h. A mixture of the desired product along with the excess 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid was observed. The reaction mixture was concentrated to dryness and the residue was co-evaporated twice with toluene to remove the residual pyridine. The residue was taken up in DCM and adsorbed onto celite and purified on Isco column (24 g), to afford the title compound as a beige solid (237 mg). LCMS [M + H]+ = 577.6

Step 2. N-(5-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00232] N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l -yl)phenyl)-4- (trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (35 mg, 0.061 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid, pinacol ester (17.83 mg, 0.085 mmol) were mixed in 1,4-dioxane (2 ml). Potassium phosphate tribasic reagent grade, >=98% (25.7 mg, 0.121 mmol) was added as a solution in 0.5 ml water and the vial was flushed with nitrogen. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.29 mg, 6.06 μηιοΐ) was added, the vial was sealed, and the mixture heated in a microwave reactor to 110°C for 30 minutes. The crude mixture was concentrated onto celite and purified on Isco (4G) column, eluting with DCM containing 0-2 % methanol. The product containing fractions were combined and concentrated to afford the title compound as a pale yellow glassy solid (34 mg). LCMS [M+H]+ = 581.4.

Step 3: N-(5-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00233] TFA (1 ml) was added to a solution of the N-(5-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-2-(trifluoromethyl)-4-(2-(trimethylsilyl)ethoxy)benzamide in DCM (2 ml) at RT and the reaction mixture was stirred at RT. LCMS showed completion of the reaction after 0.5 h. The mixture was concentrated to dryness, and the residue was triturated with diethylether. The solid was filtered and dried under high vacuum to obtain the desired product as a beige solid (22 mg). XH NMR (500MHz, MeOD-d4) δ = 8.02 (s, 1H), 7.84 - 7.74 (m, 1H), 7.06 (d, J=12.2 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.11 (br. s., 1H), 4.31 (q, J=2.7 Hz, 2H), 3.92 (t, J=5.4 Hz, 2H), 3.61 (d, J=11.4 Hz, 2H), 3.29 - 3.21 (m, 2H), 2.97 (s, 3H), 2.72 - 2.64 (m, 4H), 2.72 - 2.64 (m, 4H), 2.51 (br. s., 2H). LCMS [M+H]+ 481

Example 23: N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(l,2, 3, 6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: tert-butyl 4-(2-fluoro-4-(4-methylpiperazin-l-yl)-5-(4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamido)phenyl)-3, 6-dihydropyridine-l(2H)-carboxylate


[00234] N-(5-Bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (35 mg, 0.061 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-1-carboxylate (26.2 mg, 0.085 mmol) were mixed in 1,4-dioxane (1.5 ml). Potassium phosphate tribasic reagent grade, >=98% (25.7 mg, 0.121 mmol) was added as a solution in 0.5 ml water and the vial was flushed with nitrogen. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.29 mg, 6.06 μηιοΐ) was added, the vial was sealed, and the mixture heated in a microwave reactor to 110°C for 30 minutes. The crude mixture was concentrated onto celite and purified on silica gel chromatography, eluting with hexanes containing 0-50 % ethylacetate. The product containing fractions were combined and concentrated to afford the title compound as a white foam (27 mg). LCMS [M+H]+ = 681.2.

Step 2: N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(l,2, 3, 6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00235] TFA (1 ml) was added to a solution of the starting material in DCM (2 ml) at RT and the reaction mixture was stirred at RT. LCMS showed completion of

the reaction after 0.5 h. The reaction mixture was concentrated to dryness, and the residue was triturated with diethylether. The solid was filtered and dried under high vacuum to obtain the desired product as a pale yellow solid (29 mg, 93% yield). 1H-NMR (500MHz, METHANOL-d4) δ = 8.01 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.11 (d, J=12.1 Hz, 1H), 6.95 (s, 1H), 6.09 (br. s., 1H), 3.89 (d, J=2.4 Hz, 2H), 3.62 (d, J=11.4 Hz, 2H), 3.48 (t, J=6.1 Hz, 2H), 3.40 - 3.34 (m, 2H), 3.31 - 3.22 (m, 2H), 3.17 - 3.07 (m, 2H), 2.97 (s, 3H), 2.80 (br. s., 2H). LCMS [M+H]+ = 480

Example 24: N-[4-fluoro-2-(4-methylpiperazin-l -yl)phenyl] -6-oxo-4- (rifluoromethyl)-lH-pyridine-3-carboxamide ( Comparative Example)


Step 1 : N-(4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00236] N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (35 mg, 0.061 mmol) and l-methyl-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (18.93 mg, 0.085 mmol) were mixed in 1,4-dioxane (1.5 ml). Potassium phosphate tribasic reagent grade, >=98% (25.7 mg, 0.121 mmol) was added as a solution in 0.5 ml water and the vial was flushed with nitrogen. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.29 mg, 6.06 μηιοΐ) was added, the vial was sealed, and the mixture heated in a microwave reactor to 110°C for 30 minutes. The crude mixture was concentrated onto celite and purified on Isco (4G) column, eluting with hexanes containing 0-60 % EA. The product containing

fractions were combined and concentrated to afford the title compound as a pale yellow foam (13.5 mg, 44.7% yield). LCMS [M+H]+ = 499.6.

Step 2: N-[4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00237] TFA (1 mL) was added to a solution of the starting material in DCM (2 ml) at RT and the reaction mixture was stirred at RT. LCMS showed completion of the reaction after 1.5 h. The reaction mixture was concentrated to dryness, and the residue was triturated with diethyl ether. The solid was filtered and dried under high vacuum to obtain the desired product as a pale yellow solid.(10 mg, 65% yield). ^-NMR (500MHz, METHANOL-d4) δ = 7.89 (s, 1H), 7.70 (dd, J=6.0, 8.8 Hz, 1H), 6.97 (dd, J = 2.8, 10.0 Hz, 1H), 6.88 (dt, J=2.8, 8.4 Hz, 1H), 6.83 (s, 1H), 3.50 (d, J=l l. l Hz, 2H), 3.21 - 3.18 (m, 2H), 3.17 - 3.09 (m, 2H), 3.02 - 2.93 (m, 2H), 2.86 (s, 3H); LCMS [M+H]+ 399.

Example 25: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] ' -3-methylbenzamide


[00238] To a 25 mL RBF charged with 4-fluoro-3-methylbenzoic acid (46 mg,

0.3 mmol) was added thionyl chloride (0.364 mL, 5 mmol). The resulting suspension was heated at 80 °C for 1 h. It was evaporated to give a light yellow oil which was

treated with DCM (3 mL), 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol, obtained from Step 3, Example 8 above) followed by EtsN (0.042 mL, 0.3 mmol). The resulting dark red mixture was stirred at rt 1 h, quenched with sat. aq NaHCC (10 mL) and extracted with DCM (20 mL x 2). The combined extracts were concentrated and purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-5%) to give the title compound as a beige solid (43.1 mg, 80%).1H-NMR (500MHz, CHLOROFORM-d) δ 9.18 (s, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.59 (s, 2H), 7.82 (dd, J=1.8, 7.1 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.17 (t, J=8.8 Hz, 1H), 7.02 (d, J=11.2 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.85 - 3.78 (m, 4H), 2.92 (d, J=11.0 Hz, 2H), 2.70 (t, J=10.9 Hz, 2H), 2.46 - 2.37 (m, 8H), 1.18 (d, J=1.0 Hz, 6H); LC-MS [M + H]+ 537.43.

Example 26: N-[4-fluoro-2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(rifluoromethyl)-lH-pyridine-3-carboxamide ( Comparative Example)


[00239] A suspension of cis-l,2,6-trimethylpiperazine (0.40 g, 3.1 mmol) and potassium carbonate (0.26 g, 1.9 mmol) in toluene (4 mL) was warmed to 45 °C.

After 10 minutes 2,4-difiuoro-l -nitrobenzene (0.35 mL, 3.1 mmol) was added dropwise. The reaction was stirred at 45 °C for 1 h and then cooled to room temperature. The reaction mixture was partitioned between DCM and water and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried over magnesium sulfate. After removal of the inorganics by filtration the filtrate was concentrated onto celite and purified by flash

chromatography [0.5-10% MeOH/DCM + 1% NH4OH] to afford cis-4-(5-fluoro-2-nitrophenyl)-l,2,6-trimethylpiperazine (0.71 g, 85 %). LCMS [M+H]+: 268.2.

Step 2: cis-4-fluoro-2-( 3, 4, 5-trimethylpiperazin-l-yl)aniline


[00240] A solution of cis-4-(5-fluoro-2-nitrophenyl)-l,2,6-trimethylpiperazine

(0.155 g, 0.58 mmol) in methanol (5 mL) was hydrogenated in the presence of platinum(rV) oxide (0.013 g, 0.058 mmol) at 1 atm of H2 (g). After 6 h the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] to afford cis-4-fluoro-2-(3,4,5-trimethylpiperazin-l-yl)aniline (0.11 g, 82 %). LCMS [M+H]+: 238.1.

Step 3: cis-N-( 4-fluoro-2-(3, 4, 5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(rifluoromethyl)-!, 6-dihydropyridine-3-carboxamide


[00241] A suspension of 6-chloro-4-(trifluoromethyl)nicotinic acid (0.057 g, 0.25 mmol) and thionyl chloride (0.8 mL, 10 mmol) was heated at 80 °C for 1 h. The reaction mixture was concentrated to dryness to afford the acid chloride which was suspended in anhydrous dichloromethane (5 mL) and treated with cis-4-fiuoro-2-(3,4,5-trimethylpiperazin-l-yl)aniline (0.050 g, 0.2 mmol) and triethylamine (0.09 mL, 0.6 mmol) at room temperature. After 1 h the reaction was quenched with sat. aq NaHCCb (10 mL) and extracted into DCM. The combined extracts were concentrated and the residue was dried under reduced pressure to afford cis-6-chloro-N-(4-fiuoro-2-(3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)nicotinamide. The resulting chloropyridine intermediate was taken up in HOAc/H20 (7 mL/2mL) and sodium acetate (0.035 g, 0.42 mmol) was added. The mixture was irradiated in a microwave apparatus at 160 °C for 4 h. The reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] to afford the title compound cis-N-(4-fluoro-2-(3 ,4,5 -trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 , 6-dihydropyridine-3-carboxamide (0.063 g, 67 %). ¾-NMR (500MHz, DMSO-d6) δ = 12.44 (br. s., 1H), 9.41 (s, 1H), 7.88 (s, 1H), 7.64 (dd, J=6.6, 8.4 Hz, 1H), 6.99 - 6.86 (m, 2H), 6.81 (s, 1H), 2.97 (d, J=11.0 Hz, 2H), 2.43 (t, J=10.9 Hz, 2H), 2.37 - 2.30 (m, 2H), 2.19 (s, 3H), 1.00 (d, J=6.1 Hz, 6H); LCMS [M+H]+ 427.1

Example 27: 6^cetamido-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-4-(trifluoromethyl)pyridim


[00242] To a 5 mL microwave vial charged with 6-chloro-N-(4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)nicotinamide (60.7 mg, 0.1 mmol, prepared using the procedure described in the synthesis of Example 8), acetamide (30 mg, 0.5 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol, 10 mol%), xantphos (12 mg, 0.02 mmol, 20 mol%) and K2C03 (41 mg, 0.3 mmol) was added dioxane (3 mL). The resulting mixture was irradiated in microwave at 140 °C for 2 h. After passing through microfilter, the filtrate was concentrated, purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-5%), reversed phase C18 column (gradient: CH3CN (0.1% TFA)/H20 5-90%), porapak column and triturated with MeOH (2 mL) to give the title compound as a white solid (24.6 mg, 38% yield). XH-NMR (500MHz, CDC13) δ 8.74 (s, 1H), 8.68 - 8.56 (m, 5H), 8.15 (s, 1H), 7.04 (d, J=l l. l Hz, 1H), 3.93 - 3.86 (m, 4H), 3.84 -3.79 (m, 4H), 3.52 (d, J=4.6 Hz, 1H), 2.84 (d, J=11.0 Hz, 2H), 2.64 (t, J=10.9 Hz, 2H), 2.35 - 2.25 (m, 8H), 1.13 (d, J=6.2 Hz, 6H); LC-MS [M + H]+ 631.3.

Example 28: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-3, 5-dimethylbenzamide


[00243] To a 25 mL RBF charged with 4-fluoro-3,5-dimethylbenzoic acid (50 mg, 0.3 mmol) was added thionyl chloride (0.364 mL, 5 mmol). The resulting suspension was heated at 80 °C for 1 h. It was evaporated to give a light yellow oil which was treated with DCM (3 mL), 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol, obtained from the procedure used to produce Example 8 above) followed by EtsN (0.042 mL, 0.3 mmol). The resulting dark red mixture was stirred at rt for 1 h. After quenching with sat. NaHC03 (10 mL), it was extracted with DCM (20 mL x 2). The combined extracts were concentrated, loaded onto celite, dried and purified using Biotage SNAP KP-Sil 50 g (gradient: EtOAc/hex 0-100% then MeOH/DCM 0-8%). Fractions showing pure product were combined, concentrated, triturated with MeOH (3 mL), suction filtered and rinsed with MeOH (0.5 mL) to give a white solid. The filter cake was dried under vacuum to give a pale beige solid (4.6028-4.5767g=26.1mg, yield 47% based on 99.70% purity).1!! NMR (500MHz, CDC13) δ = 9.19 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.60 (s, 2H), 7.62 (d, J=6.7 Hz, 2H), 7.02 (d, J=11.2 Hz, 1H), 3.93 - 3.86 (m, 4H), 3.85 - 3.79 (m, 4H), 2.94 (d, J=11.0 Hz, 2H), 2.71 (t, J=10.9 Hz, 2H), 2.51 - 2.41 (m, 2H), 2.41 - 2.35 (m, 9H), 1.19 (d, J=6.2 Hz, 6H); LC-MS [M + H]+ 551.3.

Example 29: N-[4-fluoro-5-( 4-morpholin-4-ylphenyl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide

Step 1: 5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)aniline


[00244] The (2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2,6-trimethylpiperazine obtained from Example 8, Step 1 (2.16 g) was dissolved in MeOH (30 mL) and to it was added a suspension of Raney-Nickel, 2800 (269 mg, 3.14 mmol) in MeOH (5 mL), followed by hydrazine monohydrate (0.912 mL, 18.86 mmol). The reaction was exothermic. After completion of the addition, the resulting mixture was stirred at rt for 30 min. It was then heated to 50 °C and treated with additional hydrazine monohydrate (0.61 mL, 12.57 mmol), followed by Raney-Nickel, 2800 (0.162 g, 1.886 mmol). The resulting mixture was heated at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated and purified by Biotage SNAP KP-Sil 50 g (gradient: MeOH/DCM 0-15%) to give, after concentration of fractions showing product, 975 mg of the aniline product as alight brown solid. LCMS [M+H]+318.3.

Step 2: N-(5-bromo-4-fluoro-2-( (3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00245] To a 25 mL RBF charged with 6-chloro-4-(trifluoromethyl)nicotinic acid (271 mg, 1.2 mmol) was added thionyl chloride (3.64 mL, 50 mmol). The resulting suspension was heated at 80 °C for 1 h, then cooled and evaporated with a rotary evaporator to give a light yellow oil which was treated with DCM (10 mL), 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (316 mg, 1 mmol) and EtsN (0.42 mL, 3 mmol). The resulting mixture was stirred for 16 h at ambient temperature. The mixture was quenched with sat. aq NaHCCb (10 mL), extracted with DCM (30 mL x 2) and the combined extracts were evaporated and dried to give a light brown solid. A mixture of this solid, NaOAc (164 mg, 2 mmol) in HOAc/H20 (7 mL/2mL) in a 20 mL microwave vial was heated at 160 °C for 4 h. Solvents were removed using a rotary evaporator at 60 °C and the residue was treated with sat. NaHC03 (20 mL) and extracted with DCM (60 mL + 30 mL). The extracts were concentrated and purified by Biotage SNAP KP-Sil 50 g (gradient: EtOAc/hex 0-100% then MeOH/DCM 0-20%). Fractions containing product were concentrated and dried under vacuum to give a light beige solid (304 mg). LCMS [M + H]+ = 505.38.

Step 4: N-( 6-fluoro-4 '-morpholino-4-( ( 3S, 5R)-3, 4, 5-trimethylpiperazin-l -yl)-[l, 1 '-biphenylJ-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00246] To a 5 niL microwave vial charged with N-(5-bromo-4-fluoro-2- ((3 S,5R)-3,4,5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol), 4-(mo holino)phenylboronic acid (41.4 mg, 0.2 mmol), and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol, 20 mol%) was added dioxane (3 mL), followed by 1 M aq K3PO4 (0.5 mL, 0.5 mmol). The resulting mixture was irradiated in microwave at 110 °C for 2 h. LCMS showed completion of the reaction. The crude reaction mixture was loaded onto celite, dried and purified using Biotage SNAP KP-Sil 25g (gradient: EtOAc/hex 0-100% then MeOH/DCM 0-30%). Fractions showing impure product were concentrated, loaded onto celite, and repurified by Biotage SNAP C18 30g (gradient: CH3CN (0.1% TFA)/H20 5-30%). Fractions showing product were combined, passed through porapak 6cc, concentrated and dried to give the title compound as an off white solid (24.6 mg, 40% yield). ^-NMR (500 MHz, MeOD-d4) δ 7.96 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.07 -7.00 (m, 3H), 6.92 (s, 1H), 3.91 - 3.81 (m, 4H), 3.25 - 3.17 (m, 4H), 3.05 (d, J=l l. l Hz, 2H), 2.67 - 2.52 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.0 Hz, 6H); LC-MS [M+ H]+ 588.36.

Example 30: N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[6-(oxan-4-yloxy)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00247] To a 5 mL microwave vial charged with N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30.08 mg, 0.063 mmol), 2-(tetrahydropyran-4-yloxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (57.7 mg, 0.189 mmol), sodium carbonate, anhydrous (66.8 mg, 0.630 mmol) and XPhos (6.01 mg, 0.013 mmol), XPhos Pd G2

(9.92 mg, 0.013 mmol) was added water (1970 μΐ) / 1,4-dioxane (1182 μΐ) to give a white suspension. The resultant mixture was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 120 °C. The solvent (dioxane) was evaporated and 15 ml of DCM were added. The suspension was sonicated and the organic phase was removed and concentrated (3X). The resulting crude black oil was purified using a Biotage column, (100-0%, CH2C12: 10% MeOH in DCM + NH4Ac; in 10 min and isocratic for 5min [new isolera 2.3] using KP-SIL lOg column. Collected at 0% of the DCM) to yield the final product. The product was freeze dried for 2 days to yield 26.0 mg (68% yield) of the desired target compound. ¾-NMR NMR (500 MHz, MeOD) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.87 (d, J= 8.6 Hz, 1H), 7.12 (d, J= 11.9 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J= 8.6 Hz, 1H), 5.26 (tt, J= 8.4, 4.0 Hz, 1H), 3.98 (dt, J= 9.4, 4.5 Hz, 2H), 3.63 (ddd, J = 11.8, 9.1, 2.9 Hz, 2H), 3.05 (s, 4H), 2.80 (s, 4H), 2.48 (s, 3H), 2.13 - 2.06 (m, 2H), 1.82 - 1.74 (m, 2H); LCMS [M+H]+ = 576.3.

Example 31: N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00248] In a 10 niL microwave vial to a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (1048 mg, 5.06 mmol) in pyridine, anhydrous (6139 μΐ, 76 mmol) was added slowly diethyl chlorophosphate (749 μΐ, 5.19 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred at rt for 2 h. The suspension turned into a solution and then into a suspension again. To this, 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (400 mg, 1.265 mmol) was added and the reaction was heated at 70 °C for 3 h. After completion, pyridine was removed in vacuo and the residue partitioned between dichloromethane (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2SC>4. The solvent was evaporated in vacuo yielding the crude product which was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the title compound (192 mg, 30%). XH NMR (500 MHz, MeOD) δ 8.10 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.09 (d, J = 10.1 Hz, 1H), 6.90 (s, 1H), 3.00 (d, J = 11.0 Hz, 2H), 2.57 (t, J = 11.0 Hz, 2H), 2.54 - 2.49 (m, 2H), 2.35 (s, 3H), 1.14 (d, J= 6.0 Hz, 6H); LCMS [M+l]+ = 505.00.

Step 2: N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S, 5RJ-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00249] To a 5 mL microwave vial charged with N-(5-bromo-4-fluoro-2-((3R,5S)- 3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (29.85 mg, 0.059 mmol), prepared according to the method described in

Example 29), 2-cyanopyrimidine-5-boronic acid pinacol ester (40.9 mg, 0.177 mmol), sodium carbonate, anhydrous (62.6 mg, 0.591 mmol) and XPhos (5.63 mg, 0.012 mmol), XPhos Pd G2 (9.30 mg, 0.012 mmol) was added in water (1846 μΐ) / 1,4-dioxane (1108 μΐ) to give a white suspension that was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 120 °C. The solvent was evaporated and 15 ml of DCM was added. The suspension was sonicated and the organic phase was removed and concentrated (3X). The crude black oil was purified using a Biotage column, (100-0%, CH2C12: 10% MeOH in CH2C12 + NH4Ac; in 10 min and isocratic for 5min using KP-SIL lOg column. Collected at 0% of the CH2C12) to yield an impure product. The product was freeze dried for 2 days to yield the crude product that was purified via preparatory HPLC. The fractions were evaporated and the concentrate was slowly passed through a ionic exchange column Rxn CX 6cc with MeOH and NH4OH. The product was lyophilized to yield 8.1 mg (26% yield) of the title compound. ¾-NMR (500 MHz, MeOD) δ 9.14 (s, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.16 (d, J = 12.4 Hz, 1H), 6.92 (s, 1H), 3.15 (d, J = 11.6 Hz, 2H), 2.65 (t, J = 11.2 Hz, 2H), 2.61 - 2.54 (m, 2H), 2.39 (s, 3H), 2.03 (s, 1H), 1.17 (d, J = 6.1 Hz, 6H); LCMS [M+H]+ 530.

Example 32: N-[4-fluoro-5-( 6-morpholin-4-ylpyridin-3-yl)-2-[( 3S, 5R)-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridin^


[00250] A procedure was used similar to that used for Example 31 above using

N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-aihydropyridine-3-carboxamide (28.89 mg, 0.057 mmol), 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-mo holine (49.8 mg, 0.172 mmol), sodium carbonate, anhydrous (60.6 mg, 0.572 mmol) and XPhos (5.45 mg, 0.011 mmol), XPhos Pd G2 (9.00 mg, 0.011 mmol) to give 33.7 mg (82% yield) of the title compound. ¾-NMR (500 MHz, MeOD-d4) δ 8.32 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.3

Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.83 - 3.80 (m, 4H), 3.56 - 3.53 (m, 4H), 3.13 (d, J = 11.6 Hz, 2H), 2.80 (s, 2H), 2.70 (t, J = 11.3 Hz, 2H), 2.53 (s, 3H), 1.23 (d, J = 6.2 Hz, 6H); LCMS [M+H]+ 589.

Example 33: N-[4-fluoro-5-(2-methylpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00251] A procedure was used similar to that used for Example 31 above with

N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (28.40 mg, 0.056 mmol), 2-methylpyrimidin-5-ylboronic acid pinacol ester (37.1 mg, 0.169 mmol), sodium carbonate, anhydrous (59.6 mg, 0.562 mmol) and XPhos (5.36 mg, 0.011 mmol), XPhos Pd G2 (8.84 mg, 0.011 mmol) gave 17.3 mg (59% yield) of the title compound. ^-NMR (500 MHz, MeOD) δ 8.89 (s, 2H), 7.97 (d, J = 9.3 Hz, 1H), 7.96 (s, 1H), 7.14 (d, J = 12.1 Hz, 1H), 6.92 (s, 1H), 3.11 (d, J = 11.1 Hz, 2H), 2.74 (s, 3H), 2.67 - 2.56 (m, 4H), 2.40 (s, 3H), 1.17 (d, J = 6.0 Hz, 6H); LCMS [M+H]+ 519.

Example 34: 4-(difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide

Step 1: methyl 4-formyl-6-methoxynicotinate


[00252] To a solution of the commercially available 5-bromo-2-methoxyisonicotinaldehyde (5.0 g, 23.2 mmol, leq) in MeOH was added triethylamine (12eq), Pd (dppfjC^ (O. leq) at 70°C under 50 psi of CO gas in a steel bomb for 16h. Subsequent reaction work-up and flash column chromatography on silca-gel afforded 1.8 g (39% yield) of the desired compound, methyl 4-formyl-6-methoxynicotinate; LCMS [M + H]+ 196.

Step 2: methyl 4-(difluoromethyl)-6-methoxynicotinate


[00253] To a solution of the methyl 4-formyl-6-methoxynicotinate (1.8 g, 9.2 mmol, leq) in DCM was added DAST fluoride (4eq) at -78°C and the mixture was maintained at RT for 16h. TLC analysis indicated formation of less polar spot. Subsequent reaction work-up and flash column chromatography on silca-gel afforded 1.3 g (65% yield) of the desired intermediate, methyl 4-(difiuoromethyl)-6-methoxynicotinate; LCMS [M + H]+ 218.

Step 3: methyl 4-(difluoromethyl)-6-oxo-l, 6-dihydropyridine-3-carboxylate


[00254] A solution of the methyl 4-(difluoromethyl)-6-methoxynicotinate (2.5 g, 11.5 mmol, leq) and Nal (3eq) in acetonitrile was treated with TMS -chloride (3eq) at RT. The resulting mixture was heated to 90°C for 3h. TLC analysis indicated formation of polar spot. Reaction work-up and trituration with ether gave 1.7g (73% yield) of the intermediate, methyl 4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate; LCMS [M + H]+ 204.

Step 4: 4-(difluoromethyl)-6-oxo-l , 6-dihydropyridine-3-carboxylic acid


[00255] A solution of the methyl 4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (1.7 g, 8.3 mmol, leq) in MeOH : THF : Water (3:2: 1) was treated with LiOH.H20 (4.5eq) at RT and heated to 75°C for 16h. TLC analysis indicated consumption of the starting material. Removal of the organic solvent under vacuum followed by neutralization to acidic pH gave 1.15g (73% yield) of the desired acid, 4-(difluoromethyl)-6-oxo- l,6-dihydropyridine-3-carboxylic acid as a white solid; LCMS [M + H]+ 190.

Step 5: 4-(difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3S, 5R)-3, 4, 5-trimethylpiperazi -l-yl]phenyl]-6-oxo-lH-pyridine-3-carboxamide


[00256] In a 10 ml microwave vial to a suspension of 4-(difiuoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylic acid (37.2 mg, 0.197 mmol) in anhydrous pyridine (239 μΐ, 2.95 mmol) was added slowly diethyl chlorophosphate (29.1 μΐ,

0.202 mmol) at ambient temperature in an atmosphere of nitrogen. The reaction mixture was stirred at rt for 2 h. To this mixture then was added 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (obtained from Example 8, Step 3) and the reaction was heated at 70 °C for 3 h. After completion, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2S04. The solvent was evaporated in vacuo yielding the crude product. Purification was performed via Biotage column, (100-0%, DCM: 10% MeOH in DCM + NH4Ac; in 10 min and isocratic for 5min [new isolera 2.3] using KP-SIL lOg column) to yield the product that was lyophilized for 1 day to obtain after further purification using prep HPLC 15.7 mg (55% yield) of the title compound. XH-NMR (500 MHz, MeOD) δ 8.54 (d, J = 1.1 Hz, 2H), 8.01 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 55.1 Hz, 3H)7.06 (d, J = 12.1 Hz, 1H), 6.81 (s, 1H), 3.86 - 3.81 (m, 4H), 3.78 - 3.74 (m, 4H), 3.07 (d, J = 11.2 Hz, 2H), 2.60 (t, J = 11.1 Hz, 2H), 2.54 (d, J = 6.2 Hz, 2H), 2.37 (s, 3H), 1.15 (d, J = 6.1 Hz, 6H); LCMS [M+H]+ 572.

Example 35: N-[4-fluoro-5-pyridin-3-yl-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00257] The title compound (23.2 mg, 56%) was prepared according to a procedure similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (40.4 mg, 0.08 mmol) and 3-pyridinylboronic acid (20 mg, 0.16 mmol). XH-NMR (500MHz, METHANOL-d4) δ 8.75 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.98 (d, J=7.2 Hz, 2H), 7.56 (dd, J=5.0, 8.0 Hz, 1H), 7.13 (d, J=12.1 Hz, IH), 6.93 (s, IH), 3.12 (d, J=11.4 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.61 -2.52 (m, 2H), 2.40 (s, 3H), 1.19 (d, J=6.1 Hz, 6H); LC-MS [M + H]+ 504.25.

Example 36: N-[4-fluoro-5-pyridin-4-yl-2-[(3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00258] The title compound (24.0 mg, 58% yield) was prepared according to a procedure similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (40.4 mg, 0.08 mmol) and 4-pyridylboronic acid (20 mg, 0.16 mmol). ^-NMR (500 MHz, METHANOL-d4) δ 8.62 (d, J=5.3 Hz, 2H), 8.04 (d, J=8.2 Hz, IH), 7.98 (s, IH), 7.67 (d, J=4.9 Hz, 2H), 7.12 (d, J=12.5 Hz, IH), 6.93 (s, IH), 3.14 (d, J=11.4 Hz, 2H), 2.69 - 2.61 (m, 2H), 2.61 - 2.52 (m, 2H), 2.39 (s, 3H), 1.19 (d, J=6.1 Hz, 6H); LC-MS [M + H]+ 504.25.

Example 37: N-[2-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00259] The title compound was prepared similar to the sequence described above for the preparation of Example 21 above using (R)-(+)-3-(dimethylamino)pyrrolidine in place of racemic 3-(dimethylamino)pyrrolidine in Step 1 to give the title compound (31 mg, 22% yield for the last step). XH NMR (500MHz, DMSO-d6) δ = 12.56 (br. s., 1H), 9.82 (s, 1H), 8.51 (s, 2H), 7.96 (br. s., 1H), 7.32 (d, J=7.5 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=13.3 Hz, 1H), 3.76 - 3.67 (m, 8H), 3.41 - 3.38 (m, 2H), 3.26 - 3.22 (m, J=8.6, 8.6 Hz, 1H), 2.64 (br. s., 2H), 2.19 - 2.13 (m, 6H), 2.07 (br. s., 1H), 1.74 - 1.67 (m, 1H); LCMS [M+H]+ 576.3.

Example 38: N-[2-[(3S)-3-(dimethylamino)pyrrolidin-l-ylJ-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00260] The title compound was prepared similar to the sequence described above for the preparation of Example 21 using (S)-(-)-3-(dimethylamino)pyrrolidine in place of racemic 3-(dimethylamino)pyrrolidine in Step 1 to give 28 mg (23% yield) of the title compound for the last step H-NMR (500MHz, DMSO-d6) δ = 12.56 (br. s., 1H), 9.82 (s, 1H), 8.51 (s, 2H), 7.96 (br. s., 1H), 7.32 (d, J=7.5 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=13.3 Hz, 1H), 3.76 - 3.67 (m, 8H), 3.41 - 3.38 (m, 2H), 3.26 - 3.22 (m, J=8.6, 8.6 Hz, 1H), 2.64 (br. s., 2H), 2.19 - 2.13 (m, 6H), 2.07 (br. s., 1H), 1.74 - 1.67 (m, 1H); LCMS [M+H]+ 576.1.

Example 39: N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[( 3S, 5R)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


Step 1: l-bromo-2,4-difluoro-5-nitrobenzene


[00261] To a suspension of l-bromo-2,4-difluorobenzene (lOg, 52.1mmol, l.Oeq) in cold H2SO4 (37.9mL) was added Conc.HN03 (33.3mL) in a dropwise manner keeping the internal temp 20°C, stirred for 10 min at 0°C then, the reaction mixture was poured into a mixture of diethyl ether (250mL) and ice water (250mL) with vigorous stirring. The organic layer was separated and the aqueous layer was again extracted with Et20 (250mL). The combined organic layer was washed with Satd. sodium bicarbonate (2 X 200 mL) followed by satd. brine (2 X 200 mL) solution. The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO¾ 100-200 mesh) using 15% EtOAc in pet ether as an eluent to give l-bromo-2,4-difluoro-5 -nitrobenzene (52g, 72% yield) as a yellow color liquid. LCMS: M+H]+ 272.23.

Step 2: (2S, 6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2, 6-trimethylpiperazine


[00262] solution of l-bromo-2,4-difluoro-5-nitrobenzene (2.71g,

21.1 mmol, leq) in ethanol (lOOmL) was added TEA (3.49mL, 25.2mmol, 1.19eq) under argon for 20 mins then followed by addition of (2S,6R)- 1,2,6- trimethylpiperazine (5.0 g, 21.1 mmol, 1.7 eq) at RT under argon atmosphere and heated to 85°C for 16 h. TLC analysis indicated formation of polar spot. Then, the reaction mixture was cooled to RT, solvent was evaporated under reduced pressure, the crude product was poured on ice-water (300mL), and extracted with EtOAc (2X lOOmL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give crude product which was purified by combiflash column chromatography using 3% methanol in DCM as an eluent to afford l-bromo-2,4-difiuoro-5 -nitrobenzene (5.2 g, 70%) as a pale yellow color liquid. LCMS: [M+H]+ 348.15.

Step 3: 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline


[00263] To a solution of l-bromo-2,4-difluoro-5-nitrobenzene (2.5 g, 7.2 mmol, leq) in ethanol: water (30mL: 10mL) was added NH4C1 (0.95g, 57.97mmol, 4+4eq) followed by iron powder (3.24 g, 57.9 mmol, 4+4eq) at RT under argon atmosphere and heated to 80°C for 16h. TLC analysis indicated formation of polar spot. Then, the reaction mixture was cooled to RT, filtered through a celite bed washed with methanol, and the filtrate was concentrated under reduced pressure to give crude product which was purified by neutral alumina column chromatography using 100% DCM as an eluent to afford 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (1.3 g, 59.1%) as an off white solid. LCMS: [M + H]+ 316.13.

Step 4: 6-chloro-4-(trifluoromethyl)


[00264] To a solution of butyl magnesium chloride (27.8mL, 47.2mmol, 0.7eq,

1.7 M in THF) in THF was added butyl lithium (30.0mL, 74.3mmol, l. leq, 2.5M in hexane) at 0°C and the reaction mixture was stirred for 10 min, then diluted with THF (80mL) and cooled to -78°C. Then, 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (17.5g, 67.5mmol, leqm procedure described in Example 93) in THF (30mL) was added and the reaction mixture was stirred for lh at same temperature, before being poured onto crushed dry ice then slowly allowed to warm to RT for 16h. TLC indicated polar spot and the reaction mixture was concentrated and acidified with 2N HC1 (80mL) and extracted with EtOAc (2X 500mL). The organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure to give crude residue. The crude compound was recrystallized from n-pentane (30mL) and dried using high vacuum to give 6-chloro-4-(trifluoromethyl)nicotinic acid (lOg, 66.6%) as an off white solid compound. LCMS: [M+H]+ 224.05.

Step 5: methyl 6-chloro-4-(trifluoromethyl)nicotinate


[00265] solution of 6-chloro-4-(trifluoromethyl)nicotinic acid (16.6g,

75.1mmol, leq) in acetone (160mL), potassium carbonate (15.55 g, 112.6mmol, 1.5eq) and dimethyl sulphate (8.21mL,97.6 mmol,1.3eq) was added at 0°C and the reaction mixture was allowed to come to RT and stirred for 2h.TLC analysis indicated formation of a non-polar spot. The reaction mixture was concentrated under reduced pressure and gave crude residue. The crude compound was dissolved in EtOAc (500mL) and washed with brine (2 X 200mL) and water (2X200mL). The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to result in crude product; which was purified by column chromatography (silica gell00-200mesh) using as an eluent 0-2% EtOAc in petroleum ether to give methyl 6-chloro-4-(trifluoromethyl)nicotinate (13g, 72.22%) as a liquid compound. LCMS: [M+H]+ 240.08.

Step 6: methyl 4-(trifluoromethy -6-(2-(trimethylsilyl)ethoxy)nicotinate

[00266] To a suspension of methyl 6-chloro-4-(trifluoromethyl)nicotinate

(12.7g, 53.1mmol, leq) in toluene (120mL), TMS-ethanol (4.71 mL,53.1 mmol,l eq), cesium carbonate (51.8g, 159.4mmol, 3eq ) and BINAP (3.571g, 5.3mmol, O. leq) were degassed with for 15 min and Pd(OAc)2 (0.95g, 4.2mmol, 0.08eq) was added then the reaction mixture was heated to 120°C for 2h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with EtOAc (500mL), filtered with a celite pad and concentrated under reduced pressure to result in crude product which was purified by column chromatography (silica gell00-200mesh) using 5% EtOAc in petroleum ether as an eluent to afford the desired compound (9.0g, 65%) as a pale yellow color liquid. LCMS: [M + H]+: 294.15.

Step 7: 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid


[00267] To a solution of methyl 4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinate (20g, 62.3mmol, leq) in THF: MeOH: H20 (60mL: 40mL: 20mL), lithium hydroxide monohydrate (10 g, 249.2 mmol, 4 eq) was added and the reaction mixture was stirred at RT for 16h.TLC analysis indicated polar spot. The reaction was concentrated under reduced pressure and gave crude compound. The crude compound was acidified with 2N HC1 (20mL), then the obtained precipitate was filtered off and washed with diethyl ether (50mL) and dried under high vacuum to give the desired compound 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid (9.2g, 48.40%) as an off white solid . LCMS: [M + H]+ 306.20.

Step 8: N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00268] To a solution of 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid (6.0g, 19.5mmol, l.Oeq) in dry DMF (70mL), HATU (11.13g, 29.3mmol, 1.5 eq) and DIPEA (6.6mL, 39.0mmol, 2.0eq) were added at RT and the reaction mixture was stirred for 10 min. Then 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (5.8g, 19.5 mmol, l.Oeq) was added and the reaction mixture was stirred for 48 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with EtOAc (2 X500mL) and washed with cold water (2X500mL) & Brine (2X200mL), The separated organic layers were combined, dried over Na2S04 and concentrated under reduced pressure to give crude product which was purified by column chromatography (Neutral AI2O3) using as an eluent 10%- 20% EtOAc in petroleum ether to give the title compound (5.2 g, 45%) as an off white solid. LCMS: [M + H]+: 604.8.

Step 9: N-(5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide


[00269] To a 20 mL microwave vial charged with N-(5-bromo-4-fluoro-2- ((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.532 g, 0.879 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.363 g, 1.318 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.062 g, 0.088 mmol) and potassium phosphate tribasic reagent grade, >98% (0.373 g, 1.757 mmol) was added water (1.464 ml) /1,4-dioxane (13.18 ml) to give a white suspension that was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 110 °C. The reaction was monitored by LCMS, which indicated that the reaction was complete. The solvent (dioxane) was evaporated and 15 ml of DCM were added. The suspension was sonicated and the organic phase was removed and concentrated (3X).

The crude brown oil was purified using a Biotage column, (100-0%, CH2CI2: 10% MeOH in CH2C12 + NH4Ac; in 10 min and isocratic for 5 min using KP-SIL 50g column. Collected at 10% of the CH2C12) to yield the intermediate product. The fractions were evaporated and the resulting product was lyophilized to give 295 mg (49.4% yield) of the target silylated intermediate. LCMS [M-H]- = 672.1.

Step 10: N-(5-( 6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-( ( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00270] To a solution of N-(5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2- ((3R,5 S)-3,4,5 -trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (135.26 mg, 0.201 mmol) in dry DMF (401 μί) was added CsF (91 mg, 0.602 mmol) and heated at 60 °C for 1 h. The reaction was monitored by LCMS which indicated that the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water, brine solution, concentrated under reduce pressure and freeze dried for 2 days to yield the title compound (0.182 mmol, 91 % yield). ^-NMR (500 MHz, MeOD) δ 8.27 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.6, 0.9 Hz, 1H), 7.09 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.15 (d, J = 7.1 Hz, 2H), 3.11 (d, J = 9.5 Hz, 2H), 2.75 - 2.62 (m, 4H), 2.46 (s, 3H), 1.35 - 1.25 (m, 1H), 1.20 (d, J = 5.6 Hz, 6H), 0.64 - 0.58 (m, 2H), 0.39 - 0.34 (m, 2H); LCMS [M+H]+ 574.

Example 40: N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00271] A procedure similar to that employed in Example 3, Step 2 using N- (5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30.53 mg, 0.064 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (47.8 mg, 0.192 mmol), anhydrous sodium carbonate (67.8 mg, 0.640 mmol), XPhos (6.10 mg, 0.013 mmol), and XPhos Pd G2 (10.07 mg, 0.013 mmol) gave 27.4 mg (78% yield) of the title compound as a white powder.1HNMR (500 MHz, MeOD) δ 8.41 (d, J = 1.1 Hz, 2H), 7.87 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 12.0 Hz, 1H), 6.82 (s, 1H), 3.12 (s, 6H), 2.92 (s, 4H), 2.62 (s, 4H), 2.32 (s, 3H); LCMS [M+H]+ 520.

Example 41: N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-[6-(morpholin-4-ylmethyl)pyridin-3-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH^yridine-3-carboxamide


[00272] A procedure similar to that of Example 3 using N-(5-bromo-4-fluoro-2- (4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30.77 mg, 0.064 mmol) and 6-(mo holinomethyl)pyridin-3-ylboronic acid (42.9 mg, 0.193 mmol) afforded 22.5 mg (55.9 % yield) of the title compound. XH- NMR (500 MHz, MeOD) δ 8.73 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 11.8 Hz, 1H), 6.94 (s, 1H), 3.93 (s, 2H), 3.78 (s, 4H), 3.21 (s, 4H), 2.84 (s, 3H), 2.76 (s, 4H); LCMS [M+H]+ 575.

Example 42: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-ylJphenyl]-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide


[00273] The title compound was prepared according to a method similar to that used in Example 34 above using 3-(trifluoromethyl)pyrazole-4-carboxylic acid (27 mg, 0.15 mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (20 mg, 0.05 mmol) to give 18.1 mg (62% yield) of the product as a white solid. XH NMR (500MHz, METHANOL-d4) δ 8.58 (s, 2H), 8.39 (br. s., 1H), 7.98 (d, J=8.2 Hz, 1H), 7.11 (d, J=12.0 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.80 - 3.75 (m, 4H), 3.04 (d, J=11.4 Hz, 2H), 2.63 (t, J=11.2 Hz, 2H), 2.55 - 2.46 (m, 2H), 2.37 (s, 3H), 1.15 (d, J=6.2 Hz, 6H); LC-MS [M + H]+ = 569.39.

Example 43: N-(2 6-difluoro-4-(4-methylpiperazin-l -yl)-5'-(morpholinomethyl)-[ 1 , 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00274] A procedure similar to that of Example 3 using N-(5-bromo-4-fluoro- 2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (29.41 mg, 0.062 mmol), 4-(4-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)mo holine (59.4 mg, 0.185 mmol), sodium carbonate, anhydrous (65.3 mg, 0.616 mmol), XPhos (5.88 mg, 0.012 mmol), and XPhos Pd G2 (9.70 mg, 0.012 mmol) afforded 30.6 mg (81% yield) of the title compound as a white solid. XH NMR (500 MHz, MeOD) δ 7.95 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 9.2, 6.1 Hz, 2H), 7.18 - 7.14 (m, 1H), 7.09 (d, J = 11.2 Hz, 1H), 6.92 (s, 1H), 3.74 -3.66 (m, 4H), 3.57 (s, 2H), 3.04 (s, 4H), 2.68 (s, 4H), 2.49 (s, 4H), 2.39 (s, 3H) ); LCMS [M+H]+ 592 g/mol.

Example 44: N-(3'-((cyclopentylamino)methyl)-6-fluoro-4-(4-methylpiperazin-l-yl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


[00275] A procedure was employed similar that to described in Example 3 using N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30.51 mg, 0.064 mmol), 3-(N-cyclopentylaminomethyl)phenylboronic acid, pinacol ester, HC1 (64.8 mg, 0.192 mmol), anhydrous sodium carbonate, (67.8 mg, 0.639 mmol), XPhos (6.10 mg, 0.013 mmol), and XPhos Pd G2 (10.06 mg, 0.013 mmol) to give 0.68 mg (1.7% yield) of the title compound. XH NMR (500 MHz, MeOD) δ 8.08 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 12.0 Hz, 1H), 6.79 (d, J = 6.4 Hz, 1H), 4.05 (s, 2H), 3.38 (p, J = 7.3 Hz, 1H), 3.04 - 2.99 (m, 4H), 2.65 (s, 4H), 2.36 (s, 3H), 2.06 (dt, J = 12.5, 7.0 Hz, 2H), 1.81 - 1.75 (m, 2H), 1.65 - 1.54 (m, 4H); LCMS [M+H]+ = 562.7.

Example 45: N-(4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide

Step 1: 4-(4-chloro-5-fluoro-2- hylpiperazine


[00276] A microwave vial was charged with l-bromo-4-chloro-5-fluoro-2-nitrobenzene (0.50 g, 2.0 mmol), 1,2-dimethyl-piperazine (0.39 g, 2.1 mmol), palladium acetate (0.044 g, 0.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.11 g, 0.20 mmol) and cesium carbonate (2.1 g, 6.4 mmol). The vial was capped, evacuated and backfilled with nitrogen. Toluene (25 mL) was added via syringe and the reaction vial was evacuated and backfilled with nitrogen an additional time. The reaction was warmed to 50 °C overnight. The reaction mixture was concentrated onto celite and purified by flash chromatography [0-10% MeOH/DCM + 1% NH4OH] to afford an inseparable mixture of the desired Buchwald product [4-(4-chloro-5-fluoro-2-nitrophenyl)-l, 2-dimethylpiperazine] along with undesired by-product [4-(5-bromo-2-chloro-4-nitrophenyl)-l, 2-dimethylpiperazine]. This mixture was carried forward to the next step where the corresponding products were separable by flash chromatography. LCMS [M+H]+ = 288.3.

Step 2: 4-((4'-(3, 4-dimethylpiperazin-l-yl)-2 '-fluoro-5 '-nitro-[l, 1 '-biphenylJ-3-yl)methyl)morpholine


[00277] A vial was charged with the mixture obtained in Step 1 (0.22 g), 3-(4-mo holinomethyl) henylboronic acid pinacol ester (0.16 g, 0.52 mmol), XPhos Pd G2 (0.006 g, 0.007 mmol) and XPhos (0.004 g, 0.007 mmol). The vial was sealed with a septum cap and evacuated and backfilled with nitrogen. 1,4-Dioxane (4 mL) and a 2M aq. solution of sodium carbonate (0.90 mL, 1.7 mmol) were added via syringe. The vial was evacuated and backfilled an additional time before being heated at 100 °C in an aluminum block overnight. The reaction was cooled to room temperature and concentrated directly onto celite. Flash chromatography [0.5-5% MeOH/DCM + 1% NH4OH] afforded the desired 4-((4'-(3,4-dimethylpiperazin-l-yl)-2'-fluoro-5'-nitro-[1,Γ-ΜρΗβηγ1]-3-γ1^βΰιγ1)πιοφΗο1ΐηβ (0.18 g, 62%). LCMS [M+H]+: 429.7.

Step 3: 4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-amine


[00278] A mixture of 4-((4'-(3,4-dimethylpiperazin-l-yl)-2'-fluoro-5'-nitro-[l,r-
(0.18 g, 0.43 mmol), iron (0.12 g, 2.2 mmol) and acetic acid (4 mL) was heated to 80 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM and the liquids were decanted by pipette. Concentration onto celite followed by flash chromatography [0.5-10% MeOH/DCM +

1% NH4OH] afforded 4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l,r-biphenyl]-3-amine (0.32 mmol, 75 %). LCMS [M+H]+: 399.7.

Step 4: N-(4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00279] Diethyl chlorophosphate (0.186 ml, 1.285 mmol) was added to a stirring solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (0.266 g, 1.285 mmol) in pyridine (3 ml) at room temperature. After stirring for lh the solution of activated acid was added to a stirring solution of 4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (0.128 g, 0.321 mmol) also in pyridine (3 ml) at room temperature. The reaction was heated to 75 °C overnight. LCMS indicated the presence of the desired product along with the excess nicotinic acid. The reaction was concentrated onto celite and purified by RP flash on the Biotage [5-95% MeCN/water] to afford 135 mg of crude product that was not of sufficient purity by NMR and LCMS. The mixture was loaded onto celite and purified by silica gel chromatography [1-25% MeOH/DCM + 1% NH40H] to afford the title compound (106 mg, 53.4 % yield) as a colorless solid after lyophilization. XH NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.44 Hz, 1H), 7.29-7.47 (m, 4H), 7.06 (d, J=12.47 Hz, 1H), 6.81 (s, 1H), 3.58 (t, J=4.40 Hz, 4H), 3.53 (s, 2H), 2.99-3.09 (m, 2H), 2.80-2.87 (m, 1H), 2.74-2.80 (m, 1H), 2.32-2.46 (m, 6H), 2.23-2.27 (m, 1H), 0.99 (d, J=6.24 Hz, 3H); LCMS [M+H]+ 574 g/mol.

Example 46: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-morpholinopyridin-4-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00280] A procedure employed similar to that of Example 3 using N-(5-bromo- 4-fluoro-2-(4-methylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1,6-dihydropyridine-3-carboxamide (29.10 mg, 0.061 mmol), 2-morpholinopyridine-4-boronic acid, pinacol ester (53.1 mg, 0.183 mmol) gave 17.4 mg (50.7% yield) of the target compound as a white powder. l NMR (500 MHz, MeOD) δ 8.16 (d, J= 5.4 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 12.2 Hz, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.91 (d, J = 5.1 Hz, 1H), 3.84 - 3.80 (m, 4H), 3.54 - 3.50 (m, 4H), 3.03 (t, J = 4.9 Hz, 4H), 2.68 (s, J= 2.0 Hz, 4H), 2.39 (s, 3H); LCMS [M+H]+ 561 g/mol.

Example 47: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(5-(morpholinomethyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00281] A procedure employed similar to that of Example 29 above using N- (5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (19.4 mg, 0.041 mmol) and 4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl)morpholine (37.1 mg, 0.122 mmol) gave 15.5 mg (64.4% yield) of the title compound as pale yellow powder. H NMR (500 MHz, CD3CN-D20) δ 8.74 (s, 1H), 8.57 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H),

8.04 (s, 1H), 7.89 (s, 1H), 7.21 (d, J = 11.8 Hz, 1H), 6.91 (s, 1H), 3.99 (s, 2H), 3.74 (s, 4H), 3.40 (s, 4H), 3.17 (s, 4H), 2.84 (s, 3H), 2.83 (s, 4H). LCMS [M+H]+ 575 g/mol.

Example 48: N-(4-fluoro-2-(4-methylpiperazin-l-yl)-5-(5-( ( ( tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine- 3-carboxamide


[00282] A procedure was employed similar to that of Example 3 using N-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30.52mg, 0.066 mmol) and 4-((6-fiuoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl)mo holine (64.2 mg, 0.199 mmol) to give 11.9 mg (30.1% yield) of the title compound. 'HNMR (500 MHz, MeOD) δ 8.67 (t, J = 2.1 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.07 (t, J = 2.6 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.98 (s, 1H), 7.15 (d, J= 12.0 Hz, 1H), 6.92 (s, 1H), 3.99 (s, 2H), 3.98 - 3.95 (m, 2H), 3.42 (td, J= 12.0, 2.2 Hz, 2H), 3.06 - 3.02 (m, 4H), 2.85 (ddd, J= 15.2, 9.4, 4.2 Hz, 1H), 2.67 (s, J = 2.1 Hz, 4H), 2.38 (s, 3H), 1.95 (ddd, J = 6.6, 4.2, 2.0 Hz, 2H), 1.50 (ddd, J= 24.2, 12.2, 4.6 Hz, 2H); LCMS [M+H]+ 589 g/mol.

Example 49: (R)-N-( 4-fluoro-2-(4-methylpiperazin-l-yl)-5-(5-( ( ( tetrahydrofuran-3-yl)amino)methyl)pyridin-3-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine- 3-carboxamide


[00283] A procedure was employed similar to that of Example 3 using N-(5-bromo-4-fluoro-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (20.46 mg, 0.043 mmol) and (R)-N-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl)tetrahydrofuran-3-amine (39.1 mg, 0.129 mmol) to give the title compound (16.0 mg) in 60.5% yield. H NMR (500 MHz, MeOD) δ 8.85 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.23 (t, J = 2.3 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.26 (d, J = 11.8 Hz, 1H), 6.94 (s, 1H), 4.39 (d, J = 2.4 Hz, 2H), 4.11 - 4.06 (m, 2H), 4.02 (ddd, J= 11.0, 6.9, 2.5 Hz, 1H), 3.87 (dd, J = 10.9, 5.7 Hz, 1H), 3.76 (dt, J = 15.5, 8.4 Hz, 1H), 2.94 (s, 3H), 2.45 (dtd, J = 13.4, 8.1, 5.0 Hz, 1H), 2.13 (dtd, J= 11.3, 7.6, 3.3 Hz, 1H); LCMS [M+H]+ 575 g/mol.

Example 50: (R)-N-(4-(3, 4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


Step 1: (R)-4-(4-chloro-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine


[00284] A vial was charged with l-bromo-4-chloro-5-fluoro-2 -nitrobenzene

(1.0 g, 3.93 mmol), (R)-l,2-dimethyl-piperazine dihydrochloride (0.772 g, 4.13 mmol), palladium(II) acetate (0.088 g, 0.393 mmol), Xantphos (0.227 g, 0.393 mmol) and cesium carbonate (5.12 g, 15.72 mmol). The vial was sealed with a septum and evacuated and back-filled with nitrogen. Toluene (15 ml) was added and the vial was evacuated and back-filled again. The reaction was warmed to 50 °C. After 7.5 h total reaction time, LCMS indicated the complete consumption of the starting material. The reaction mixture was transferred to a round bottom flask with DCM and then concentrated onto celite. Flash [0.5-10% MeOH/DCM + 1% NH4OH] afforded 490 mg (41.2% yield) of the title compound. LCMS [M+H]+ = 288.3

Step 2: (R)-4-((4'-(3,4-dimethylpiperazin-l-yl)-2'-fluoro-5'-nitro-[ 1 , l '-biphenyl] -3-yl)methyl)morpholine


[00285] mL vial was charged with a mixture of (R)-4-(4-chloro-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (0.050 g, 0.174 mmol), 3-(4-moφholinomethyl)phenylboronic acid pinacol ester (0.074 g, 0.243 mmol), XPhos Pd G2 (2.73 mg, 3.48 μηιοΐ) and XPhos (1.657 mg, 3.48 μηιοΐ). The vial was sealed with a cap/septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (2 ml) and 2M Aq sodium carbonate (0.434 ml, 0.869 mmol) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated in an aluminum block overnight at 100 °C. LCMS indicated very clean conversion to the desired product. The reaction mixture was loaded onto celite and purified by flash chromatography [0.1-5% MeOH/DCM + 1% NH4OH] to afford the product (0.152 mmol, 87 % yield) as a yellow film.

Step 3: (R)-4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-amine


[00286] A mixture of (R)-4-((4'-(3,4-dimethylpiperazin-l-yl)-2'-fluoro-5'-nitro- [1,Γ-ΜρΗβηγ1]-3-γ1^βΰιγ1)πιοφΗο1ΐηβ (0.065 g, 0.152 mmol), iron (0.042 g, 0.758 mmol) and acetic acid (2 ml) was heated to 80 °C for 1 h. The heating block was tumed off and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM and decanted by pipette to a round bottom flask. LCMS indicated complete conversion to the desired product. Concentration onto celite followed by flash [0.1-10% MeOH/DCM + 1% NH4OH] afforded the product (0.123 mmol, 81 % yield) as a brown film that was pure by LCMS. LCMS [M + H]+ = 399.5.

Step 4: (R)-N-(4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00287] Diethyl chlorophosphate (0.071 ml, 0.492 mmol) was added to a stirring solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (0.102 g, 0.492 mmol) in pyridine (1.5 ml) at room temperature. After stirring for 30 minutes the solution of activated acid was added to a stirring solution of (R)-4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-(mo holinomethyl)-[l,Γ-biphenyl]-3-amine (0.049 g, 0.123 mmol) also in pyridine (1.5 ml) at room temperature. The reaction was heated to 75 °C for ~3 h. The reaction was concentrated onto celite and purified by flash [1-25% MeOH/DCM + 1% NH4OH] to afford crude product that was -92% pure [254 nm]. This material was loaded onto celite and repurified on the biotage [5-95% MeCN/water - no modifier] to afford the title compound (0.022 mmol, 17.99 % yield) as a tan solid that was pure by LCMS. l NMR (500MHz, DMSO-de) δ = 9.41 (br. s., 1H), 7.97 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.47 - 7.29 (m, 5H), 7.06 (d, J=12.5 Hz, 1H), 6.69 (br. s., 1H), 3.57 (t, J=4.3 Hz, 4H), 3.52 (s, 2H), 3.07 - 2.97 (m, 2H), 2.86 - 2.74 (m, 2H), 2.45 -2.40 (m, 2H), 2.39 - 2.34 (m, 5H), 2.21 (s, 3H), 0.98 (d, J=6.2 Hz, 3H); LCMS [M+H]+ 574 g/mol.

Example 51: (S)-N-(4-(3, 4-dimethylpiperazin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


[00288] The title compound was prepared similar to the sequence described above for the preparation of Example 50 above using (S)- 1,2-dimethyl-piperazine hydrochloride in place of racemic 1,2-dimethyl-piperazine in Step 1, to give 19.0 mg (28% yield) of the title compound in the last step. ¾i NMR (500MHz, DMSO-de) δ = 9.44 (s, 1H), 7.96 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.47 - 7.28 (m, 4H), 7.06 (d, J=12.5 Hz, 1H), 6.73 (s, 1H), 3.57 (t, J=4.3 Hz, 4H), 3.52 (s, 2H), 3.07 - 2.98 (m, 2H), 2.86 - 2.74 (m, 2H), 2.45 - 2.33 (m, 6H), 2.26 - 2.19 (m, 4H), 0.98 (d, J=6.1 Hz, 3H); LCMS [M+H]+: 588.4.

Example 52: N-( 5-fluoro-3 '-(morpholinomethyl)-4-( ( 3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


[00289] The sequence described above for the preparation of Example 50 using cis- 1,2,6-trimethyl-piperazine in place of racemic 1,2-dimethyl-piperazine was used to give 7 mg (21% yield) of the title compound in the final step. ¾ NMR (500MHz, DMSO-de) δ = 9.30 (br. s., 1H), 8.01 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.48 - 7.28 (m, 4H), 7.04 (d, J=12.3 Hz, 1H), 6.55 (br. s., 1H), 3.57 (t, J=43 Hz, 4H), 3.52 (s, 2H), 3.01 (d, J=10.9 Hz, 2H), 2.40 - 2.31 (m, 7H), 2.20 (s, 3H), 1.02 (d, J=6.1 Hz, 6H); LCMS [M+H]+ = 602.4.

Example 53: N-( 4-( 3-(dimethylamino)pyrrolidin-l -yl)-6-fluoro-3 '-(morpholinomethyl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


Step 1: 1 -(2-fluoro-3'-(morpholinomethyl)-5-nitro-[ 1 , 1 '-biphenyl]-4-yl)-N,N-dimethylpyrrolidin-3-amine


[00290] A vial was charged with a mixture of l-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.092 g, 0.28 mmol, prepared as described in Example 21 above), 3-(4-morpholinomethyl)phenylboronic acid pinacol ester (0.12 g, 0.39 mmol), XPhos Pd G2 (0.0044 g, 0.005 mmol) and XPhos (0.0026 g, 0.005 mmol). The vial was sealed with a septum cap and evacuated and backfilled with nitrogen. 1,4-Dioxane (4 mL) and 2M Aq sodium carbonate (0.70 mL, 1.4 mmol) were added via syringe. The vial was evacuated and backfilled an additional time before being heated at 95 °C overnight. The reaction was cooled to room temperature and concentrated directly onto celite. Flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded 1 -(2-fluoro-3'-(morpholinomethyl)-5 -nitro-[ 1 , 1 '-biphenyl] -4-yl)-N,N-dimethylpyrrolidin-3-amine (0.110 g, 86 %). LCMS [M+H]+: 429.5.

Step 2: l-(5-amino-2-fluoro-3'-(morpholinomethyl)-[ 1 , Γ -biphenyl] '-4-yl)-N,N-dimethylpyrrolidin-3-amine

[00291] A mixture of l-(2-fluoro-3'-(mo holinomethyl)-5-nitro-[l, -bi henyl]- 4-yl)-N,N-dimethylpyrrolidin-3-amine (0.11 g, 0.26 mmol), iron (0.070 g, 1.3 mmol) and acetic acid (3 mL) was heated to 85 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM and the liquids were decanted by pipette. Concentration onto celite followed by flash chromatography [0.1-10% MeOH/DCM + 1% NH40H] afforded l-(5-amino-2-fluoro-3'-(mo holinomethyl)-[l,Γ-biphenyl]-4-yl)-N,N-dimethylpyrrolidin-3-amine (0.061 g, 60 %). LCMS [M+H]+: 399.5.

Step 3: N-(4-(3-(dimethylamino)pyrrolidin-l-yl)-6-fluoro-3'-(morpholinomethyl)-[1, 1 '-biphenyl] -3-yl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


[00292] Diethyl chlorophosphate (0.090 mL, 0.61 mmol) was added to a stirring solution of 6-hydroxy-4-(trifluoromethyl)nicotinic acid (0.130 g, 0.61 mmol) in pyridine (2 mL) at room temperature. After stirring for 45 minutes the solution of activated acid was added to a stirring solution of l-(5-amino-2-fluoro-3'-(morpholinomethyl)-[l, -biphenyl]-4-yl)-N,N-dimethylpyrrolidin-3-amine (0.061 g, 0.15 mmol) also in pyridine (2 mL) at room temperature. The reaction was heated to 75 °C for 5 h. The reaction mixture was concentrated onto celite and reverse phase chromatography [5-95% MeCN/water; CI 8 column] afforded the title compound (28.0 mg, 30 % yield). XH-NMR (500 MHz, DMSO-d6) δ 12.57 (br. s., 1H), 9.82 (d,

J=5.14 Hz, 1H), 7.97 (br. s., 1H), 7.34-7.43 (m, 3H), 7.22-7.33 (m, 2H), 6.80 (d, J=5.38 Hz, 1H), 6.66 (dd, J=5.99, 14.31 Hz, 1H), 3.58 (br. s., 4H), 3.51 (d, J=5.87 Hz, 2H), 3.40-3.42 (m, 2H), 3.26 (m, 1H), 2.64 (br. s., 1H), 2.38 (br. s., 4H), 2.12-2.22 (m, 7H), 2.09 (d, J=3.79 Hz, 1H), 1.71 (d, J=7.70 Hz, 1H); LCMS [M+H]+ = 588.5.

Example 54: N-(6-chloro-4-(4-methylpiperazin-l-yl)-3'-(morpholinomethyl)-[l, 1 '-biphenylJ-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (Comparative Example)


[00293] ml microwave vial containing a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (103 mg, 0.499 mmol) in pyridine, anhydrous (603 μΐ, 7.48 mmol) was added slowly diethyl chlorophosphate (72.1 μΐ, 0.499 mmol) at rt in an atmosphere of nitrogen. The reaction mixture was stirred at rt for 1 h. To this mixture was added 6-chloro-4-(4-methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (50 mg, 0.125 mmol, prepared in a similar manner to examples hereinabove) and the reaction was heated at 70 °C for 2 h. After completion, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2S04. The solvent was evaporated in vacuo yielding the crude product. Purification was performed via preparative HPLC to yield the title compound (10.4 mg, 12% yield). ¾ NMR (500 MHz, MeOD) δ 8.47 (s, 1H), 7.96

(s, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 5.6 Hz, 2H), 7.36 (s, 1H), 6.92 (s, 1H), 3.72 - 3.70 (m, 4H), 3.64 (s, 2H), 3.05 (t, J = 4.4 Hz, 4H), 2.80 (s, 4H), 2.54 (s, 4H), 2.48 (s, 3H); LCMS [M+H]+ 591 g/mol.

Example 55: N-[4-methoxy-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH^yridme-3-carboxamide (Comparative Example)


Step 1: cis-4-(4-bromo-5-methoxy-2-nitrophenyl)-l,2, 6-trimethylpiperazine


[00294] A solution of l-bromo-4-fluoro-2-methoxy-5-nitrobenzene (0.250 g,

1.0 mmol) in PhMe (1 mL) was slowly added to a rapidly stirring mixture of cis-1,2,6-trimethylpiperazine (0.13 g, 1.0 mmol) and K2CO3 (0.070 g, 0.50 mmol) in PhMe (2 mL) at 45 °C. After 2 h the heat was turned off and the reaction was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated onto celite and purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded cis-4-(4-bromo-5-methoxy-2-nitrophenyl)-l,2,6-trimethylpiperazine (0.33 g, 92 %). LCMS [M+H]+: 358.3.

Step 2: 4-(5-(2-methoxy-5-nitro-4-(cis-3, 4,5-trimethylpiperazin-l -yl)phenyl)pyrimidin-2-yl)morpholine


[00295] A reaction vial was charged with a mixture of cis-4-(4-bromo-5-methoxy-2-nitrophenyl)-l,2,6-trimethylpiperazine (0.11 g, 0.31 mmol), 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (0.098 g, 0.34 mmol), XPhos Pd G2 (5 mg, 6 μηιοΐ) and XPhos (3 mg, 6 μηιοΐ). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (3 mL) and 2 M aqueous sodium carbonate (0.5 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 90 °C in an aluminum block for 18 h. After cooling to room temperature the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford 4-(5-(2-methoxy-5-nitro-4-(cis-3,4,5-trimethylpiperazin-l-yl)phenyl)pyrimidin-2-yl)moipholine (0.14 g, 100 %). LCMS [M+H]+: 443.3.

Step 3: 4-methoxy-5-(2-morpholinopyrimidin-5-yl)-2-(cis-3, 4, 5-trimethylpiperazin-l-yl)aniline


[00296] A mixture of 4-(5-(2-methoxy-5-nitro-4-(cis-3,4,5-trimethylpiperazin-
(0.14 g, 0.31 mmol), SnCl2 (0.24 g, 1.2 mmol) and EtOH (5 mL) was heated to 75 °C for 1 h. The heat was turned off and the reaction was allowed to stir at room temperature overnight. The reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] to afford 4-methoxy-5-(2-morpholinopyrimidin-5-yl)-2-(cis-3,4,5-trimethylpiperazin-l-yl)aniline (0.11 g, 83 %). LCMS [M+H]+: 413.6.

Step 4: N-( 4-methoxy-5-(2-morpholinopyrimidin-5-yl)-2-(cis-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)- -dihydropyridine-3-carboxamide


[00297] 4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid (0.056 g,

0.18 mmol) was activated with HATU (0.069 g, 0.18 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.18 mmol) in DMF (0.5 mL) at room temperature. The solution of activated acid was added to a solution of 4-methoxy-5-(2-moφholinopyrirnidin-5-yl)-2-(cis-3,4,5-trimethylpiperazin-l-yl)aniline (0.050 g, 0.12 mmol) in DMF (1 mL) and the reaction was heated to 55 °C for 18 h. After cooling to room temperature the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-7.5% MeOH/DCM + 0.5% NH4OH]. The silyl protected amide was dissolved in DCM (2 mL) and treated with TFA (1 mL) at room temperature. After stirring for 2 h the volatiles were removed under a stream of air and the title compound was isolated by a catch and release protocol using a SCX2 silica cartridge to afford the title compound (0.067 g, 92 %). ¾i NMR (500MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.47 (s, 2H), 7.90 (s, 1H), 7.57 (s, 1H), 6.85 - 6.74 (m, 2H), 3.81 (s, 3H), 3.75 - 3.72 (m, 4H), 3.70 - 3.66 (m, 4H), 3.00 (br d, J=10.9 Hz, 3H), 2.47 - 2.43 (m, IH), 2.38 - 2.30 (m, 2H), 2.21 (s, 3H), 1.02 (d, J=6.1 Hz, 6H); LCMS [M+H]+: 602.5.

Example 56: N-(2-(4-methylpiperazin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide (Comparative Example)


[00298] The procedure followed was similar to that used for Example 3 above using N-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (51.9 mg, 0.108 mmol) and 2-(4^ο ηο1ίηο^ήη^ίη6-5-boronic acid pinacol ester (95 mg, 0.325 mmol) to afford the title compound (39.5 mg, 55% yield) as a white solid. IH NMR (500 MHz, DMSO) δ 9.45 (s, IH), 8.63 (s, 2H), 8.01 (d, J = 2.0 Hz, IH), 7.98 (s, IH), 7.42 (dd, J = 8.3, 2.2 Hz, IH), 7.25 (d, J = 8.3 Hz, IH), 6.80 (s, IH), 3.74 (q, J = 4.5 Hz, 4H), 3.68 (q, J = 4.5 Hz, 4H), 2.87 (t, J = 4.4 Hz, 4H), 2.47 (s, 4H), 2.22 (s, 3H); LCMS [M+H]+ 544.

Example 57: N-[2-(4-methylpiperazin-l-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide ( omparative Example)


[00299] 6-Hydroxy-4-(trifluoromethyl)nicotinic acid (69.2 mg, 0.327 mmol) was dissolved/suspended in SOCl2 (1 mL) and stirred at 70 °C for 2 h. The SOCl2 was

removed under reduced pressure (h/v lh). The residue was dissolved in DCM and 4-(4-methylpiperazin-l-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (100 mg, 0.273 mmol, prepared using methods similar to those described for Example 29) was added in one portion before pyridine (28.7 μΐ, 0.355 mmol) was added. The reaction mixture was stirred for 3d, diluted with sat. aq. sodium bicarbonate solution and extracted with DCM (3 x 5 mL). The combined organic phases were loaded on silica gel and subjected to purification via Biotage (25 g column, MeOH/DCM 0-30 %, 30 CV) to give the title compound (15 mg, 8.91 % yield). XH-NMR (500 MHz, MeOD) δ 8.77 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 8.1, 2.3 Hz, 1H), 8.02 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (dd, J = 8.3, 2.1 Hz, 1H), 7.42 (t, J = 4.2 Hz, 1H), 6.94 (s, 1H), 3.79 (s, 2H), 3.75 - 3.73 (m, 4H), 3.15 (s, 4H), 2.72 (s, 4H), 2.63 (s, 3H); LCMS [M+H]+ 557.

Example 58: N-(5-(2-morpholinopyrimidin-5-yl)-2-((3R,5S)-3, 4,5-trimethylpiperazin-1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide

(Comparative Example)


[00300] N-(5-bromo-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-&hydropyridine-3-carboxamide (39 mg, 0.08 mmol) and 2-(4-moφholino)pyrimidine-5-boronic acid pinacol ester (35 mg, 0.12 mmol) were employed in a procedure similar to Step 3, Example 31 to give the title compound as a beige solid (13.0 mg, 28% yield). XH-NMR (500MHz, METHANOL-d4) δ 8.64 (s, 2H), 8.17 (s, 1H), 8.00 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 6.92 (s, 1H), 3.87 - 3.81 (m, 4H), 3.81 - 3.75 (m, 4H), 3.00 (d, J=11.4 Hz, 2H), 2.67 (t, J=l l. l Hz, 2H), 2.59 - 2.47 (m, 2H), 2.39 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LC-MS [M + H]+ 572.26.

Example 59: N-[5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[rac-( 3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl]-4-(trifluoromethyl)phenyl]-6 >xo-4-(trifluo

pyridine-3-carboxamide


Step 1: (2S, 6R)-1,2, 6-trimethyl-4-(2-nitro-5-(trifluoromethyl)phenyl)piperazine


[00301] To a solution of 3-fluoro-4-nitrobenzotrifiuoride (1 g, 4.78 mmol) in

DMSO (2 ml) was added (2R,6S)-l,2,6-trimethylpiperazine (0.644 g, 5.02 mmol) and diisopropylethylamine (0.9 ml, 5.25 mmol). Slight exothermicity was observed. The resulting dark red solution was stirred at RT for lh. Only traces of the starting material were observed. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (3 x 25 ml). The combined organic phase was washed with water, and brine, dried over Na2S04 and concentrated to obtain an orange oil as the desired product. (1.481 g, 98 %). After standing overnight,, the oil became an orange solid. This was taken to the next step without any purification. LCMS [M+H]+ 318.4.

Step 2: (2S, 6R)-4-(4-bromo-2-nitro-5-(trifluoromethyl)phenyl)-l, 2, 6-trimethylpiperazine


[00302] To a solution of (2S,6R)-l,2,6-trimethyl-4-(2-nitro-5- (trifluoromethyl)phenyl)piperazine (1.150 g, 3.62 mmol) in acetic acid (10 ml) was added bromine (0.467 ml, 9.06 mmol). Slight exothermicity was observed. The resulting dark red solution was stirred at 80°C for 4 h. 52% conversion was observed. 0.2 ml bromine and 3 ml acetic acid were added and the reaction mixture was heated overnight at 80 °C for 22 h. A small amount of starting material was observed. The mixture was allowed to cool to RT, concentrated, the residue was taken up in DCM, neutralized with Satd. NaHCC soln., washed with brine, dried over Na2S04 and concentrated to obtain the crude product. It was purified on a 40 g Isco column, eluting with DCM containing 0-2 % MeOH, to yield the desired product as a light brown solid (378 mg, 26 %). LCMS [M+H]+ 396.5

Step 3: 5-bromo-4-(trifluoromethyl)-2-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)aniline


[00303] To a solution of (2S,6R)-4-(4-bromo-2-nitro-5-(trifluoromethyl)phenyl)- 1,2,6-trimethylpiperazine (345 mg, 0.871 mmol) in acetic acid (4 ml), was added iron powder, 99% (243 mg, 4.35 mmol). The resulting dark brown solution was stirred at 80 °C. The reaction mixture became a slurry and the conversion was complete in 12 min. The mixture was allowed to cool to RT, concentrated, the residue was taken up in DCM, neutralized with Satd. NaHCCb soln., washed with brine, dried over Na2S04 and concentrated to afford the crude product. It was purified on reverse phase Isco column (15.5), eluting with water containing 0-80 % CH3CN to collect the title compound as a yellow solid (300 mg, 94 %). LCMS [M+H]+ 366.5

Step 4: N-(5-bromo-4-(trifluoromethyl)-2-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00304] To a 10 mL RBF charged with 6-chloro-4-(trifluoromethyl)nicotinic acid (115 mg, 0.512 mmol), was added thionyl chloride (894 μΐ, 12.29 mmol) . The resulting suspension was heated at 80 °C for 1 h. It was evaporated to give a light yellow oil which was taken up in DCM (3 mL). 5-bromo-4-(trifluoromethyl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (150 mg, 0.410 mmol) and triethylamine (171 μΐ, 1.229 mmol) were added and the resulting mixture was stirred at RT for 1 h.. After basifying with sat. NaHCCb (5 mL), it was extracted with DCM (5 x 2 mL ). The extracts were combined and concentrated to obtain the crude as a pale brown waxy solid. The reaction was combined with HOAc/H20 (3.6 mL/ 1.2 mL) in a 5 mL microwave vial and was heated in the microwave at 160 °C for 5 h Solvents were removed on a rotovap at 60 °C and the residue was treated with sat. NaHCOs (30 mL). It was extracted with DCM (2 x 45 ml). The extracts were combined, dried over Na2S04, concentrated onto celite and purified on silica gel column (12 G), eluting with DCM containing 0-5 % MeOH. The desired product was obtained as a light purple coloured solid (131 mg, 58 %). LCMS [M+H]+ 555.1

Step 5: N-[5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]-4-(Mfluoromethyl)phenyl]-6 >xo-4-(Mfluoromethyl)-lH^yridine-^


[00305] N-(5 -bromo-4-(trifluoromethyl)-2-((3 S , 5R)-3 ,4, 5 -trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (50 mg, 0.09

mmol), 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester (37 mg, .126 mmol), XPhos Pd G2 (14 mg, 0.018 mmol), Xphos (9 mg, 0.018 mmol) and sodium carbonate, anhydrous (95 mg, 0.9 mmol) were taken in a microwave vial. 1,4-Dioxane (4 ml) and water (1 ml) were added and stirred for 5 min. The white suspension was purged with argon and the reaction mixture was heated in the microwave for 60 min at 110 °C. The mixture was concentrated onto celite and purified on preparative column, eluting with water/acetonitrile gradient to isolate the title compound as a white solid (10.5 mg, 17 %). 1H NMR (500MHz, METHANOL-d4) δ = 8.30 (s, 2H), 8.05 (s, 1H), 7.99 (br. s., 1H), 7.62 (s, 1H), 7.01 - 6.84 (m, 1H), 3.87 - 3.82 (m, 4H), 3.79 - 3.75 (m, 4H), 3.15 (d, J=11.7 Hz, 2H), 3.02 (br. s., 2H), 2.90 - 2.81 (m, 2H), 2.66 - 2.64 (m, 3H), 1.29 (d, J=6.2 Hz, 6H); LCMS [M+H]+ 640.7.

Example 60: N-[4-fluoro-2-(4-methylpiperazin-l-yl)-5-(2-morpholin-4-ylpyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00306] The title compound was prepared similar to the sequence described for the preparation of Example 3 using 2-morpholinopyridine-4-boronic acid, pinacol ester. XH NMR (500 MHz, MeOD) δ 8.16 (d, J = 5.4 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 12.2 Hz, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.91 (d, J = 5.1 Hz, 1H), 3.84 - 3.80 (m, 4H), 3.54 - 3.50 (m, 4H), 3.03 (t, J = 4.9 Hz, 4H), 2.68 (s, J = 2.0 Hz, 4H), 2.39 (s, 3H); LCMS [M+l]+ = 561.4.

Example 61: N-[4-methyl-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[rac-(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridm^


Step 1 : 5-bromo-4-methyl-2-( ( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l -yljaniline


[00307] To a solution of l-bromo-4-fluoro-2-methyl-5-nitrobenzene (2.34g, 10 mmol) in DMSO (5 mL) was added (2S,6R)-l,2,6-trimethylpiperazine (1.35g, 10.5 mmol). The resulting dark red mixture was stirred at 80 °C for 1.5 h. Orange precipitates formed upon cooling. The reaction mixture was diluted with H20 (60 mL), basified with 1 M aq NaOH (10 mL, 10 mmol) and extracted with EtOAc (60 mL + 30 mL). The combined extracts were concentrated and dried under vacuum to give the N02 intermediate as a dark orange solid (3.36 g). LCMS [M + H]+ 342.2.To a solution of the above dark orange solid (3.36 g) and hydrazine monohydrate (1.46 mL, 30 mmol) in MeOH (45 mL) at 60 °C was added a suspension of Raney -Nickel (0.214 g, 2.5 mmol) in MeOH (5 mL) portionwse over 5 min. After addition, the reaction mixture was heated at 60 °C for 30 min. The reaction turned from dark orange red to light brown. It was passed through celite, and rinsed with MeOH (20 mL x 2). The combined filtrate was concentrated to give a light brown oil which was purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-5%) to give the title compound as a pink solid (2.349 g, 74%). LCMS [M + H]+ 312.1.

Step 2: N-(5-bromo-4-methyl-2-((3S, 5R)-3, 4, 5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00308] To a 25 mL RBF charged with 6-chloro-4-(trifluoromethyl)nicotinic acid (542 mg, 2.4 mmol) was added thionyl chloride (4.37 mL, 60 mmol). The resulting suspension was heated at 80 °C for 1 h. It was evaporated to give a light yellow oil which was treated with DCM (15 mL), 5-bromo-4-methyl-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (625 mg, 2 mmol) and EtsN (0.84 mL, 6 mmol). The resulting mixture was stirred at rt for 1 h. After basifying with sat. NaHC03 (30 mL), it was extracted with DCM (30 mL x 2). The combined extracts were concentrated to give a beige solid. LCMS [M + H]+ 519.1. A mixture of the above solid, NaOAc (328 mg, 4 mmol) in HOAc/H20 (10 mL/3mL) in a 20 mL microwave vial was micro waved at 160 °C for 5 h. Solvents were removed and the residue was treated with sat. NaHCCb (30 mL) and extracted with DCM (60 mL + 30 mL). The combined extracts were concentrated and purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-15%) and triturated with MeOH (10 mL) to give the title compound as a pale yellow solid (761 mg, 71%). LCMS [M+ H]+ 501.2.

Step 3: N-( 4-methyl-5-(2-morpholinopyrimidin-5-yl)-2-( ( 3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6 >xo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00309] The title compound (white solid, 26.4 mg, 45%) was prepared according to a procedure similar to the last step of Example 29 using N-(5-bromo-4-methyl-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50 mg, 0.1 mmol) and 2-(4^ο ηο1ίηο^Γίπ^ίη6-5-

boronic acid pinacol ester (58 mg, 0.2 mmol). H NMR (500MHz, METHANOL-d4) δ = 8.37 (s, 2H), 7.96 (s, 1H), 7.74 (s, 1H), 7.16 (s, 1H), 6.91 (s, 1H), 3.86 - 3.76 (m, 8H), 3.01 (d, J=11.4 Hz, 2H), 2.71 - 2.62 (m, 2H), 2.61 - 2.53 (m, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.18 (d, J=1.0 Hz, 6H); LCMS [M + H]+ 586.3.

Example 62: 2-(difluoromethyl)-N-(5-(2-((2S, 6R)-2, 6-dimethylmorpholino)pyrimidin-5-yl)-2-((S)-3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-fluorobenzamide


[00310] A mixture of 2-(difluoromethyl)-4-fluorobenzoic acid (171 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol) and N,N-diisopropylethylamine (0.21 ml, 1.2 mmol) in DMF (2 mL) was heated at 70 °C for 1 min to afford a clear light brown solution before (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline (181 mg, 0.6 mmol) was added in one portion. The resulting mixture was heated at 70 °C for 1.5 h. It was diluted with EtOAc (20 mL) and washed with H20 (30 mL x 2), concentrated and purified by flash chromatography (EtO Ac/hex 0-100%, then MeOH/DCM 0-5%) to give (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-2-(difluoromethyl)-4-fluorobenzamide as a light brown solid (265 mg, 92%). LCMS [M + H]+ 474.1. It was redissolved in dioxane (12 mL) and divided equally into 3 portions (each 4 mL, 0.185 mmol). The title compound (formic acid salt, white solid, 38.9 mg, 33%) was prepared according to a method similar to that described in Example 31 using (2-((2S,6R)-2,6-dimethylmo holino)pyrimidin-5-yl)boronic acid (66 mg, 0.278 mmol) and (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-2-(difluoromethyl)-4-fluorobenzamide in dioxane (0.185 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.57 (s, 2H), 8.37 (br s, 1H), 7.96 (br d, J=8.2 Hz, 1H), 7.89 (br dd, J=5.6, 8.0 Hz, 1H), 7.56 (dd, J=2.3, 9.3 Hz, 1H), 7.51 - 7.25 (m, 2H), 7.18 (d, J=11.9 Hz, 1H), 4.65 (dd, J=1.3, 13.1 Hz, 2H), 3.71 -3.63 (m, 2H), 3.39 - 3.35 (m, 1H), 3.31 - 3.23 (m, 2H), 3.14 - 3.06 (m, 1H), 3.02 (br d, J=10.1 Hz, 2H), 2.86 - 2.79 (m, 1H), 2.73 (s, 3H), 2.64 (dd, J=10.7, 13.3 Hz, 2H), 1.30 (d, J=6.5 Hz, 3H), 1.25 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 587.4.

Example 63: N-[5-(l, 3-benzodioxol-5-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l -yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00311] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 3,4-methylenedioxyphenylboronic acid. H NMR (500 MHz, MeOD) δ 7.94 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 5.8 Hz, 3H), 6.92 (s, 1H), 6.90 (d, J= 8.7 Hz, 1H), 5.99 (s, 2H), 3.07 (d, J= 8.4 Hz, 2H), 2.63 (d, J= 7.3 Hz, 4H), 2.42 (s, 3H), 1.18 (d, J= 5.4 Hz, 6H); LCMS [M+l]+ = 547.21.

Example 64: N-[5-( 5-acetamidopyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00312] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 2-acetamidopyridine-5-boronic acid, pinacol ester in as the boronic ester coupling partner. H NMR (500 MHz, MeOD) δ 8.47 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.96 - 7.92 (m, 3H), 7.09 (d, J = 12.1 Hz, 1H), 6.92 (s, 1H), 3.09 (d, J= 10.5 Hz, 2H), 2.67 - 2.59 (m, 4H), 2.41 (s, 3H), 2.20 (s, 3H), 1.18 (d, J= 5.8 Hz, 6H); LCMS [M+l]+ = 561.28.

Example 65: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenylJ-4-methoxy-6-oxo-lH-pyridine-3-carboxamide


[00313] In a 5 ml microwave vial to a suspension of 4-methoxy-6-oxo-l,6-dihydropyridine-3-carboxylic acid (50.7 mg, 0.300 mmol) in pyridine, anhydrous (364 μΐ, 4.49 mmol) was added slowly diethyl chlorophosphate (44.4 μΐ, 0.307 mmol) at rt in an atmosphere of nitrogen. The reaction mixture was stirred at rt for 2 h. To this was added 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)aniline (30 mg, 0.075 mmol, preparation described in Example 8) and the reaction was heated at 70 °C for 3 h. The pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, dried over anhydrous Na2S04, and solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography to obtain the title compound (15 mg, 36% yield) as a brown solid. XH NMR (500 MHz, MeOD) δ 8.55 (d, J = 1.1 Hz, 4H), 8.49 (d, J = 1.2 Hz, 14H), 8.31 (s, 2H), 7.12 (d, J = 11.9 Hz, 2H), 6.84 (dd, J = 9.9, 5.9 Hz, 15H), 6.08 (d, J = 4.6 Hz, 2H), 4.14 (s, 6H), 3.86 - 3.80 (m, 43H), 3.76 (dd, J = 9.0, 4.1 Hz, 43H), 3.19 (s, 7H), 3.02 (d, J = 10.7 Hz, 5H), 2.84 (s, 11H), 2.65 - 2.60 (m, 9H), 2.61 - 2.51 (m, 42H), 2.43 (s, 7H), 1.25 (d, J = 6.0 Hz, 42H); LCMS [M+l]+ = 552.3.

Example 66: N-[5-[2-(cyclopropylmethoxy)pyridin-4-yl]-4-fluoro-2-[( 3R, 5SJ-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00314] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 2-(cyclopropylmethoxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine as the boronic ester coupling partner. H NMR (500 MHz, MeOD) δ 8.14 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.13 (d, J = 5.4 Hz, 1H), 7.07 (d, J = 12.3 Hz, 1H), 6.97 (s, 1H), 6.91 (s, 1H), 4.14 (d, J = 7.1 Hz, 2H), 3.10 (d, J = 11.3 Hz, 2H), 2.62 (t, J = 11.2 Hz, 2H), 2.54 (ddd, J = 10.3, 6.9, 4.1 Hz, 2H), 2.37 (s, 3H), 1.35 - 1.25 (m, 1H), 1.16 (d, J= 6.2 Hz, 6H), 0.61 (q, J= 5.9 Hz, 2H), 0.37 (q, J = 4.7 Hz, 2H); LCMS [M+l]+ =574.22.

Example 67: N-[5-[2-[(cyclohexylamino)methyl]phenyl]-4-fluoro-2-[( 3R, 5SJ-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridm^


Step 1 : N-( 6-fluoro-2 '-formyl-4-( ( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l -yl)-[l, 1 '-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide


[00315] N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-methoxy-4-(trifluoromethyl)nicotinamide (125 mg, 0.241 mmol), 2-

formylphenylboronic acid (50.5 mg, 0.337 mmol), sodium carbonate, anhydrous (255 mg, 2.407 mmol), XPhos Pd G2 (37.9 mg, 0.048mg) and Xphos (22.95 mg, 0.048 mmol) were mixed in a microwave vial. Water (3 ml) and 1,4-dioxane (3 ml) were added and stirred for 5 min. The white suspension was purged with argon and the reaction mixture was heated in the microwave for 30 min at 110 °C. The reaction mixture was concentrated onto celite and purified on Isco (4G) column, eluting with DCM containing 0-2 % MeOH to obtain the desired product as an off white foam. (124 mg, 90%). LCMS [M+H]+ 545.4

Step 2: N-(2'-((cyclohexylamino)methyl)-6-fluoro-4-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)-[l '-biphenyl]-3-yl)-6-methox -4-(Mfluoromethyl)nicotimmide


[00316] N-(6-fluoro-2'-formyl-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)-[l,r-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide (70 mg, 0.122 mmol), N-(6-fluoro-2'-foimyl-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)-[l,r-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide (70 mg, 0.122 mmol) and acetic acid, glacial, 99.8% (0.028 ml, 0.488 mmol) were mixed in anhydrous DCE. A cloudy solution was obtained. After 5-10 min, sodium triacetoxyborohydride (36.9 mg, 0.174 mmol) was added and the reaction mixture was stirred ovemight at RT. The reaction was complete (by LCMS). The reaction was quenched with sat aq NaHCCb solution (basic). The organic phase was separated, the aqueous phase was extracted with DCM (x2), the combined organic phase was washed with brine, dried over Na2S04 and concentrated to afford the crude product. It was purified by isco column (4G), eluting with DCM containing 0-5% MeOH. The appropriate fractions were combined and concentrated to afford the desired product as a white foam (49 mg, 64 %). LCMS [M+H]+ = 628.6.

Step 3: N-(2'-( (cyclohexylamino)methyl)-6-fluoro-4-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)-[l , 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide hydrochloride salt:


[00317] To a solution of N-(2'-((cyclohexylamino)methyl)-6-fluoro-4-((3S,5R)- 3,4,5-trimethylpiperazin-l-yl)-[l,r-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide (48 mg, 0.076 mmol) in methanol (1.5. ml) was added concentrated HCl (1.0 ml) and the reaction mixture was heated at 80 °C. The reaction was complete after 2.5 h. The reaction mixture was allowed to cool to RT, concentrated to dryness, co-evaporated with MeOH first and then with DCM to yield the desired product as an off white solid (30 mg, 51 %). XH NMR (500MHz, METHANOL-d4) δ = 8.02 - 7.88 (m, 1H), 7.72 - 7.65 (m, 1H), 7.63 - 7.59 (m, 1H), 7.50 - 7.43 (m, 2H), 7.36 - 7.30 (m, 1H), 7.16 (d, J=10.8 Hz, 1H), 6.82 (s, 1H), 4.30 -4.02 (m, 2H), 3.60 - 3.50 (m, 2H), 3.33 - 3.25 (m, 2H), 3.00 - 2.88 (m, 5H), 1.89 -1.78 (m, 2H), 1.69(br. s., 2H), 1.56 (d, J=12.6 Hz, 1H), 1.44 - 1.31 (m, 6H), 1.23 -1.15 (m, 5H), 1.12 - 1.04 (m, 1H), 1.12 - 1.04 (m, 1H); LCMS [M+H]+ = 614.6.

Example 68: N-[5-( 3-chloro-4-morpholin-4-ylphenyl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-


[00318] The title compound (light brown solid, 50.7 mg, 80%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol, example 31) and 3-chloro-4-(4-mo holinyl)benzeneboronic acid pinacol ester (65 mg, 0.2 mmol). H NMR

(500MHz, METHANOL-d4) δ = 7.97 (s, IH), 7.91 (d, J=8.2 Hz, IH), 7.59 (s, IH), 7.48 (d, J=8.2 Hz, IH), 7.22 (d, J=8.1 Hz, IH), 7.06 (d, J=12.1 Hz, IH), 6.92 (s, IH), 3.92 - 3.85 (m, 4H), 3.15 - 3.05 (m, 6H), 2.68 - 2.52 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 622.1.

Example 69: N-[5-( 3, 4-dihydro-2H-l, 5-benzodioxepin- 7-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo


[00319] The title compound (light beige solid, 44.6 mg, 77%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 3,4-dihydro-2H-l,5-benzodioxepin-7-ylboronic acid (38.8 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d4) δ = 7.96 (s, IH), 7.89 (d, J=8.3 Hz, IH), 7.19 - 7.15 (m, IH), 7.13 (d, J=8.1 Hz, IH), 7.06 - 7.00 (m, 2H), 6.92 (s, IH), 4.25 - 4.19 (m, 4H), 3.06 (d, J=l l. l Hz, 2H), 2.67 - 2.52 (m, 4H), 2.39 (s, 3H), 2.23 - 2.17 (m, 2H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M+ H]+ =575.3.

Example 70: N-[5-(2, 3-dihydro-l, 4-benzodioxin-6-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo


[00320] The title compound (off white solid, 43.7 mg, 78%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-

trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 2,3-dihydro-l,4-benzodioxin-6-ylboronic acid (36 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d4) δ = 7.96 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.07 - 6.98 (m, 3H), 6.95 - 6.87 (m, 2H), 4.29 (s, 4H), 3.06 (d, J=11.2 Hz, 2H), 2.66 - 2.52 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ =561.2.

Example 71: N-[4-fluoro-5-(4-methyl-2, 3-dihydro-l, 4-benzoxazin-7-yl)-2-[(3R, 5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00321] The title compound (pale beige solid, 28.9 mg, 50%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-l,4-benzoxazine (55 mg, 0.2 mmol). H NMR (500MHz, METHANOL-d4) δ = 7.96 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.00 (d, J=12.2 Hz, 1H), 6.94 - 6.92 (m, 1H), 6.92 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.33 - 4.28 (m, 2H), 3.32 - 3.28 (m, 2H), 3.04 (d, J=l l . l Hz, 2H), 2.93 (s, 3H), 2.66 - 2.47 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 574.4.

Example 72: N-[5-(2-acetamidopyrimidin-5-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00322] The title compound was prepared in a manner similar to Example 31 using N-(5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetamide in place of 2-cyanopyrimidine-5-boronic acid pinacol ester. H NMR (500 MHz, MeOD) δ 8.81 (s, 2H), 7.98 (s, 1H), 7.96 (d, J = 4.7 Hz, 1H), 7.15 (d, J = 12.0 Hz, 1H), 6.93 (s, 1H), 3.16 (d, J = 7.0 Hz, 2H), 2.80 (s, 2H), 2.71 (t, J = 11.1 Hz, 3H), 2.52 (s, 3H), 2.28 (s, 3H), 1.23 (d, J = 5.9 Hz, 6H); LCMS [M+l]+ = 562.2.

Example 73: N-[4-fluoro-5-(l-phenyl-3, 6-dihydro-2H-pyridin-4-yl)-2-[( 3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl]phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00323] The procedure was similar to Example 39 using N-(5-bromo-4-fluoro-2- ((3 S,5R)-3,4,5 -trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (60 mg, 0.099 mmol) and 1,2,3,6-tetrahydro-l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyridine (39.6 mg, 0.139 mmol) to give, after deprotection of the silyloxy intermediate, 20 mg (74% yield) of the title compound as a pale yellow orange powder. H NMR (500MHz, METHANOL-d4) δ = 8.04 - 7.98 (m, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.34 (t, J=8.0 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 7.08 (d, J=12.1 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.20 (br. s., 1H), 4.00 - 3.93 (m, 2H), 3.62 - 3.57 (m, 2H), 3.55 - 3.48 (m, 2H), 3.37 (br. s., 2H), 3.00 (s, 3H), 2.92 (t, J=12.3 Hz, 2H), 2.74 (br. s., 2H), 1.49 - 1.42 (m, 6H); LCMS [M+H]+ 584.6.

Example 74: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl] phenyl] benzamide


[00324] The title compound (pale beige solid, 25.3 mg, 50%) was prepared in a manner similar to Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and benzoyl chloride (17 μί, 0.15 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.25 (s, 1H), 8.69 (d, J=8.2 Hz, 1H), 8.60 (d, J=1.2 Hz, 2H), 7.94 (d, J=7.1 Hz, 2H), 7.64 -7.54 (m, 3H), 7.03 (d, J=11.4 Hz, 1H), 3.93 - 3.86 (m, 4H), 3.85 - 3.79 (m, 4H), 2.93 (d, J=10.9 Hz, 2H), 2.70 (t, J=10.9 Hz, 2H), 2.50 - 2.41 (m, 2H), 2.39 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 505.4.

Example 75: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] ' -3-methoxybenzamide


[00325] The title compound (beige solid, 4.6 mg, 8%) was prepared in a manner similar to Example 34 using 4-fluoro-3-methoxybenzoic acid (34 mg, 0.2

mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.14 (s, IH), 8.57 (d, J=8.3 Hz, IH), 8.51 (d, J=l. l Hz, 2H), 7.58 (dd, J=2.0, 8.1 Hz, IH), 7.31 (t, J=5.8 Hz, IH), 7.14 (dd, J=8.4, 10.5 Hz, IH), 6.94 (d, J=11.2 Hz, IH), 3.93 (s, 3H), 3.83 - 3.78 (m, 4H), 3.74 - 3.71 (m, 4H), 2.82 (d, J=10.9 Hz, 2H), 2.61 (t, J=10.9 Hz, 2H), 2.36 - 2.30 (m, 2H), 2.29 (s, 3H), 1.08 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 553.3.

Example 76: 3, 5-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00326] The title compound (beige solid, 32.4 mg, 55%) was prepared in a manner similar to Example 34 using 3,5-dichlorobenzoic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, IH), 8.52 (d, J=8.2 Hz, IH), 8.50 (d, J=1.2 Hz, 2H), 7.71 (s, 2H), 7.50 (s, IH), 6.95 (d, J=11.2 Hz, IH), 3.84 - 3.78 (m, 4H), 3.75 - 3.69 (m, 4H), 2.82 (d, J=11.0 Hz, 2H), 2.63 (t, J=10.9 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.31 (s, 3H), 1.11 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 573.2.

Example 77: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^


[00327] solution of ethyl 2-diazoacetate (50 g, 438 mmol, leq) in DCM

(500 mL) was added dropwise a solution of TFAA (70 mL, 482 mmol, 1.1 eq, in DCM) at 0°C under argon, then the reaction mixture was continued for 2 h. TLC analysis indicated formation of polar spot. The reaction mixture was neutralized with sat NaHCCb solution and extracted with DCM (3x300mL). The combined organic layer was washed with CU2SO4 solution and dried over Na2S04; then concentrated to give ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (50g, 55%) as a green oil. TLC: EtOAc : Pet ether (2:8); Rf: 0.4.

Step 2: 5-ethyl 1 -methyl (Z)-4-diazo-3-(trifluoromethyl)pent-2-enedioate


[00328] To a stirred solution of methyl 2-(triphenyl-15-phosphaneylidene)acetate

(52.56 g, 157 mmol, 1.5 eq) in diethyl ether (308 mL) was added ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (22 g, 104 mmol, 1 eq) at 10°C under argon atmosphere, then the reaction mixture was stirred at RT for 24h. TLC analysis indicated formation of polar spot. The reaction mixture was filtered and washed with diethyl ether then the filtrate was concentrated to crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-10% diethyl ether in pentane as eluent to afford 5-ethyl 1 -methyl (Z)-4-diazo-3-(trifluoromethyl)pent-2-enedioate (19 g, 68.19%) as yellow oil. TLC system: diethyl ether : pentane (3:7); Rf: 0.4.

Step 3: ethyl 6-methoxy-4-(trifluoromethyl)pyridazine-3-carboxylate


[00329] To a stirred solution of 5-ethyl 1-methyl (Z)-4-diazo-3- (trifluoromethyl)pent-2-enedioate (19 g, 71.42 mmol, leq) in diethyl ether (190 mL) was portion wise added TPP (22.4 g, 85.71 mmol, 1.2 eq) at 10°C then allowed to remain at RT for 16h. TLC analysis indicated formation of polar spot. The reaction mixture was filtered then the filtrate was concentrated to crude residue. The crude residue was purified by column chromatography (silica gel, 230-400mesh) using 0-20% acetone in pet ether as eluent to afford ethyl 6-methoxy-4-(trifluoromethyl)pyridazine-3-carboxylate (5 g, 28.90%) as yellow oil. LCMS: [M+H]+ 251.14.

Step 4: ethyl 6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridazine-3-carboxylate


[00330] To a stirred solution of 6-methoxy-4-(trifluoromethyl)pyridazine-3-carboxylate (4.5g, 18mmol, leq) in ACN (80mL) was added Nal (8.1g, 54 mmol, 3eq) and TMS-C1 (5.86 g, 54 mmol, 3 eq) at RT under argon atmosphere, then the reaction mixture was heated to 80°C for 2 h. TLC analysis indicated formation of polar spot. The reaction mixture was concentrated to crude residue, which was diluted with water and extracted with EtO Ac (3X 100 mL). The combined organic layer was dried over Na2S04 then concentrated to crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-5% MeOH in DCM as eluent to afford (3.2 g, 76.20%) as pale yellow solid. LCMS: [M+ H]+ 237.04.

Step 5: 6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridazine-3-carboxylic acid


[00331] To a solution of ethyl 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridazine-3-carboxylate (205 mg, 0.923 mmol) in THF (923 μΐ) was added lithium hydroxide monohydrate (77 mg, 1.846 mmol) dissolved in water (923 μΐ), and

the mixture was stirred for 1 h at room temperature. The reaction was concentrated, adjusted to a pH of 3, and extracted with DCM. The compound was not soluble in DCM. Purification was carried out using an anion exchange column to give the title compound (150 mg, 78% yield). LCMS [M-H] 206.98.

Step 6: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[( 3R, 5SJ-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrida


[00332] The title compound was prepared similar to the sequence described above for the preparation of Example 34 using 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridazine-3-carboxylic acid in place of l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid. XH NMR (500 MHz, MeOD) δ 8.57 (d, J = 1.1 Hz, 2H), 8.28 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.12 (d, J = 11.9 Hz, 1H), 3.86 - 3.83 (m, 4H), 3.78 - 3.75 (m, 4H), 3.08 (d, J = 11.5 Hz, 2H), 2.80 (s, 2H), 2.67 (t, J = 11.2 Hz, 2H), 2.50 (s, 3H), 1.21 (d, J = 6.3 Hz, 6H); LCMS [M+l]+ = 591.4.

Example 78: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl] phenyl] benzamide


(S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine


[00333] A solution of l-bromo-2,4-difluoro-5-nitrobenzene (3.85 mL, 30.5 mmol) in toluene (10 mL) was added dropwise to a rapidly stirring mixture of (S)-l,2-dimethylpiperazine dihydrochloride (5.70 g, 30.5 mmol) and potassium carbonate (10.5 g, 76 mmol) in toluene (70 mL) at room temperature. After stirring for 20 minutes the reaction was warmed to 45 °C for 30 minutes. After the reaction was cooled to room temperature the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [1-10% MeOH/DCM + 0.5% NH4OH] afforded (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (7.41 g, 73 %). LCMS [M+H]+: 332.1.

Step 2: (S)-4-(5-(4-(3, 4-dimethylpiperazin-l-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yljmorpholine


[00334] A 100 mL round bottomed flask was charged with a mixture of (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (1.60 g, 4.8 mmol), 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (1.50 g, 5.2 mmol), XPhos Pd G2 (0.075 g, 0.10 mmol) and XPhos (0.045 g, 0.10 mmol). The flask was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-dioxane (40 mL) and 2 M aqueous sodium carbonate (12 mL) were added via syringe and the flask was evacuated and backfilled an additional time. The reaction was heated to 90 °C for 3 h in an oil bath. After cooling to room temperature the reaction was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with additional DCM. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded (S)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-nitrophenyl)pyrirnidin-2-yl)morpholine (2.0 g, >95%). LCMS [M+H]+: 417.2.

Step 3: Preparation of (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)aniline


[00335] A mixture of (S)-4-(5-(4-(3,4-dimethylpiperazin-l-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yl)morpholine (2.0 g, 5.0 mmol), iron powder (1.1 g, 20 mmol) and acetic acid (25 mL) was heated to 80 °C for 90 minutes. After cooling to room temperature the reaction was transferred to a large Erlenmeyer flask and diluted with DCM (250 mL). The acetic acid was carefully neutralised by the addition of aqueous sodium bicarbonate. The whole was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with additional DCM.

The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration, the filtrate was concentrated onto celite. Purification by flash chromatography [0.5-10% DCM/MeOH + 0.5% NH4OH] afforded (S)-2-(3 ,4-dimethylpiperazin- 1 -yl)-4-fiuoro-5 -(2-mo holinopyrimidin-5-yl)aniline (1.34 g, 70 %). LCMS [M+H]+: 387.3.

Step 4: Preparation of (S)-N-(2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)benzamide


[00336] Benzoyl chloride (0.010 mL, 0.10 mmol) was added dropwise to a stirring solution of (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-mo holinopyrimidin-5-yl)aniline (0.025 g, 0.065 mmol) and triethylamine (0.026 mL, 0.19 mmol) in DCM (3 mL) at room temperature. After stirring for 2 h at room temperature the reaction was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford the title compound (S)-N-(2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)phenyl)benzamide (0.028 g, 88 %). XH NMR (500MHz, DMSO-d6) δ = 9.57 (s, 1H), 8.57 (s, 2H), 8.04 - 7.93 (m, 3H), 7.67 - 7.53 (m, 3H), 7.18 (d, J=12.1 Hz, 1H), 3.79 - 3.75 (m, 4H), 3.71 - 3.67 (m, 4H), 3.06 - 2.98 (m, 2H), 2.91 - 2.78 (m, 4H), 2.22 (br. s., 4H), 0.97 (d, J=6.0 Hz, 3H); LCMS [M+H]+: 491.4.

Example 79: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJfuran-2-carboxamide


[00337] The title compound was prepared similar to the sequence described above for the preparation of Example 78 using 2-furoyl chloride in place of benzoyl chloride in Step 4. XH NMR (500MHz, DMSO-d6) δ = 9.37 (s, IH), 8.55 (s, 2H), 8.20 (d, J=8.6 Hz, IH), 7.99 (s, IH), 7.30 (d, J=3.4 Hz, IH), 7.24 (d, J=12.0 Hz, IH), 6.74 (dd, J=1.7, 3.5 Hz, IH), 3.79 - 3.75 (m, 4H), 3.72 - 3.66 (m, 4H), 3.00 - 2.82 (m, 5H), 2.27 (br. s., 4H), 1.02 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 481.3.

Example 80: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJpyridine-3-carboxamide


[00338] The title compound was prepared similar to the sequence described above for the preparation of Example 78 using nicotinoyl chloride hydrochloride in place of benzoyl chloride in Step 4. XH NMR (500 MHz, DMSO-d6) δ 9.82 (s, IH), 9.13 (br. s., IH), 8.78 (d, J=4.52 Hz, IH), 8.57 (d, J=1.10 Hz, 2H), 8.30 (d, J=8.19 Hz, IH), 7.89 (d, J=8.31 Hz, IH), 7.61 (dd, J=4.89, 7.83 Hz, IH), 7.15 (d, J=11.86 Hz, IH), 3.75-3.80 (m, 4H), 3.67-3.71 (m, 4H), 3.05 (br. s., 2H), 2.75-2.91 (m, 2H), 2.21 (br. s., 4H), 0.98 (br. s., 3H); LCMS [M+H]+: 492.4.

Example 81: N-[4-chloro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


Step 1: (S)-4-(4-bromo-5-chloro-2-nitrophenyl)-l,2-dimethylpiperazine


[00339] A solution of l-bromo-2-chloro-4-fluoro-5-nitrobenzene (1.0 g, 3.9 mmol) in toluene (2 mL) was added dropwise to a rapidly stirring mixture of (S)-l,2-dimethylpiperazine dihydrochloride (0.73 g, 3.9 mmol) and potassium carbonate (1.4 g, 9.8 mmol) in toluene (10 mL) at room temperature. After stirring for 20 minutes at room temperature the reaction was warmed to 45 °C for 18 h. After the reaction was cooled to room temperature the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [1-10% MeOH/DCM + 0.5% NH4OH] afforded (S)-4-(4-bromo-5-chloro-2-nitrophenyl)-l,2-dimethylpiperazine (0.66 g, 48 %). LCMS [M+H]+: 348.0.

Step 2: (S)-4-(5-(2-chloro-4-(3, 4-dimethylpiperazin-l-yl)-5-nitrophenyl)pyrimidin-2-yl)morpholine


[00340] A vial was charged with (S)-4-(4-bromo-5-chloro-2-nitrophenyl)-l,2-dimethylpiperazine (0.40 g, 1.1 mmol), 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (0.37 g, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (7 mL) and 2 M aqueous sodium carbonate (3 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 100 °C for 3 h. After cooling to room temperature the reaction mixture was concentrated onto celite and flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (S)-4-(5-(2-chloro-4-(3,4-dimethylpiperazin-l-yl)-5-nitrophenyl)pyrimidin-2-yl)morpholine (0.28 g, 56 %). LCMS [M+H]+: 433.2.

Step 3: (S)-4-chloro-2-(3,4^ime (2-morpholinopyri


[00341] A mixture of (S)-4-(5-(2-chloro-4-(3,4-dimethylpiperazin-l-yl)-5-nitrophenyl)pyrimidin-2-yl)morpholine (0.12 g, 0.28 mmol), iron powder (0.080 g, 1.4 mmol), hydrochloric acid (0.12 mL, 1.4 mmol), MeOH (5 mL) and water (1 mL) was heated to 85 °C for 1 h. After cooling to room temperature the reaction was

diluted with MeOH and filtered through celite, eluting with additional MeOH. The filtrate was concentrated onto celite and flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded (S)-4-chloro-2-(3,4-dimethylpiperazin-l-yl)-5-(2-mo holinopyrimidin-5-yl)aniline (0.046 g, 41 %). LCMS [M+H]+: 403.3.

Step 4: (S)-N-(4-chloro-2-(3, 4-dimethylpiperazin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00342] A suspension of 6-chloro-4-(trifluoromethyl)nicotinic acid (0.030 g,

0.13 mmol) and thionyl chloride (0.32 mL, 4.5 mmol) was heated at 80 °C for 1 h. The reaction mixture was concentrated to dryness to afford the acid chloride which was suspended in anhydrous DCM (2 mL) and treated with a solution of (S)-4-chloro-2-(3,4-dimethylpiperazin-l-yl)-5-(2-morpholinopyrimidin-5-yl)aniline (0.045 g, 0.11 mmol) and triethylamine (0.05 mL, 0.3 mmol) in DCM (2 mL) at room temperature. After stirring for 18 h at room temperature the reaction mixture was quenched with a saturated aqueous NaHCCb solution (10 mL) and extracted with DCM. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (S)-6-chloro-N-(4-chloro-2-(3,4-dimethylpiperazin-l-yl)-5-(2-mo holinopyrirnidin-5-yl)phenyl)-4-(trifluoromethyl)nicotinamide. A mixture of the prepared amide and sodium acetate (0.018 g, 0.22 mmol) in HOAc/H20 (4 mL/1 mL) was irradiated at 160 °C for 4 h. The reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford the title compound (S)-N-(4-chloro-2-(3,4-dimethylpiperazin-l-yl)-5-(2-mo holinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (0.019 g, 29 %). l NMR

(500MHz, DMSO-d6) δ = 12.58 (br. s., 1H), 9.55 (s, 1H), 8.46 (s, 2H), 8.24 (br. s., 1H), 7.93 (br. s., 1H), 7.80 (s, 1H), 7.28 (s, 1H), 6.88 - 6.79 (m, 2H), 6.64 (s, 1H), 3.78 - 3.75 (m, 4H), 3.70 - 3.68 (m, 4H), 3.06 - 2.99 (m, 3H), 2.84 (d, J=11.0 Hz, 3H), 2.25 (br. s., 2H), 1.00 (d, J=6.0 Hz, 3H); LCMS [M+H]+: 592.4.

Example 82: N-[4-chloro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00343] The title compound was prepared similar to the sequence described above for the preparation of Example 81 using cis-l,2,6-trimethylpiperazine in place of (S)-l,2-dimethylpiperazine dihydrochloride in Step 1. H N-MR (500MHz, DMSO-d6) δ = 12.60 (br. s., 1H), 9.56 (s, 1H), 8.46 (s, 2H), 7.91 (s, 1H), 7.79 (s, 1H), 7.25 (s, 1H), 6.82 (s, 1H), 3.79 - 3.74 (m, 5H), 3.73 - 3.66 (m, 5H), 3.01 (d, J=10.6 Hz, 3H), 2.42 - 2.35 (m, 2H), 2.22 (br. s., 3H), 1.02 (d, J=5.9 Hz, 6H); LCMS [M+H]+: 606.3.

Example 83: N-[4-fluoro-5-( 2-morpholin-4-ylpyridin-4-yl)-2-[( 3R, 5S)-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00344] The title compound (pale yellow solid, 23.6 mg, 39%) was prepared similar to the procedure of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-

carboxamide (50.5 mg, 0.1 mmol) and 2-morpholinopyridine-4-boronic acid, pinacol ester (58 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.18 (d, J=5.3 Hz, IH), 7.98 (s, IH), 7.95 (d, J=7.8 Hz, IH), 7.08 (d, J=12.2 Hz, IH), 6.97 (s, IH), 6.95 - 6.90 (m, 2H), 3.86 - 3.80 (m, 4H), 3.58 - 3.49 (m, 4H), 3.11 (d, J=11.2 Hz, 2H), 2.64 (t, J=11.2 Hz, 2H), 2.60 - 2.53 (m, 2H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 589.4.

Example 84: N-[4-fluoro-5-[6-(2-methoxyethoxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridim


[00345] The title compound (pale yellow solid, 41.2 mg, 68%) was prepared similar to the procedure of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (56 mg, 0.2 mmol). l NMR (500MHz, METHANOL-d4) δ = 8.31 (s, IH), 7.97 (s, IH), 7.92 (d, J=8.2 Hz, IH), 7.89 (d, J=8.7 Hz, IH), 7.09 (d, J=11.8 Hz, IH), 6.93 (s, IH), 6.92 (d, J=7.6 Hz, 2H), 4.51 -4.44 (m, 2H), 3.79 (dd, J=4.1, 5.1 Hz, 2H), 3.44 (s, 3H), 3.08 (d, J=l l . l Hz, 2H), 2.67 - 2.54 (m, 4H), 2.40 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 578.4.

Example 85: N-[4-fluoro-5-(3-morpholin-4-ylphenyl)-2-[(3R,5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH^yridme-3-carboxamide


[00346] The title compound (46.0 mg, 77%) was prepared similar to the procedure of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]mo holine (58 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d4) δ = 7.97 (s, IH), 7.90 (d, J=7.9 Hz, IH), 7.34 (t, J=7.9 Hz, IH), 7.13 (s, IH), 7.07 - 7.02 (m, 2H), 7.00 (d, J=8.3 Hz, IH), 6.92 (s, IH), 3.86 (d, J=3.1 Hz, 4H), 3.25 - 3.17 (m, 4H), 3.07 (d, J=l l.l Hz, 2H), 2.67 - 2.51 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+588.4.

Example 86: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl] phenyl] -2-methoxybenzamide


[00347] The title compound (beige solid, 48.1 mg, 86%) was prepared by a procedure similar to that of Example 34 using 4-fluoro-5-(2-moφholinopyrimiαm-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-methoxybenzoyl chloride (22 μί, 0.15 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 10.41 (s, IH), 8.66 (d, J=8.4 Hz, IH), 8.59 (s, 2H), 8.33 (d, J=7.8 Hz, IH), 7.55 (t, J=7.8 Hz, IH), 7.18 (t, J=7.5 Hz, IH), 7.09 (d, J=8.3 Hz, IH), 6.97 (d, J=11.6 Hz, IH), 4.12 (s, 3H), 3.92 - 3.85 (m, 4H), 3.85 - 3.78 (m, 4H), 3.03 - 2.96 (m, 2H), 2.63 (t, J=11.0 Hz, 2H), 2.51 - 2.42 (m, 2H), 2.37 (s, 3H), 1.14 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 535.4.

Example 87: 2-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00348] The title compound (off-white solid, 42.7 mg, 75%) was prepared by a procedure similar to that of Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-chloro-4-fluorobenzoylchloride (20 μί, 0.15 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.22 (s, IH), 8.69 (d, J=8.3 Hz, IH), 8.59 (s, 2H), 7.86 (dd, J=6.1, 8.7 Hz, IH), 7.26 (dd, J=2.4, 8.4 Hz, IH), 7.16 (t, J=8.2 Hz, IH), 7.04 (d, J=11.2 Hz, IH), 3.92 -3.86 (m, 4H), 3.85 - 3.78 (m, 4H), 2.92 - 2.86 (m, 2H), 2.66 (t, J=10.9 Hz, 2H), 2.42 -2.32 (m, 5H), 1.14 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 557.4.

Example 88: 5-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide

[00349] The title compound (beige solid, 53.4 mg, 87%) was prepared by a procedure similar to that of Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 5-fluoro-2-(trifluoromethyl)benzoyl chloride (23 μί, 0.15 mmol). l NMR (500MHz, CHLOROFORM-d) δ = 8.64 - 8.53 (m, 4H), 7.83 (dd, J=5.0, 8.7 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.03 (d, J=11.2 Hz, 1H), 3.93 - 3.87 (m, 4H), 3.85 - 3.78 (m, 4H), 2.85 (d, J=10.9 Hz, 2H), 2.64 (t, J=10.9 Hz, 2H), 2.32 - 2.21 (m, 5H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 591.4.

Example 89: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-ylJphenylJ-3-methoxybenzamide


[00350] The title compound (yellow solid, 39.3 mg, 72%) was prepared by a procedure similar to that of Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 3-methoxybenzoyl chloride (21 μί, 0.15 mmol). 'H NMR (500MHZ, CHLOROFORM-d) δ = 9.25 (s, 1H), 8.69 (d, J=8.3 Hz, 1H), 8.60 (s, 2H), 7.54 - 7.52 (m, 1H), 7.47 -7.44 (m, 1H), 7.17 - 7.12 (m, 1H), 7.03 (d, J=11.2 Hz, 1H), 3.93 (s, 3H), 3.91 - 3.87 (m, 4H), 3.82 (d, J=1.0 Hz, 4H), 2.92 (d, J=11.0 Hz, 2H), 2.71 (t, J=11.0 Hz, 2H), 2.52 - 2.42 (m, 2H), 2.39 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 535.4.

Example 90: N-[4-fluoro-5-[4-(2-methoxyethoxy)phenyl]-2-[(3R,5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH^yridme-3-carboxamide

[00351] The title compound (grey solid, 37.6 mg, 63%) was prepared by a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-(2-methoxyethoxy)phenylboronic acid (39 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 7.97 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.07 - 7.01 (m, 3H), 6.92 (s, 1H), 4.18 (dd, J=3.8, 5.4 Hz, 2H), 3.82 - 3.76 (m, 2H), 3.46 (s, 3H), 3.07 (d, J=11.0 Hz, 2H), 2.68 - 2.53 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.0 Hz, 6H); LCMS [M + H]+ 577.4.

Example 91: N-[5-[5-chloro-6-(2-methylpropoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00352] The title compound (light brown solid, 48.1 mg, 77%) was prepared by a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 3-chloro-2-isobutoxypyridine-5-boronic acid (46 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.24 (s, 1H), 7.97 (d,

J=7.8 Hz, 2H), 7.92 (d, J=8.3 Hz, IH), 7.10 (d, J=12.1 Hz, IH), 6.93 (s, IH), 4.21 (d, J=6.6 Hz, 2H), 3.09 (d, J=11.2 Hz, 2H), 2.68 - 2.60 (m, 2H), 2.60 - 2.53 (m, 2H), 2.39 (s, 3H), 2.15 (td, J=6.7, 13.4 Hz, IH), 1.18 (d, J=6.1 Hz, 6H), 1.08 (d, J=6.7 Hz, 6H); LCMS [M + H]+ 610.3.

Example 92: N-[5-[3-chloro-4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00353] The title compound (light brown solid, 26.9 mg, 43%) was prepared by a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and (3-chloro-4-(cyclopropylmethoxy)phenyl)boronic acid (45.3 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d4) δ = 7.97 (s, IH), 7.90 (d, J=8.3 Hz, IH), 7.58 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.13 (d, J=8.6 Hz, IH), 7.06 (d, J=12.1 Hz, IH), 6.93 (s, IH), 3.98 (d, J=6.8 Hz, 2H), 3.07 (d, J=l l. l Hz, 2H), 2.67 - 2.53 (m, 4H), 2.40 (s, 3H), 1.38 - 1.30 (m, IH), 1.18 (d, J=6.0 Hz, 6H), 0.70 - 0.64 (m, 2H), 0.46 - 0.41 (m, 2H); LCMS [M+ H]+ 607.3.

Example 93: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

Step 1: 5-bromo-2-chloro-4-iodopyridine


[00354] A stirred solution of DIP A (4.02 niL, 28.8 mmol, l . leq) in dry THF

(50 mL) was cooled to -78°C and n-BuLi (10.47 niL, 26.18 mmol, 1.0 eq, 2.5M in hexane) was added dropwise under an argon atmosphere. Then, the reaction mixture was stirred for 30 min. at the same temp., followed by the addition of a solution of 2-chloro-5-bromopyridine (5.0g, 26.178 mmol, 1.0 eq) in dry THF (50mL) and stirred for lh at the same temp. Then, a solution of iodine (6.64g, 26.178 mmol, l .Oeq) in THF (50mL) was added dropwise at -78°C. After completion of addition the reaction mixture was allowed to warm to RT over 4h. The reaction progress was monitored by TLC. The reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate, and extracted with EtOAc (3 x lOOmL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to obtain the crude compound. The crude compound was recrystallized from ethanol (20 mL) to give the title compound (5 g, 60.3%) as an off white solid. LCMS: [M+H]+ 317.86.

Step 2: 5-bromo-2-chloro-4-(trifluoromethyl)pyridine


[00355] To a stirred solution of 5-bromo-2-chloro-4-iodopyridine (20.0 g,

63.09 mmol, 1.0 eq) in DMF (200 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (16.15 mL, 126.18 mmol, 2.0 eq) and Cul (24.02 g, 126.18 mmol, 2.0 eq) were added at RT under argon atmosphere and the reaction mixture was heated to 100°C for 6h.

TLC analysis indicated a non-polar spot. The reaction mixture was diluted with water (200 mL) and filtered off and washed with w-pentane (1L) and cold water (3L). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure at 30°C. The crude compound was purified by column chromatography (Silica gel, 100-200 mesh) using 5% EtOAc in pet ether as an eluent to afford the title compound (9.0 g, 55.2%) as a liquid compound. TLC: 5% EtOAc in pet ether; Rf: 0.7

Step 3: 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine


[00356] solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (24.0 g,

93.02 mmol, 1.0 eq) in methanol (200 mL), was added 30% NaOMe (33.08 mL, 186.04 mmol, 2.0 eq). Then, the reaction mixture was heated at 70°C for 6 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with water and extracted with EtOAc (3 X 200mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure at 30°C. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 5% EtOAc in pet ether as an eluent to give 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine (15g, 63.47%) as an off white solid. TLC: 5% EtOAc in pet ether; Rf: 0.8.

Step 4: 6-methoxy-4-(trifluoromethyl)nicotinic acid


[00357] A solution of w-butyl magnesium chloride (20% in THF; 27.8 mL,

27.79 mmol, 1.2 eq) was added to a solution of w-butyl lithium (2.5M in hexane; 23.16 mL, 92.64 mmol, 4 eq) under argon atm. After 10 min, the reaction mixture was diluted with dry THF (80 mL) and cooled to -78°C. A solution of 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine (6 g, 23.16 mmol, 1.0 eq ) in dry THF (30 mL) was added to the above reaction mixture at -78°C and stirred for lh at the same temperature. Then, crushed dry ice was added at -78°C. After addition, the reaction mixture was allowed to remain at RT for 16h. TLC analysis indicated formation of polar spot. The reaction mixture was concentrated under reduced pressure and acidified with 2N aq. HC1 (20 mL), then the obtained solid was filtered off and

washed with w-pentane to give 6-methoxy-4-(trifluoromethyl)nicotinic acid (3.5g, 67.3%) as an off white solid compound. LCMS: [M+H]+ 221.99, M+H.

Step 5: methyl 6-methoxy-4-(trifluoromethyl)nicotinate


[00358] To a stirred solution of 6-methoxy-4-(trifluoromethyl)nicotinic acid

(22 g, 99.5 mmol, 1.0 eq) in acetone (160 mL) was added K2C03 (20.5 g, 149.25 mmol, 1.5 eq) followed by the dropwise addition of dimethylsulphate (16.3g,129.4 mmol, 1.3eq) at 0°C and the reaction mixture was allowed to remain at RT over 2h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was concentrated under reduced pressure to crude residue, which was redissolved in EtOAc (500 mL) and washed with water and brine. The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-2% EtOAc in pet ether as an eluent to afford methyl 6-methoxy-4-(trifluoromethyl)nicotinate (19 g, 81.5%) as a white solid. [M+H]+ 236.37.

Step 6: methyl 6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxylate


[00359] To a stirred solution of methyl 6-methoxy-4-(trifluoromethyl)nicotinate (3 g, 12.76 mmol, l.Oeq) in ACN (30 mL) was added TMS-Cl (4.54 g, 38.28 mmol, 3.0 eq) and Nal (5.7 g, 38.28 mmol, 3.0 eq ) at RT under argon atm. Then, the reaction mixture was heated to reflux for 3h. TLC analysis indicated formation of polar spot. Then, the reaction mixture was diluted with water (500mL) and extracted with EtOAc (3x lOOmL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-5% EtOAc in pet ether as eluent to afford methyl 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylate (1.2 g, 42.8%) as an off-white solid. LCMS: [M+H]+ 221.96.

Step 7: methyl l-methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxylate


[00360] To a stirred solution of methyl 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylate (13.0 g, 58.82 mmol, 1.0 eq) in DMF (130 mL) was added methyl iodide (4.3 mL, 70.58 mmol, 1.2eq) and cesium carbonate (28.6 g, 88.2 mmol, 1.5eq) at RT under argon atmosphere. Then, the reaction mixture was stirred at RT for lh. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with cold water (1L) and extracted with EtOAc (3x 150mL). The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-30% EtOAc in pet ether as eluent to give methyl l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylate (10 g, 72.4% yield) as off-white solid. LCMS: 99.26% with [M+H]+ 235.98.

Step 8: l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid


[00361 ] To a stirred solution of methyl l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylate (9.0 g, 38.29 mmol, l.Oeq) in THF: MeOH: H20 (220 mL, 3: 1: 2) was added LiOH.H20 (4.7 g, 114.8 mmol, 3.0eq) at RT and the reaction mixture was stirred at RT for 16h. TLC analysis indicated formation of polar spot. The reaction mixture was concentrated under reduced pressure to crude product. The crude product was acidified with aqueous 2N HCl (20mL), the resulting precipitate was filtered off and washed with diethyl to give l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (6.0 g, 71.42%) as an off white solid. LCMS: [M+H]+ 221.95.

Step 9: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[( 3R, 5SJ-3, 4, 5-trimethylpiperazin-l-ylj henyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

[00362] In a 5 ml microwave vial to a suspension of l-methyl-6-oxo-4- (trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (59.6 mg, 0.270 mmol) in pyridine, anhydrous (327 μΐ, 4.04 mmol) was added slowly diethyl chlorophosphate (59.4 μΐ, 0.411 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred at rt for 2 h. The suspension turned brown. To this, 4-fluoro-5-(2-moφholinopyrimiαm-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)aniline (27 mg, 0.067 mmol) was added and the reaction was heated at 70 °C for 16 h. After completion, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2SC>4. The solvent was evaporated in vacuo yielding the crude product which was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound. ¾ NMR (500 MHz, MeOD) δ 8.55 (d, J= 1.1 Hz, 2H), 8.24 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.08 (d, J= 12.1 Hz, 1H), 6.94 (s, 1H), 3.85 - 3.82 (m, 4H), 3.78 - 3.75 (m, 4H), 3.64 (s, 3H), 3.04 (d, J = 11.3 Hz, 2H), 2.60 (t, J = 11.2 Hz, 2H), 2.50 (dd, J = 8.3, 5.9 Hz, 2H), 2.34 (s, 3H), 1.15 (d, J= 6.2 Hz, 6H); LCMS [M+l]+ = 604.24.

Example 94: N-[5-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00363] The procedure followed was similar to Example 39 using N-(5-bromo- 4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid, pinacol ester (24.28 mg, 0.116 mmol) followed by deprotection of the intermediate to afford after purification 16 mg (63% for final step) of the title compound as a beige solid. XH NMR (500MHz, METHANOL-d4) δ = 7.94 (s, 1H), 7.78 (d, J=8.1 Hz, 1H), 6.96 (d, J=12.6 Hz, 1H), 6.94 - 6.89 (m, 1H), 6.08 (br. s., 1H), 4.39 - 4.20 (m, 2H), 3.99 - 3.82 (m, 2H), 3.03 (d, J=10.6 Hz, 2H), 2.65 - 2.47 (m, 6H), 2.39 (s, 3H), 1.17 (d, J=5.9 Hz, 6H); LCMS [M+H]+ 509.7

Example 95: N-[4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yl] -5-(l , 2, 3, 6-tetrahydropyridin-4-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00364] The product was obtained after TFA deprotection of the intermediate resulting from a reaction between N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(mfluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (50 mg, 0.083 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate (35.7 mg, 0.116 mmol) using a method similar to that in Example 39 to give, after deprotection, the title compound in 94% yield for the final step. H NMR (500MHz, METHANOL-d4) δ = 8.06 (s, 1H), 7.82 (d, J=8.1 Hz, 1H), 6.96 (d, J=12.5 Hz, 1H), 6.80 (s, 1H), 6.05 (br. s., 1H), 3.66 (d, J=2.7 Hz, 2H), 3.24 (t, J=5.8 Hz, 2H), 3.02 (d, J=l l. l Hz, 2H), 2.65 - 2.47 (m, 6H), 2.36 (s, 3H), 1.16 (d, J=6.1 Hz, 6H); LCMS [M+H]+ 508.6

Example 96: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide


[00365] The title compound (white solid, 18.1 mg, 62%) was prepared according to a procedure similar to that used in Example 34 with 3-(trifluoromethyl)pyrazole-4-carboxylic acid (27 mg, 0.15 mmol) and (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-morpholinopyrimidin-5-yl)aniline (20 mg, 0.05 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.58 (s, 2H), 8.39 (br. s., 1H), 7.98 (d, J=8.2 Hz, 1H), 7.11 (d, J=12.0 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.80 - 3.75 (m, 4H), 3.04 (d, J=11.4 Hz, 2H), 2.63 (t, J=11.2 Hz, 2H), 2.55 - 2.46 (m, 2H), 2.37 (s, 3H), 1.15 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 563.4.

Example 97: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-3,5-dimethylbenzamide


[00366] The title compound (pale beige solid, 26.1 mg, 47%) was prepared according to a procedure similar to Example 78 using 4-fluoro-3,5-dimethylbenzoic acid (50 mg, 0.3 mmol) and (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-mo holinopyrimidin-5-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.19 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.60 (s, 2H), 7.62 (d, J=6.7 Hz, 2H), 7.02 (d, J=11.2 Hz, 1H), 3.93 - 3.86 (m, 4H), 3.85 - 3.79 (m, 4H), 2.94 (d, J=11.0 Hz, 2H), 2.71 (t, J=10.9 Hz, 2H), 2.51 - 2.41 (m, 2H), 2.41 - 2.35 (m, 9H), 1.19 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 551.3.

Example 98: N-[5-( 3-chloro-5-cyano-4-hydroxyphenyl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00367] The procedure used was similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyl)ethoxy)benzonitrile (43.9 mg, 0.116 mmol) followed by deprotection of the resulting intermediate using TFA to give the title compound as a tan solid. XH NMR (500MHz, DMSO-d6) δ = 12.55 (br. s., 1H), 9.45 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.39 (br. s., 1H), 7.22 (br. s.,lH), 6.95 (d, J=12.8 Hz, 1H), 6.81 (s, 1H), 3.02 (d, J=8.7 Hz, 2H), 2.50 - 2.44 (m, 4H), 2.27 (br. s., 3H), 1.04 (d, J=5.0 Hz, 6H); LCMS [M+H]+ 578.6

Example 99: N-[5-(5-cyano-6-phenylmethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00368] The procedure used was similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)- 6-(2-(trimethylsilyl)ethoxy)nicotinamide (300 mg, 0.495 mmol) and 2-(benzyloxy)-5-(trimethylstannyl)nicotinonitrile (222 mg, 0.595 mmol) to give, after deprotection with TFA, 66 mg (20% yield) of the title compound. XH NMR (500MHz, METHANOL-d4) δ = 8.61 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.05 (br. s., 1H), 7.98 (d, J=8.1 Hz, 1H), 7.53 (d, J=7.3 Hz, 2H),7.41 (t, J=7.4 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.24 (d, J=11.2 Hz, 1H), 6.95 (s, 1H), 5.69 - 5.56 (m, 2H), 3.69 - 3.49 (m, 2H), 3.48 -3.36 (m, 2H), 3.11- 2.92 (m, 5H), 1.46 (br. s., 6H); LCMS [M+H]+ 635.7.

Example 100: N-[5-(4 yanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00369] In a 5 mL microwave vial N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (52.13 mg, 0.086 mmol), 4-cyanophenylboronic acid (18.97 mg, 0.129 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (6.10 mg, 8.61 μηιοΐ) and potassium phosphate tribasic reagent grade (36.5 mg, 0.172 mmol) were dissolved in water (172 μΐ) / 1,4-dioxane (1550 μΐ) (9 : 1 mixture) to give a white suspension. The suspension was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 120 °C. The solvent was evaporated and 15 mL of CH2CI2 were added. The suspension was sonicated and extracted from water (15 mL). The solvent was evaporated in vacuo yielding the crude product which was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the protected intermediate. The product was dissolved in 2 mL of DCM and trifluoroacetic acid (132 μΐ, 1.722 mmol) was added. The purple solution was stirred for 1 h and the solvent was evaporated. The residue was purified using a cation exchange column eluting with MeOH:NH4OH. The residue was freeze dried for 2 days to afford the title compound. H NMR (500 MHz, MeOD) δ 7.96 (d, J= 6.7 Hz, 2H), 7.81 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 7.4 Hz, 2H), 7.09 (d, J= 12.3 Hz, 1H), 6.91 (s, 1H), 3.10 (d, J= 11.3 Hz, 2H), 2.63 (t, J = 11.2 Hz, 2H), 2.55 (dt, J = 6.0, 5.1 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H); 19F NMR (471 MHz, MeOD) δ -63.78 (s), -120.23 (s); LCMS [M+l]+ = 528.17.

Example 101: N-[4-fluoro-5-[6-(oxan-4-yloxy)pyridin-3-yl]-2-[(3R, 5SJ-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00370] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-(tetrahydropyran-4-yloxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine as the borolane starting material. H NMR (500 MHz, MeOD) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.86 (d, J= 9.6 Hz, 1H), 7.07 (d, J= 12.0 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J= 8.7 Hz, 1H), 5.25 (tt, J= 8.4, 4.0 Hz, 1H), 4.01 - 3.94 (m, 2H), 3.63 (ddd, J = 11.8, 9.1, 2.9 Hz, 2H), 3.06 (d, J = 11.2 Hz, 2H), 2.61 (t, J= 11.1 Hz, 2H), 2.54 (s, 2H), 2.13 - 2.06 (m, 2H), 1.83 - 1.73 (m, 2H), 1.16 (d, J= 6.2 Hz, 6H); LCMS [M+l]+ = 604.39.

Example 102: N-[5-(3 yanophenyl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00371] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 3-cyanophenylboronic acid. H NMR

(500 MHz, MeOD) δ 7.96 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 12.2 Hz, 1H), 6.91 (s, 1H), 3.09 (d, J = 11.3 Hz, 2H), 2.63 (t, J = 11.1 Hz, 2H), 2.55 (s, 2H), 2.37 (s, 3H), 1.16 (d, J= 6.2 Hz, 6H); LCMS [M+l]+ = 528.32.

Example 103: N-[5-[2-(dimethylamino)pyrimidin-5-yl]-4-fluoro-2-[( 3R, 5SJ-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00372] The title compound was prepared according a method similar to that used for the preparation of Example 100 using N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine. H NMR (500 MHz, MeOD) δ 8.51 (d, J = 1.1 Hz, 2H), 7.97 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 12.1 Hz, 1H), 6.90 (s, 1H), 3.22 (s, 6H), 3.05 (d, J = 11.2 Hz, 2H), 2.61 (t, J = 11.2 Hz, 2H), 2.53 (d, J = 6.0 Hz, 2H), 2.36 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H); LCMS [M+l]+ = 548.34.

Example 104: N-[5-(5, 6-dimethoxypyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00373] The title compound was prepared according a method similar to that used for the preparation of Example 100 with (5,6-dimethoxypyridin-3-yl)boronic acid in place of 4-cyanophenylboronic acid. XH NMR (500 MHz, MeOD) δ 7.97 (s,

1H), 7.90 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.07 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 3.06 (d, J = 11.3 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.54 (s, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H). 19F NMR (471 MHz, MeOD) δ -63.76 (s), -120.32 (s); LCMS HSS [M+l]+ = 564.29.

Example 105: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl] phenyl] -l,3-benzodioxole-4-carboxamide


[00374] The title compound (light beige solid, 39.9 mg, 71%) was prepared according to a method similar to that used for Example 34 using l,3-benzodioxole-4-carboxylic acid (33 mg, 0.2 mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.86 (s, 1H), 8.77 (d, J=8.4 Hz, 1H), 8.60 (s, 2H), 7.70 (dd, J=2.4, 7.0 Hz, 1H), 7.08 - 7.00 (m, 3H), 6.22 (s, 2H), 3.92 - 3.85 (m, 4H), 3.84 - 3.79 (m, 4H), 2.96 - 2.89 (m, 2H), 2.66 (t, J=10.9 Hz, 2H), 2.45 - 2.37 (m, 5H), 1.17 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 549.2.

Example 106: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl] phenyl] -4-methoxybenzamide

[00375] The title compound (beige solid, 52.4 mg, 96%) was prepared through a procedure similar to that of Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 4-methoxybenzoyl chloride (20 μί, 0.15 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.15 (s, IH), 8.67 (d, J=8.3 Hz, IH), 8.60 (d, J=1.2 Hz, 2H), 7.92 (d, J=8.2 Hz, IH), 7.90 (s, IH), 7.04 (d, J=8.8 Hz, 2H), 7.02 (d, J=11.4 Hz, IH), 3.93 (s, 3H), 3.91 - 3.87 (m, 4H), 3.84 - 3.80 (m, 4H), 2.93 (d, J=11.0 Hz, 2H), 2.69 (t, J=11.0 Hz, 2H), 2.46 (dt, J=3.1, 6.6 Hz, 2H), 2.39 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 535.3.

Example 107: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] benzamide


[00376] The title compound (light beige solid, 49.0 mg, 93%) was prepared using a procedure similar to Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 4-fluorobenzoyl chloride (18 μί, 0.15 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.19 (s, IH), 8.65 (d, J=8.2 Hz, IH), 8.59 (s, 2H), 7.95 (t, J=6.6 Hz, 2H), 7.27 -7.22 (m, 2H), 7.03 (d, J=11.2 Hz, IH), 3.93 - 3.85 (m, 4H), 3.85 - 3.78 (m, 4H), 2.92 (d, J=11.0 Hz, 2H), 2.70 (t, J=11.0 Hz, 2H), 2.49 - 2.37 (m, 5H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 523.4.

Example 108: N-[4-fluoro-5-( 3-fluoro-5-morpholin-4-ylphenyl)-2-[( 3R, 5S) -3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00377] The title compound (brown solid, 28.3 mg, 45%) was prepared through a procedure similar to that of Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 3-ΑυοΓθ-5^ο ηο1ίηορ1ΐ6^^θΓοηίΰ acid (45 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 7.97 (s, IH), 7.90 (d, J=8.3 Hz, IH), 7.58 (s, IH), 7.45 (d, J=8.7 Hz, IH), 7.13 (d, J=8.6 Hz, IH), 7.06 (d, J=12.1 Hz, IH), 6.93 (s, IH), 3.98 (d, J=6.8 Hz, 2H), 3.07 (d, J=l l . l Hz, 2H), 2.67 -2.53 (m, 4H), 2.40 (s, 3H), 1.38 - 1.30 (m, IH), 1.18 (d, J=6.0 Hz, 6H), 0.70 - 0.64 (m, 2H), 0.46 - 0.41 (m, 2H); LCMS [M + H]+ 607.3.

Example 109: 2-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] benzamide


[00378] The title compound (beige solid, 38.2 mg, 70%) was prepared through a procedure similar to that of Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-chlorobenzoyl chloride (19 μί, 0.15 mmol). 'H NMR (500MHZ, CHLOROFORM-d) δ = 9.15 (s, IH), 8.71 (d, J=8.3 Hz, IH), 8.61 (s, 2H), 7.81 (dd, J=1.8, 7.5 Hz, IH), 7.54 - 7.41 (m, 3H), 7.04 (d, J=11.4 Hz, IH), 3.93 - 3.86 (m, 4H), 3.84 - 3.78 (m, 4H), 2.94 - 2.88 (m, 2H), 2.66 (t, J=10.9 Hz, 2H), 2.43 - 2.30 (m, 5H), 1.14 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 539.4.

Example 110: 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] '-3-methoxybenzamide


[00379] The title compound (light beige solid, 46.7 mg, 84%) was prepared through a procedure similar to that of Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-fluoro-3-methoxybenzoyl chloride (28 mg, 0.15 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.73 (d, J=12.7 Hz, IH), 8.74 (d, J=8.3 Hz, IH), 8.60 (s, 2H), 7.73 (t, J=7.2 Hz, IH), 7.26 (t, J=8.4 Hz, IH), 7.18 (t, J=8.0 Hz, IH), 7.04 (d, J=11.4 Hz, IH), 3.98 (s, 3H), 3.92 - 3.86 (m, 4H), 3.85 - 3.78 (m, 4H), 2.92 (d, J=10.9 Hz, 2H), 2.67 (t, J=10.8 Hz, 2H), 2.54 (br. s., 2H), 2.40 (s, 3H), 1.17 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 553.5.

Example 111: 3, 4-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] benzamide


[00380] The title compound (beige solid, 37.5 mg, 67%) was prepared through a procedure similar to that of Example 34 using 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 3,4-difluorobenzoyl chloride (19 μί, 0.15 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.73 (d, J=12.7 Hz, IH), 8.74 (d, J=8.3 Hz, IH), 8.60 (s, 2H), 7.73 (t, J=7.2 Hz, IH), 7.26 (t, J=8.4 Hz, IH), 7.18 (t, J=8.0 Hz, IH), 7.04 (d, J=11.4 Hz, IH), 3.98 (s, 3H), 3.92 - 3.86 (m, 4H), 3.85 - 3.78 (m, 4H), 2.92 (d, J=10.9 Hz, 2H), 2.67 (t, J=10.8 Hz, 2H), 2.54 (br. s., 2H), 2.40 (s, 3H), 1.17 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 541.3.

Example 112: N-[4-fluoro-5-(4-methoxyphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00381] The title compound (grey solid, 42.7 mg, 79%) was prepared according to a procedure similar to that of Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-methoxyphenylboronic acid (30 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 7.96 (s, IH), 7.91 (d, J=8.3 Hz, IH), 7.49 (d, J=7.5 Hz, 2H), 7.04 (d, J=12.2 Hz, IH), 7.01 (d, J=8.8 Hz, 2H), 6.93 (s, IH), 3.85 (s, 3H), 3.07 (d, J=11.0 Hz, 2H), 2.68 - 2.54 (m, 4H), 2.40 (s, 3H), 1.19 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 533.4.

Example 113: N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^


[00382] The title compound (grey solid, 47.5 mg, 81%) was prepared according to a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-(cyclopropylmethoxy)phenylboronic acid (38 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 7.96 (s, IH), 7.91 (d, J=8.2 Hz, IH), 7.47 (d, J=7.6 Hz, 2H), 7.04 (d, J=12.1 Hz, IH), 7.00 (d, J=8.8 Hz, 2H), 6.93 (s, IH), 3.88 (d, J=6.8 Hz, 2H), 3.07 (d, J=10.6 Hz, 2H), 2.68 - 2.55 (m, 4H), 2.40 (s, 3H), 1.33 - 1.25 (m, IH), 1.18 (d, J=6.0 Hz, 6H), 0.68 - 0.61 (m, 2H), 0.42 - 0.35 (m, 2H); LCMS [M + H]+ 573.3.

Example 114: N-[4-fluoro-5-( 4-pyrrolidin-l-ylphenyl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00383] The title compound (brown solid, 43.2 mg, 74%) was prepared according to a procedure similar to that of Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (55 mg, 0.2 mmol). H NMR (500MHz, METHANOL-d4) δ = 7.95 (s, IH), 7.90 (d, J=8.3 Hz, IH), 7.41 (d, J=7.7 Hz, 2H),

7.00 (d, J=12.2 Hz, IH), 6.92 (s, IH), 6.65 (d, J=8.7 Hz, 2H), 3.04 (d, J=11.0 Hz, 2H), 2.66 - 2.52 (m, 4H), 2.40 (s, 3H), 2.09 - 2.01 (m, 4H), 1.18 (d, J=6.0 Hz, 6H); LCMS [M + H]+ 572.4.

Example 115: 3-acetamido-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00384] The title compound (off-white solid, 41.9 mg, 70%) was prepared according to a procedure similar to that of Example 34 using 3-acetylaminobenzoic acid (36 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, IH), 8.57 (d, J=8.2 Hz, IH), 8.50 (s, 2H), 8.05 (br. s., IH), 7.71 (d, J=8.2 Hz, IH), 7.56 (d, J=7.7 Hz, IH), 7.42 (t, J=7.9 Hz, IH), 7.23 (br. s., IH), 6.94 (d, J=l l. l Hz, IH), 3.83 - 3.77 (m, 4H), 3.75 - 3.69 (m, 4H), 2.83 (d, J=11.0 Hz, 2H), 2.59 (t, J=10.8 Hz, 2H), 2.46 (br. s., 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.07 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 562.4.

Example 116: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l-methylindazole-3-carboxamide

[00385] The title compound was prepared similar to the sequence described above for the preparation of Example 78 using l-methyl-lH-indazole-3-carbonylchloride in place of benzoyl chloride in Step 4. XH NMR (500MHz, DMSO-d6) δ = 9.94 (s, IH), 8.59 (s, 2H), 8.54 (d, J=8.6 Hz, IH), 8.24 (d, J=8.2 Hz, IH), 7.82 (d, J=8.6 Hz, IH), 7.54 (t, J=7.6 Hz, IH), 7.37 (t, J=7.5 Hz, IH), 7.29 (d, J=11.7 Hz, IH), 4.22 (s, 3H), 3.80 - 3.77 (m, 4H), 3.72 - 3.69 (m, 4H), 3.02 - 2.89 (m, 4H), 2.66 -2.57 (m, 2H), 2.32 (s, 3H), 1.06 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 545.3.

Example 117: N-[4-fluoro-5-( 4-morpholin-4-ylphenyl)-2-[( 3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l-methylindazole-3-carboxamide


[00386] The title compound was prepared similar to the sequence described above for the preparation of Example 116 using 4-(morpholino)phenylboronic acid in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester in Step 2. H NMR (500MHz, DMSO-d6) δ = 9.94 (s, IH), 8.56 (d, J=8.6 Hz, IH), 8.25 (d, J=8.2 Hz, IH), 7.82 (d, J=8.7 Hz, IH), 7.54 (t, J=7.7 Hz, IH), 7.45 (br d, J=7.7 Hz, 2H), 7.37 (t, J=7.5 Hz, IH), 7.22 (d, J=12.1 Hz, IH), 7.08 (d, J=8.8 Hz, 2H), 4.21 (s, 3H), 3.80 -3.75 (m, 4H), 3.21 - 3.17 (m, 4H), 3.00 - 2.89 (m, 5H), 2.67 - 2.58 (m, 4H), 2.32 (s, 3H), 1.07 (d, J=6.1 Hz, 3H); LCMS [M+H]+: 543.4.

Example 118: N-[4-fluoro-5-[3-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

Step 1: N-( 6-fluoro-3 '-formyl-4-( ( 3S, 5R) -3, 4, 5-trimethylpiperazin-l biphenylJ-3-yl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00387] A procedure similar to that of Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (130 mg, 0.215 mmol) and 3-formylphenylboronic acid (45.1 mg, 0.301 mmol) afforded the title compound (84 mg, 62% yield). LCMS [M + H]+: 631.8.

Step 2: N-( 6-fluoro-3 '-( nethyl(oxetan-3-yl)amino)methyl)-4-( 3S, 5R)-3, 4, 5- Mmethylpiperazin-l-yl)-[l '-biphenyl]-3-yl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide


[00388] N-(6-fluoro-3'-formyl-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)-[l,r-biphenyl] -3 -yl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (40 mg, 0.063 mmol), N-methyl-3-oxetanamine (11.05 mg, 0.127 mmol) and acetic acid, glacial, 99.8% (15.23 mg, 0.254 mmol) were mixed in anhydrous DCE. A cloudy solution was obtained. After 5-10 min, sodium triacetoxyborohydride (40.3 mg, 0.190 mmol) was added and the reaction mixture was stirred at RT. There was no difference observed between 7.5h and overnight at RT. A small amount of the starting material (approx. 5%) of the starting material was observed along with the desired product. The reaction mixture was quenched with sat aq NaHCCb solution (basic). The organic phase was separated, the aqueous phase was extracted with DCM (x2), then the combined organic phase was washed with brine, dried over Na2S04 and concentrated to obtain the crude product. It was purified on reverse phase isco column (5.5G), eluting with water containing 0-60 % acetonitrile. The appropriate fractions were combined and concentrated to afford the desired product as a white foam (31 mg, 70% yield). LCMS [M+H]+ = 700.6.

Step 3: N-( 6-fluoro-3 '-( (methyl(oxetan-3-yl)amino)methyl)-4-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)-[l, 1 '-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide, trifluoroacetic acid salt.


[00389] The product of the foregoing procedure was dissolved in DCM (2 mL) and TFA (0.5 ml) was added. The reaction mixture was stirred at RT. LCMS showed completion of the reaction after 8 min.. The reaction mixture was concentrated to dryness, and the residue was triturated with ether to collect the title compound as a white powder. (32 mg, 82% yield). ¾ NMR (500MHz, METHANOL-d4) δ = 7.94 (t, J=3.9 Hz, 2H), 7.65 (s, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 6.87 (s, 1H), 4.74 - 4.66 (m, 2H), 4.65 - 4.53 (m, 2H), 4.52 - 4.46 (m, 1H), 4.31 (s, 2H), 3.52 - 3.44 (m, 2H), 3.29 (br s, 2H), 2.83 - 2.83 (m, 1H), 2.99 - 2.80 (m, 4H), 2.74 (s, 3H), 1.38 (d, J=6.4 Hz, 6H); LCMS [M+H]+ 602.

Example 119: N-[4-fluoro-5-[3-[( 4-fluoropiperidin-l-yl)methyl]phenyl]-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-carb


[00390] A sequence similar to that of Example 118 was used with 4-fiuoropiperidine as the amine in the reductive amination step to provide 26 mg (70% yield) of the title compound as the TFA salt. H NMR (500MHz, METHANOL-d^ δ = 7.97 - 7.91 (m, 2H), 7.69 - 7.63 (m, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.13 (d, J=11.7 Hz, 1H), 6.87 (s, 1H), 4.37 (s, 2H), 3.58 - 3.26 (m, 9H), 3.00 - 2.81 (m, 5H), 2.38 - 2.12 (m, 2H), 2.06 - 1.85 (m, 2H), 1.44 - 1.32 (m, 6H). LCMS [M+H]+ 618.7.

Example 120: N-[2-(3, 4, 6, 7,9,9a-hexahydro-lH-pyrazino[2, l-c][l,4]oxazin-8-yl)-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: 8-(4-bromo-5-fluoro-2-nitrophenyl)octahydropyrazino[2, l-c][l, 4]oxazine


stirred for 5 minutes at room temperature. Then a solution of l-bromo-2,4-difluoro-5-nitrobenzene (1024 mg, 4.30 mmol) in toluene (1ml) was added dropwise from a pipette (2 ml of toluene were used to rinse the vial) and the reaction was stirred at 50 °C for 3h30min. Then the reaction mixture was partitioned into water and DCM and the product was extracted by DCM (3x20mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by Flash chromatography [0-10% MeOH/DCM] to afford the desired 8-(4-bromo-5-fluoro-2-nitrophenyl)octahydropyrazino[2,l-c][l,4]oxazine (1.3361 g, 3.67 mmol, 85 % yield) as an orange powder. LCMS [M+H]+: 360.2.

Step 2: 8-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)octahydropyrazino[2, l-c][l, 4]oxazine


[00392] A 30mL vial was charged with a mixture of 8-(4-bromo-5-fluoro-2-nitrophenyl)octahydropyrazino[2,l-c][l,4]oxazine (112 mg, 0.311 mmol), 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (127 mg, 0.435 mmol), XPhos Pd G2 (4.89 mg, 6.22 μηιοΐ) and XPhos (2.96 mg, 6.22 μηιοΐ). Then sodium carbonate solution (2molar) (0.777 ml, 1.555 mmol) was added via syringe and the vial was flushed with argon. The reaction was stirred at 90 °C for 2 hours then the reaction mixture was partitionned into water and DCM and the product was extracted by DCM (3x20mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by flash chromatography [0-10% MeOH/DCM] to afford the desired 8-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)octahydropyrazino[2,l-c] [l,4]oxazine (143.6 mg, 0.291 mmol, 94 % yield) as a brown oil. LCMS [M+H]+ 444.9.

Step 3: 4-fluoro-2-(hexahydropyrazino[2, 1-c] [l,4]oxazin-8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)aniline


[00393] To a solution of 8-(5-fluoro-4-(2-mo holinopyrimidin-5-yl)-2-nitrophenyl)octahydropyrazino[2,l-c][l,4]oxazine (143.6 mg, 0.323 mmol) in a mixture of MeOH (5 ml) and water (1 ml) was added zinc dust (106 mg, 1.615 mmol) followed by 4 drops of hydrochloric acid (ACS) (11.78 mg, 0.323 mmol). The reaction mixture was stirred at 90 °C for 40 minutes then the crude mixture was filtered through a pad of celite using methanol to elute the product. Then the filtrate was concentrated under vacuum and the crude mixture was dry loaded and purified by Flash chromatography [0-10% MeOH/DCM] to afford the desired 4-fluoro-2-(hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-5-(2-mo holinopyrimidin-5-yl)aniline (53.2 mg, 0.128 mmol, 39.7 % yield) as a yellow oil. LCMS [M+H]+ 415.1.

Step 4: N-(4-fluoro-2-(hexahydropyrazino[2, l-c][l, 4]oxazin-8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide


[00394] To a solution of 4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinic acid (51.3 mg, 0.167 mmol) in N,N-dimethylformamide (DMF) (5mL) were added HATU (98 mg, 0.257 mmol) and N,N-diisopropylethylamine (0.133 ml, 0.770 mmol). The reaction mixture was stirred for 5 minutes before adding a solution of 4-fluoro-2-(hexahydropyrazino[2,l-c] [l,4]oxazin-8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)aniline (53.2 mg, 0.128 mmol) in ImL of DMF (use of 2xlmL of DMF to rinse). Then the reaction mixture was stirred at room temperature overnight. The crude material was dry loaded and purified by flash chromatography [4-100% water/ ACN] to afford the desired N-(4-fiuoro-2-(hexahydropyrazino [2, 1 -c] [ 1 ,4] oxazin-8( lH)-yl)-5 -(2-morpholinopyrimidin-5 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (12.7 mg, 0.018 mmol, 13.92 % yield) as a tan solid. LCMS [M+H]+ 704.3.

Step 5: N-(4-fluoro-2-(hexahydropyrazino[2, l-cJ[l,4Joxazin-8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide (TFA salt)


[00395] To a solution of N-(4-fluoro-2-(hexahydropyrazino[2,l-c] [l,4]oxazin- 8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-4-(trifluoromethyl)-6-(2-

(trimethylsilyl)ethoxy Nicotinamide (12.7 mg, 0.018 mmol) in DCM (3 ml) was added trifluoroacetic acid (2 ml, 26.1 mmol). The reaction mixture was stirred at 60 °C for 3 hours then the TFA and solvent were removed under vacuum to give the desired N-(4-fluoro-2-(hexahydropyrazino[2,l-c] [l,4]oxazin-8(lH)-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide TFA salt (15.3 mg, 0.014 mmol, 76 % yield) as a light brown powder. XH NMR (500 MHz, DMSO-d6) δ = 9.62 (s, 1 H), 8.54 (s, 2 H), 8.02 (s, 1 H), 7.92 (d, J=8.31 Hz, 1 H), 7.24 (d, J=11.74 Hz, 1 H), 6.85 (s, 1 H), 4.05 (br d, J=10.88 Hz, 1 H), 3.96 (br d, J=11.13 Hz, 1 H), 3.80 - 3.74 (m, 6 H), 3.71 - 3.65 (m, 6 H), 3.59 - 3.44 (m, 3 H), 3.36 (br d, J=11.49 Hz, 1 H), 3.29 (br d, J=11.98 Hz, 2 H), 3.23 - 3.06 (m, 2 H), 2.85 (br t, J=11.68 Hz, 1 H); LCMS [M+H]+ 604.31.

Example 121: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl] phenyl] -l-methylpyrazole-4-carboxamide


[00396] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using 1 -methyl- lH-pyrazole-4-carboxylic acid in place of 3-(trifluoromethyl)pyrazole-4-carboxylic acid for Step 4. H NMR (500MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.55 (d, J=1.0 Hz, 2H), 8.30 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.11 (d, J=12.2 Hz, 1H), 3.91 (s, 3H), 3.77 - 3.75 (m, 4H), 3.70 - 3.67 (m, 4H), 3.06 - 2.94 (m, 2H), 2.85 - 2.75 (m, 2H), 2.36 (dd, J=2.3, 10.6 Hz, 1H), 2.30 - 2.20 (m, 4H), 0.97 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 495.3.

Example 122: N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl] phenyl] -l-methylpyrazole-4-carboxamide


[00397] The title compound was prepared similar to the sequence described above for the preparation of Example 78 using 4-(morpholino)phenylboronic acid in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester in Step 2. H NMR (500MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.09 - 7.00 (m, 3H), 3.91 (s, 3H), 3.79 - 3.74 (m, 4H), 3.19 -3.15 (m, 4H), 3.03 - 2.92 (m, 2H), 2.85 - 2.76 (m, 2H), 2.40 - 2.35 (m, 1H), 2.31 -2.21 (m, 4H), 0.98 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 493.4.

Example 123: N-[5-(5-cyano-6-hydroxypyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo


Step 1: N-(5-( 5-(benzyloxy)-5-cyanopyridin-3-yl)-4-fluoro-2-( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide


[00398] To a solution of N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (300 mg, 0.495 mmol) and 2-(benzyloxy)-5-(trimethylstannyl)nicotinonitrile (222 mg, 0.595 mmol) in dry DMF (2 ml) at RT under N2, was added CsF (151 mg, 0.991 mmol), copper(I) iodide (9.44 mg, 0.050 mmol) and tetrakis(triphenylphosphine)palladium(0) polymer bound (573 mg, 0.495 mmol). The reaction mixture was stirred overnight at 60°C. The major product was the deprotected one. The mixture was concentrated to dryness, partitioned between EtOAc and satd. aq citric acid solution. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with sodium bicarbonate solution (8 ml), dried over Na2S04 and concentrated to obtain the crude product which was adsorbed on celite and purified on isco (12 g), eluting with DCM containing 0-10 % MeOH. The deprotected product was isolated as a beige solid (66 mg, 20 %). LCMS [M+H]+ 635.7


[00399] N-(5-(6-(benzyloxy)-5-cyanopyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (20 mg) was dissolved in MeOH and subjected to hydrogenolysis at 45°C in an H-cube. The reaction was complete in lh. The solution was concentrated and purified on a preparatory column, eluting with water/acetonitrile gradient. The desired product was isolated as a white solid. (5 mg, 26 %). H NMR (500MHz, METHANOL-d4) ) δ ppm 1.24 - 1.30 (m, 6 H) 2.68 - 2.87 (m, 5 H) 3.13 - 3.19 (m, 2 H) 3.22 - 3.32 (m, 2 H) 6.83 (br s, 1 H) 7.07 (br d, J=11.86 Hz, 1 H) 7.79 (d, J=8.31 Hz, 1 H) 7.87 (br s, 1 H) 7.91 (s, 1 H) 8.24 (br s, 1 H). LCMS [M+H]+ 545.7

Example 124: N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^


[00400] The title compound (brown solid, 37.4 mg, 61%) was prepared by a procedure similar to Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and
acid (45 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d^ δ = 7.97 (s, IH), 7.92 (d, J=8.3 Hz, IH), 7.33 (d, J=8.7 Hz, IH), 7.30 (d, J=14.2 Hz, IH), 7.12 (t, J=8.7 Hz, IH), 7.05 (d, J=12.4 Hz, IH), 6.93 (s, IH), 3.92 - 3.83 (m, 4H), 3.18 - 3.11 (m, 4H), 3.08 (br d, J=10.9 Hz, 2H), 2.69 - 2.54 (m, 4H), 2.40 (s, 3H), 1.19 (d, J=6.0 Hz, 6H); LCMS [M+ H]+ 606.3.

Example 125: N-[5-[3-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^

[00401] The title compound (light brown solid, 47.3 mg, 82%) was prepared according to a procedure similar to Example 100 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 3-(cyclopropylmethoxy)phenylboronic acid (38 mg, 0.2 mmol). H NMR (500MHz, METHANOLS) δ = 7.97 (s, IH), 7.92 (d, J=8.2 Hz, IH), 7.34 (t, J=8.0 Hz, IH), 7.11 (d, J=7.7 Hz, IH), 7.09 (s, IH), 7.05 (d, J=12.0 Hz, IH), 6.92 (s, IH), 6.93 (d, J=6.6 Hz, 2H), 3.88 (d, J=6.8 Hz, 2H), 3.08 (br d, J=l l . l Hz, 2H), 2.68 - 2.54 (m, 4H), 2.40 (s, 3H), 1.33 - 1.24 (m, IH), 1.19 (d, J=6.0 Hz, 6H), 0.67 - 0.61 (m, 2H), 0.42 - 0.35 (m, 2H); LCMS [M + H]+ 573.4.

Example 126: 3-(dimethylamino)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5SJ-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00402] The title compound (light pink solid, 30.8 mg, 55%) was prepared according to a procedure similar to Example 34 using 3-(dimethylamino)benzoic acid (33 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, METHANOL-d4) δ = 8.56 (s, 2H), 8.21 (d, J=8.3 Hz, IH), 7.38 (t, J=8.0 Hz, IH), 7.29 (s, IH), 7.22 (d, J=7.6 Hz, IH), 7.11 (d, J=11.9 Hz, IH), 7.01 (dd, J=2.4, 8.3 Hz, IH), 3.88 - 3.83 (m, 4H), 3.80 - 3.76 (m, 4H), 3.05 (s, 7H), 2.64 (t, J=l l . l Hz, 2H), 2.56 - 2.48 (m, 2H), 2.37 (s, 3H), 1.15 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 548.3.

Example 127: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl] phenyl] -l,3-oxazole-4-carboxamide

[00403] The title compound (light beige solid, 30.7 mg, 61%) was prepared according to a procedure similar to that of Example 34 using oxazole-4-carboxylic acid (23 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.78 (s, 1H), 8.61 (d, J=8.3 Hz, 1H), 8.58 (d, J=1.2 Hz, 2H), 8.35 (s, 1H), 7.97 (s, 1H), 7.28 (s, 1H),6.98 (d, J=11.4 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.84 - 3.79 (m, 4H), 2.96 (d, J=9.7 Hz, 2H), 2.72 - 2.58 (m, 4H), 2.41 (s, 3H), 1.17 (d, J=5.5 Hz, 6H); LCMS [M + H]+ 496.4.

Example 128: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylj 'phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


Step 2: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

[00404] The title compound was prepared according to a procedure similar to

Example 78 using l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (obtained as described in Example 93, Step 8) as the acylating agent. XH NMR (500MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.45 (s, 2H), 8.23 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.02 (d, J=12.2 Hz, 1H), 6.80 (s, 1H), 3.71 - 3.66 (m, 4H), 3.63 - 3.59 (m, 4H), 3.46 (s, 3H), 3.01 - 2.91 (m, 2H), 2.78 - 2.66 (m, 2H), 2.35 - 2.27 (m, 2H), 2.20 - 2.09 (m, 4H), 0.90 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 590.3.

Example 129: N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l-methyl-6 >xo-4-(trifluoromethyl)pyridine-3-carboxamide


[00405] The title compound was prepared similar to the sequence described above for the preparation of Example 128 using (S)-4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-4'-morpholino-[l, -biphenyl]-3-amine which was derived from a sequence using 4-(morpholino)phenylboronic acid in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester in Step 2 of Example 78. l NMR (500MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.24 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.31 (br s, 1H), 7.30 (br s, 1H), 7.00 - 6.94 (m, 3H), 6.80 (s, 1H), 3.70 - 3.67 (m, 4H), 3.45 (s, 3H), 3.11 - 3.07 (m, 4H), 2.98 - 2.90 (m, 2H), 2.79 - 2.66 (m, 2H), 2.36 - 2.27 (m, 3H), 2.18 - 2.11 (m, 4H), 0.91 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 588.4.

Example 130: N-[4-fluoro-5-(2-propan-2-yloxypyrimidin-5-yl)-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^


[00406] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using (2-isopropoxypyrimidin-5-yl)boronic acid in place of 4-cyanophenylboronic acid. H NMR (500 MHz, MeOD) δ 8.73 (s, 2H), 7.97 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 6.90 (s, 1H), 5.37 (dt, J = 12.3, 6.1 Hz, 1H), 3.08 (d, J = 11.3 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.54 (d, J = 6.1 Hz, 2H), 2.36 (s, 3H), 1.41 (d, J = 6.2 Hz, 6H), 1.16 (d, J = 6.2 Hz, 6H); LCMS [M+l]+ = 563.39.

Example 131 : N-[5-( 5 yanopyridin-3-yl)-4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00407] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-cyanopyridine-5-boronic acid pinacol ester. XH NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.96 (t, J = 4.0 Hz, 2H), 7.13 (d, J = 12.3 Hz, 1H), 6.91 (s, IH), 3.12 (d, J = 11.4 Hz, 2H), 2.64 (t, J = 11.2 Hz, 2H), 2.55 (dd, J = 13.2, 7.0 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H); LCMS [M+l]+ = 529.38.

Example 132: N-[5-( 5-cyano-5-methylpyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00408] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-cyano-3-methylpyridine-5-boronic acid, pinacol ester. XH NMR (500 MHz, MeOD) δ 8.72 (s, IH), 8.07 (s, IH), 7.98 (d, J = 8.2 Hz, IH), 7.97 (s, IH), 7.12 (d, J = 12.3 Hz, IH), 6.91 (s, IH), 3.12 (d, J = 11.4 Hz, 2H), 2.64 (d, J = 10.9 Hz, 2H), 2.62 (s, 3H), 2.54 (dd, J = 9.0, 5.2 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H); 19F NMR (471 MHz, MeOD) δ -63.75 (s), -119.92 (s); LCMS HSS [M+l]+ = 543.30.

Example 133: N-[5-(2 yanopyridin-4-yl)-4-fluoro-2-[(3R,5S)-3,4,5 rimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00409] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-cyanopyridine-4-boronic acid pinacol ester in place of 4-cyanophenylboronic acid. H NMR (500 MHz, MeOD) δ 8.75 (d, J = 5.3 Hz, IH), 8.12 (s, IH), 8.03 (d, J= 8.2 Hz, IH), 7.98 (s, IH), 7.88 (d, J= 5.2 Hz, IH), 7.12 (d, J = 12.6 Hz, IH), 6.91 (s, IH), 3.14 (d, J = 11.7 Hz, 2H), 2.63 (t, J = 11.2 Hz, 2H), 2.58 -2.50 (m, 2H), 2.36 (s, 3H), 1.16 (d, J= 6.2 Hz, 6H); LCMS [M+l]+ = 529.38.

Example 134: N-[4-fluoro-5-[2-methoxy-6-(trifluoromethyl)pyridin-4-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00410] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-methoxy-6-trifluoromethylpyridine-4-boronic acid. l NMR (500 MHz, MeOD) δ 7.97 (s, 2H), 7.53 (s, 1H), 7.19 (s, 1H), 7.10 (d, J = 12.5 Hz, 1H), 6.91 (s, 1H), 4.01 (s, 3H), 3.12 (d, J = 11.5 Hz, 2H), 2.63 (t, J = 11.2 Hz, 2H), 2.58 - 2.52 (m, 2H), 2.37 (s, 3H), 1.16 (d, J= 6.1 Hz, 6H); LCMS [M+l]+ = 602.06.

Example 135: N-[4-fluoro-5-(2-methoxy-6-methylpyridin-4-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridme-3-carboxamide


[00411] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 6-methoxy-2-picoline-4-boronic acid, pinacol ester. XH NMR (500 MHz, MeOD) δ 7.95 (s, 2H), 7.07 (d, J = 12.2 Hz, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 3.93 (s, 3H), 3.12 (d, J = 8.1 Hz, 2H), 2.65 (d, J = 7.1 Hz, 4H), 2.48 (s, 3H), 1.19 (d, J = 5.5 Hz, 6H); LCMS [M+l]+ = 548.04.

Example 136: N-[4-fluoro-5-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


The title compound was prepared similar to the sequence described the preparation of Example 31 using 2-methoxy-3- (trifluoromethyl)pyridine-5-boronic acid. H NMR (500 MHz, MeOD) δ 8.54 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 4.08 (s, 3H), 3.08 (d, J = 11.3 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.55 (dd, J = 8.1, 6.1 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.2 Hz, 6H); LCMS [M+l]+ = 602.3.

Example 137: 4-cyano-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-methoxypyridine-3-carboxamide


Step 1: 5-bromo-4-iodo-2-methoxypyridine


[00413] A solution of DIPA (14.8 niL, 117.6 mmol, and l.leq) in dry THF

(150mL) was cooled to -78 °C, and n-BuLi (42 niL, 106.95 mmol, 1 eq, 2.5 M) was added dropwise. Then, the reaction mixture was stirred for 30 min, 5-bromo-2-methoxypyridine (20.0 g, 106.95 mmol, 1.0 eq) in dry THF (115mL) was added dropwise, then the reaction mixture was stirred at -78°C for lh. The reaction mixture was quenched with iodine (27.6 g, 106.95 mmol, and leq) in THF (80 mL) added dropwise and the reaction mixture was stirred for 16h.TLC analysis indicated a non-polar spot. The reaction was quenched with sodium thiosulfate solution (500 mL), extracted with EtOAc (1000 mL) and the separated organic layers were combined and dried over Na2S04. Concentration under reduced pressure gave crude compound; which was recrystallized from ethanol (120mL) to give 5-bromo-4-iodo-2-methoxypyridine (12 g, 35.9%) as an off white solid. LCMS: [M+H]+ 315.83.

Step 2: 5-bromo-2-methoxyisonicotinonitrile


[00414] suspension of 5-bromo-4-iodo-2-methoxypyridine (10 g, 31.85 mmol, leq) in DMF (100 mL) was added CuCN (5.7 g, 63.7 mmol, 2.0 eq). The reaction mixture was heated at 100°C for 16 h. TLC analysis indicated polar spot. The reaction mixture was diluted with water (200 mL) and filtered off and washed with EtOAc (500 mL) and cold water (300 It). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure at 30°C. This was purified by column chromatography using silica (100-200 mesh) eluting with 5% EtOAc in pet ether to give 5-bromo-2-methoxyisonicotinonitrile (4g, 59.7% yield) as a solid compound. GCMS: [M+H]+ 213.

Step 3: methyl 4-cyano-6-methoxynicotinate


[00415] To a stirred solution of 5-bromo-2-methoxyisonicotinonitrile (4 g, 18.86 mmol, leq) in MeOH (33 mL) was added TEA (33 mL, 226.32 mmol, 12 eq) and Pd2(dppf)Cl2.DCM (1.5 g, 1.89 mmol, 0.1 eq) at RT and the reaction mixture was degassed with argon for 5min. Then the reaction mixture was heated to 90°C for 16 h under CO gas (250psi) in a sealed bomb. TLC analysis indicated formation of polar spot. The reaction mixture was filtered through a celite pad then the filtrate was concentrated to crude compound. The crude compound was purified by column chromatography (silica gel, 100-2000 mesh) using 20% EtOAc in Pet ether as eluent to afford methyl 4-cyano-6-methoxynicotinate (2 g, 55.5% yield) as solid. LCMS: [M+H] 193.0.

Step 4: 4-cyano-6-methoxynicotinic acid


[00416] To a suspension of methyl 4-cyano-6-methoxynicotinate (2 g, 10.36 mmol, leq) in THF: MeOH: H20 (9 mL: 3 mL: 6 mL) (33mL), lithium hydroxide monohydrate (248 mg, 249.2 mmol, 4.0 eq) was added. The reaction mixture was stirred at RT for 16 h. TLC analysis of indication of polar spot. The reaction was concentrated under reduced pressure gave crude compound. This was acidified with 2N HC1 (20 mL), precipitate was formed and filtered off and washed with diethyl ether (50mL) and filtered off and dried on vacuum to give 4-cyano-6-methoxynicotinic acid (0.9mg, 48.6% yield) as an off white solid compound. LCMS: [M+]H+ 177.17.

Step 5: 4-cyano-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-methoxypyridine-3-carboxamide

[00417] The title compound was prepared in a manner similar to the preparation of Example 34 using 4-cyano-6-methoxynicotinic acid in place of 1 -methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid. H NMR (500 MHz, MeOD) δ 8.76 (d, J = 10.2 Hz, 1H), 8.56 (s, 2H), 7.50 (s, 1H), 7.46 (dd, J = 12.0, 8.2 Hz, 1H), 7.14 (t, J= 12.6 Hz, 1H), 4.10 (d, J= 1.4 Hz, 3H), 3.82 (dd, J= 6.4, 2.9 Hz, 4H), 3.77 -3.73 (m, 4H), 2.89 (d, J = 12.1 Hz, 1H), 2.67 (t, J = 11.0 Hz, 1H), 2.64 (dt, J = 30.5, 11.2 Hz, 2H), 2.57 - 2.51 (m, 1H), 2.57 - 2.44 (m, 2H), 2.20 (s, 3H), 1.04 (dd, J = 22.7, 6.3 Hz, 6H); Major rotamer reported: LCMS [M+l]+= 561.43.

Example 138: 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] benzamide


[00418] The title compound (beige solid, 32.4 mg, 55%) was prepared according to a procedure similar to Example 34 using 3,5-dichlorobenzoic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.50 (d, J=1.2 Hz, 2H), 7.71 (s, 2H), 7.50 (s, 1H), 6.95 (d, J=11.2 Hz, 1H), 3.84 - 3.78 (m, 4H), 3.75 - 3.69 (m, 4H), 2.82 (d, J=11.0 Hz, 2H), 2.63 (t, J=10.9 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.31 (s, 3H), 1.11 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 573.2.

Example 139: 2, 6-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ benzamide


[00419] The title compound (beige solid, 32.4 mg, 55%) was prepared according to a procedure similar to Example 34 using 3,5-dichlorobenzoic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, IH), 8.52 (d, J=8.2 Hz, IH), 8.50 (d, J=1.2 Hz, 2H), 7.71 (s, 2H), 7.50 (s, IH), 6.95 (d, J=11.2 Hz, IH), 3.84 - 3.78 (m, 4H), 3.75 - 3.69 (m, 4H), 2.82 (d, J=11.0 Hz, 2H), 2.63 (t, J=10.9 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.31 (s, 3H), 1.11 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 573.2.

Example 140: 3-chloro-2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00420] The title compound (light yellow solid, 46.9 mg, 82%) was prepared by a procedure similar to Example 34 using 3-chloro-2-fluorobenzoic acid (35 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrirnidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.78 (d, J=12.5 Hz, IH), 8.71 (d, J=8.3 Hz, IH), 8.58 (s, 2H), 8.08 (t, J=7.3 Hz, IH), 7.61 (t, J=7.5 Ηζ,ΙΗ), 7.29 (t, J=7.6 Hz, 1H), 7.04 (d, J=\ 1.4 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.83 -3.78 (m, 4H), 2.89 (t, J=7.0 Hz, 2H), 2.67 (t, J=10.9 Hz, 2H), 2.56 - 2.47 (m, 2H), 2.38 (s, 3H), 1.16 (d, J=6.2 Hz, 6H); LCMS [M+ H]+ 557.3.

Example 141: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide


[00421] The title compound (beige solid, 51.7 mg, 89%) was prepared by a procedure similar to Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-(trifluoromethyl)benzoyl chloride (22 μΐ,, 0.15 mmol). l NMR (500MHz, CHLOROFORM-d) δ = 8.62 - 8.53 (m, 4H), 7.80 (d, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.64 (t, J=6.8 Hz, 2H), 7.00 (d, J=11.2 Hz, 1H), 3.92 - 3.84 (m, 4H), 3.84 -3.76 (m, 4H), 2.85 (d, J=11.0 Hz, 2H), 2.62 (t, J=10.9 Hz, 2H), 2.31 - 2.17 (m, 5H), 1.11 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 573.4.

Example 142: N-[5-[6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo m

[00422] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 6-(dimethylarmno)pyridine-3-boronic acid pinacol ester. ¾ NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.74 (dd, J= 9.0, 0.8 Hz, 1H), 7.04 (d, J= 12.2 Hz, 1H), 6.91 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 3.12 (s, 6H), 3.04 (d, J = 11.2 Hz, 2H), 2.61 (t, J = 11.1 Hz, 2H), 2.57 -2.50 (m, 2H), 2.37 (s, 3H), 1.16 (d, J= 6.1 Hz, 6H); LCMS [M+l]+ = 547.28.

Example 143: tert-butyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-3, 6-dihydro-2H-pyridine-l-carboxylate


Step 1: tert-butyl 4-(2-fluoro-5-(4-(trifluoromethyl)-6-(2- ( trimethylsilyl)ethoxy)nicotinamido)-4-( ( 3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-3, 6-dihydropyridine-l(2H)-carboxylate


[00423] A procedure similar to Example 39 was employed using N-(5-bromo- 4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (250 mg, 0.413 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate (191 mg, 0.619 mmol to give the title compound. LCMS [M+H] = 708.7.

Step 2: tert-butyl 4-(2-fluoro-5-(4-(trifluoromethyl)-6-(2- ( trimethylsilyl)ethoxy)nicotinamido)-4-( ( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-3, 6-dihydropyridine-l -carboxylate


[00424] TFA (0.6 ml) was added to a solution of tert-butyl 4-(2-fluoro-5-(4- (trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinanudo)-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate in DCM (20 ml) at RT and the reaction mixture was stirred at RT. LCMS after 10 min showed completion of the reaction. The reaction mixture was concentrated to dryness (bath temperature <25°C), the residue was dissolved in MeOH and passed through a cation exchange resin cartridge (Porapak Rxn CX 60 cc) to collect the title compound as an off white powder. (706 mg, 91% ). ¾ NMR (500MHz, METHANOL-d^ δ = 8.01 - 7.93 (m, 1H), 7.84 -7.73 (m, 1H), 7.01 - 6.93 (m, 1H), 6.92 - 6.86 (m, 1H), 6.10 - 5.93 (m, 1H), 4.17 - 4.02 (m, 2H), 3.71 - 3.58 (m, 2H), 3.06 - 2.99 (m, 2H), 2.65 - 2.49 (m, 6H), 2.43 - 2.36 (m, 3H), 1.62 - 1.43 (m, 9H), 1.17 (br d, J=5.7 Hz, 6H); LCMS [M+H]+ 608.6

Example 144: N-[4-fluoro-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]-5-[4- (trifluoromethyl)phenyl]phenyl]-6 )XO-4-(trifluorom


[00425] The title compound (tan solid, 43.8 mg, 75%) was prepared using a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5- trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-(trifluoromethyl)phenylboronic acid (38 mg, 0.2 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 8.66 (s, IH), 8.50 (d, J=8.1 Hz, IH), 7.88 (s, IH), 7.70 (s, 4H), 7.04 (d, J=11.6 Hz, IH), 7.01 (s, 1H),2.85 (br d, J=11.0 Hz, 2H), 2.68 (br t, J=10.9 Hz, 2H), 2.41 - 2.27 (m, 5H), 1.15 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 571.1.

Example 145: N-[4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]-5-[4- (trifluoromethoxy)phenyl]phenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo


[00426] The title compound (light solid, 37.6 mg, 64%) was prepared by a procedure similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-(trifluoromethoxy)phenylboronic acid (41 mg, 0.2 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 8.67 (s, IH), 8.47 (d, J=8.2 Hz, IH), 7.86 (s, IH), 7.60 (d, J=7.8 Hz, 2H), 7.29 (br d, J=8.4 Hz, 2H), 7.05 -6.99 (m, 2H), 2.84 (br d, J=10.9 Hz, 2H), 2.67 (br t, J=10.9 Hz, 2H), 2.40 - 2.29 (m, 5H), 1.15 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 587.2.

Example 146: N-[4-fluoro-5-phenyl-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00427] The title compound (grey solid, 29.4 mg, 56%) was prepared by a procedure similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and phenylboronic acid (24 mg, 0.2 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.67 (s, 1H), 8.48 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.44 (t, J=7.6 Hz, 2H), 7.39 - 7.34 (m, 1H), 7.04 -6.98 (m, 2H), 2.85 (br d, J=10.9 Hz, 2H), 2.67 (br t, J=10.9 Hz, 2H), 2.42 - 2.29 (m, 5H), 1.15 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 503.2.

Example 147: N-[5-( 4-chlorophenyl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l -yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00428] The title compound (grey solid, 31.5 mg, 57%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 4-chlorophenylboronic acid (31 mg, 0.2 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 8.66 (s, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.51 (d, J=7.7 Hz, 2H), 7.44 - 7.39 (m, 2H), 7.04 - 6.98 (m, 2H), 2.84 (br d, J=11.0 Hz, 2H), 2.67 (br t, J=10.8 Hz, 2H), 2.40 - 2.30 (m, 5H), 1.15 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 537.3.

Example 148: N-[4-fluoro-5-[l-[(4-methoxyphenyl)methyl]-3, 6-dihydro-2H-pyridin- 4-yl]-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00429] N-(4-Fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (15 mg, 0.030 mmol), 4-methoxybenzaldehyde (8.05 mg, 0.059 mmol) and acetic acid, glacial, 99.8% (7.10 mg, 0.118 mmol) were mixed in anhydrous DCE. A cloudy solution was obtained. After 5-10 min, sodium triacetoxyborohydride (18.79 mg, 0.089 mmol) was added and the reaction mixture was stirred at RT for 18 h. LCMS showed complete disappearance of the starting material and formation of the desired product. The reaction was quenched with sat aq NaHCCb solution (basic). The organic phase was separated, the aqueous phase was extracted with DCM (2X), then the combined organic phase was washed with brine, dried over Na2S04 and concentrated to obtain the crude product. It was purified on isco column (4 G), eluting with DCM containing 0-8 % DCM. The appropriate fractions were combined and concentrated to afford the title compound as a white foam (11 mg, 56%). ¾ NMR (500MHz, METHANOL-d4) δ = 7.97 - 7.89 (m, 1H), 7.81 - 7.70 (m, 1H), 7.35 - 7.27 (m, 2H), 6.98 - 6.83 (m, 4H), 6.03 - 5.95 (m, 1H), 3.83 - 3.76 (m, 3H), 3.69 - 3.62 (m, 2H), 3.25 -3.17 (m, 2H), 3.05 - 2.95 (m, 2H), 2.84 - 2.73 (m, 2H), 2.61 - 2.48 (m, 6H), 2.35 (s, 3H), 1.17 - 1.12 (m, 6H); LCMS [M+H]+ 628.4

Example 149: N-[4-fluoro-5-( 5-methylpyridazin-4-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00430] N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (50 mg, 0.083 mmol) and 3-methylpyridazine-5-boronic acid, pinacol ester (25.4 mg, 0.116 mmol) using a procedure similar to Example 39 afforded the silyl ether intermediate, which was deprotected using TFA and isolated to give the title compound in 61% yield. XH NMR (500MHz, METHANOL-d4) δ = 9.32 - 9.20 (m, 1H), 8.12 - 8.03 (m, 1H), 8.01 - 7.95 (m, 1H), 7.86 - 7.80 (m, 1H), 7.23 - 7.10 (m, 1H),6.98 - 6.88 (m, 1H), 3.21 - 3.12 (m, 2H), 2.78 - 2.74 (m, 3H), 2.72 - 2.61 (m, 4H), 2.49 - 2.38 (m, 3H), 1.20 (br d, J=4.6 Hz, 6H); LCMS [M+H]+ 519.5

Example 150: N-[4-fluoro-5-[l-(2-methylpropyl)-3, 6-dihydro-2H-pyridin-4-yl]-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00431] A procedure similar to Example 148 was used with N-(4-fluoro-5- (1,2,3, 6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide and isobutyraldehyde to give the desired product. ¾ NMR (500 MHz, METHANOL-d4) δ = 7.87 - 7.76 (m, 1H), 7.74 - 7.62 (m, 1H), 6.87 - 6.81 (m, 1H), 6.81 - 6.77 (m, 1H), 5.96 - 5.84 (m, 1H), 3.29 - 3.22 (m, 2H), 2.95 - 2.86 (m, 2H), 2.80 - 2.71 (m, 2H), 2.56 - 2.50 (m, 2H), 2.50 -2.45 (m, 2H), 2.45 - 2.37 (m, 2H), 2.37 - 2.30 (m, 2H), 2.29 - 2.23 (m, 3H), 1.94 - 1.83 (m, 1H), 1.08 - 1.01 (m, 6H), 0.91 - 0.86 (m, 6H); LCMS [M+H]+ 564.4

Example 151: N-[5-[ 1 -(cyclopropylmethyl)-3, 6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00432] A procedure similar to Example 148 was used with cyclopropylbutyraldehyde to give the title compound in 77% yield. ^ NMR (500MHz, METHANOLS) δ = 7.96 - 7.90 (m, 1H), 7.88 - 7.82 (m, 1H), 7.04 - 6.97 (m, 1H), 6.96 - 6.91 (m, 1H), 6.11 - 6.03 (m, 1H), 3.86 - 3.74 (m, 2H), 3.40 - 3.35 (m, 2H), 3.11 - 3.02 (m, 2H), 2.98 - 2.90 (m, 2H), 2.86 - 2.77 (m, 2H), 2.69 - 2.57 (m, 4H), 2.48 - 2.38 (m, 3H), 1.22 - 1.17 (m, 6H), 1.16 - 1.09 (m, 1H), 0.78 - 0.73 (m, 2H), 0.44 - 0.37 (m, 2H); LCMS [M+H]+ 562.5

Example 152: N-[4-fluoro-2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l -yl ]-5-[l-(3, 3,3-trifluoropropyl)-3, 6-dihydro-2H-pyridin-4-yl]phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00433] A procedure similar to that used for Example 148 was employed using

4,4,4-trifluorobutanal to give the title compound in 83% yield. Η NMR (500MHz, METHANOL-d4) δ = 7.97 - 7.91 (m, 1H), 7.83 - 7.73 (m, 1H), 6.98 - 6.93 (m, 1H), 6.93 - 6.91 (m, 1H), 6.06 - 5.98 (m, 1H), 3.27 - 3.22 (m, 2H), 3.07 - 3.01 (m, 2H), 2.83 - 2.75 (m, 4H), 2.63 - 2.49 (m, 8H), 2.40 - 2.37 (m, 3H), 1.19 - 1.15 (m, 6H); LCMS [M+H]+ 604.5

Example 153: N-[4-fluoro-5-[l-[(4-fluorophenyl)methyl]-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00434] A procedure similar to that used for Example 148 with 4-fluorobenzaldehyde gave the title compound in 73 % yield. XH NMR (500MHz, METHANOLS) δ = 7.97 - 7.90 (m, 1H), 7.83 - 7.73 (m, 1H), 7.49 - 7.37 (m, 2H), 7.15 - 7.05 (m, 2H), 6.99 - 6.88 (m, 2H), 6.05 - 5.96 (m, 1H), 3.73 - 3.67 (m, 2H), 3.25 - 3.19 (m, 2H), 3.08 - 2.99 (m, 2H), 2.81 - 2.75 (m, 2H), 2.63 - 2.53 (m, 6H), 2.42 - 2.37 (m, 3H), 1.21 - 1.16 (m, 6H); LCMS [M+H]+ 616.6.

Example 154: N-[4-fluoro-5-[l-(pyridin-3-ylmethyl)-3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00435] A procedure similar to Example 148 using nicotinaldehyde afforded the title compound in 38 % yield. XH NMR (500MHz, METHANOLS) δ = 8.49 -8.45 (m, 1H), 8.40 - 8.33 (m, 1H), 7.84 - 7.77 (m, 2H), 7.70 - 7.60 (m, 1H), 7.37 -7.33 (m, 1H), 6.86 - 6.78 (m, 2H), 5.94 - 5.86 (m, 1H), 3.67 - 3.60 (m, 2H), 3.13 - 3.08 (m, 2H), 2.96 - 2.87 (m, 2H), 2.69 - 2.63 (m, 2H), 2.54 - 2.45 (m, 6H), 2.32 -2.28 (m, 3H), 1.08 - 1.05 (m, 6H); LCMS [M+H]+ 599.5

Example 155: N-[4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-5-[l-(thiophen- 3-ylmethyl)-3,6-dihydro-2H-pyridin-4-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00436] A procedure similar to Example 148 using thiophene-3-carbaldehyde afforded the title compound in 73 % yield. XH NMR (500MHz, METHANOLS) δ = 7.99 - 7.90 (m, 1H), 7.83 - 7.73 (m, 1H), 7.42 (dd, J=3.1, 4.6 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.23 - 7.15 (m, 1H), 6.99 - 6.86 (m, 2H), 6.08 - 5.95 (m, 1H), 3.82 - 3.71 (m, 2H), 3.28 - 3.20 (m, 2H), 3.02 (br d, J=10.9 Hz, 2H), 2.85 - 2.74 (m, 2H), 2.63 - 2.50 (m, 6H), 2.41 - 2.35 (m, 3H), 1.20 - 1.14 (m, 6H); LCMS [M+H]+ 604.5

Example 156: N-[5-[5-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^


[00437] A procedure similar to Example 39 using N-(5-bromo-4-fluoro-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide and 3-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine afforded the silyoxy intermediate which was deprotected using TFA to give the title compound in 71% yield for the last step. XH NMR (500MHz, METHANOL-d4) δ = 8.22 - 8.17 (m, 1H), 8.16 - 8.08 (m, 1H), 7.93 - 7.88 (m, 1H), 7.87 - 7.80 (m, 1H), 7.50 - 7.44 (m, 1H), 7.10 - 7.00 (m, 1H), 6.86 - 6.79 (m, 1H), 3.90 - 3.83 (m, 2H), 3.16 - 3.08 (m, 2H), 3.01 - 2.81 (m, 2H), 2.73 - 2.65 (m, 2H), 2.63 - 2.43 (m, 3H), 1.23 - 1.18 (m, 7H), 0.59 - 0.52 (m, 2H), 0.33 - 0.27 (m, 2H); LCMS [M+H]+ 574.6

Example 157: N-[4-fluoro-5-(6-hydroxypyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00438] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine. This compound was isolated during the purification step as a side product. ¾ NMR (500 MHz, DMSO) δ 9.50 (s, 1H), 7.91 (s, 1H), 7.69 (d, J= 8.7 Hz, 1H), 7.60 (d, J= 9.6 Hz, 1H), 7.49 (s, 1H), 7.00 (d, J= 12.6 Hz, 1H), 6.80 (s, 1H), 6.44 (d, J = 9.5 Hz, 1H), 3.00 (d, J= 10.9 Hz, 2H), 2.44 (t, J = 11.0 Hz, 2H), 2.36 - 2.31 (m, 2H), 2.19 (s, 3H), 1.00 (d, J = 6.1 Hz, 6H); 19F NMR (471 MHz, DMSO) δ -61.34 (s), -119.33 (s); LCMS HSS [M+l]+ = 520 35 Major rotamer reported

Example 158: N-[4-fluoro-5-(2-piperazin-l-ylpyrimidin-5-yl)-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00439] The title compound was prepared similar to the sequence described above for the preparation of Example 31 using 2-(4-boc-piperazino)pyrimidine-5-boronic acid pinacol ester and deprotecting the intermediate Boc-protected piperidine with TFA. XH NMR (500 MHz, MeOD) δ 8.56 (d, J = 0.9 Hz, 2H), 7.97 (s, IH), 7.90 (d, J = 8.2 Hz, IH), 7.08 (d, J = 12.1 Hz, IH), 6.89 (s, IH), 3.97 - 3.92 (m, 4H), 3.07 - 3.02 (m, J = 10.8, 5.6 Hz, 6H), 2.61 (t, J = 11.1 Hz, 2H), 2.57 - 2.48 (m, 2H), 2.36 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); LCMS HSS [M+l]+ = 589.34.

Example 159: 3-chloro-5-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00440] The title compound (beige solid, 42.5 mg, 74%) was prepared by a procedure similar to Example 34 using 3-chloro-5-fiuorobenzoic acid (35 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrirnidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). ¾i NMR (500MHz, CHLOROFORM-d) δ = 9.26 (s, IH), 8.60 (d, J=8.1 Hz, IH), 8.57 (d, J=l.l Hz, 2H), 7.68 (s, IH), 7.54 (td, J=1.8, 8.7 Hz, IH), 7.32 (td, J=2.1, 8.0 Hz, IH), 7.03 (d, J=\ 1.2 Hz, IH), 3.92 - 3.85 (m, 4H), 3.83 - 3.78 (m, 4H), 2.90 (br d, J=\ 1.0 Hz, 2H), 2.71 (br t, J=10.9 Hz, 2H), 2. 49 - 2.41 (m, 2H), 2.38 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M+ H]+ 557.4.

Example 160: 3, 5-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00441] The title compound (beige solid, 41.5 mg, 74%) was prepared by a procedure similar to Example 34 using 3,5-difluorobenzoic acid (32 mg, 0.2 mmol) and 4-fluoro-5-(2-moφholinopyrirnidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.23 (s, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.57 (d, J=1.0 Hz, 2H), 7.46 - 7.40 (m, 2H), 7.08 - 7.00 (m, 2H), 3.92 - 3.85 (m, 4H), 3.83 - 3.78 (m, 4H), 2.89 (br d, J=11.0 Hz, 2H), 2.70 (t, J=10.9 Hz, 2H), 2.46 - 2.40 (m, 2H), 2.38 (s, 3H), 1.17 (d, J=6.2 Hz, 6H); LCMS [M+ H]+ 541.4.

Example 161: N-[4-fluoro-5-[2-[(2R, 6S)-2, 6-dimethylmorpholin-4-ylJpyrimidin-5-ylJ-2-[(3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: Preparation of (2-((2S, 6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)boronic acid


[00442] To a mixture of 2-chloropyrimidine-5-boronic acid (1.584 g, 10 mmol) and cis-2,6-dimethylmorpholine (1.29 mL, 10.5 mmol) in EtOH (5 mL) was added triethylamine (1.54 mL, 11 mmol). The resulting suspension was stirred at 60 °C for 1 h. Solvents were removed and the residue oil solidified to a crystalline pale yellow solid. It was triturated with H20 (20 mL), suction filtered, rinsed with H20 (20 mL), air dried and dried under vacuum to give the title compound as a pale yellow solid (827 mg, 35%). LCMS [M + H]+ 238.14.

Step 2: Preparation of N-(5-(2-((2S, 6R)-2, 6-dimethylmorpholino)pyrimidin-5-yl)-4-fluoro-2-((3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1 , 6-dihydropyridine-3-carboxami


[00443] The title compound (brown solid, 39.1 mg, 60%) was prepared by a procedure similar to Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and (2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)boronic acid (47 mg, 0.2 mmol). H NMR (500MHz, METHANOL-d4) δ = 8.54 (s, 2H), 7.98 (s, IH), 7.90 (d, J=8.2 Hz, IH), 7.09 (d, J=12.0 Hz, IH), 6.93 (s, IH), 4.64 (dd, J=1.3, 13.1 Hz, 2H), 3.67 (ddd, J=2.3, 6.3, 10.5 Hz, 2H), 3.07 (br d, J=11.0 Hz, 2H), 2.66 - 2.55 (m, 6H), 2.40 (s, 3H), 1.25 (d, J=6.1 Hz, 6H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 618.4.

Example 162: N-[4-fluoro-2-[( 3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl ]-5-[l-( 1, 3-thiazol-2-ylmethyl)-3, 6-dihydro-2H-pyridin-4-yl]phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00444] The procedure was similar to Example 148 using thiazole-2-carbaldehyde and N-(4-fluoro-5-(l,2,3,64etrahydropyridin-4-yl)-2 (3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide to give the title compound in 81 % yield. ¾ NMR (500MHz, METHANOLS) δ = 7.97 - 7.91 (m, 1H), 7.83 - 7.73 (m, 2H), 7.62 - 7.57 (m, 1H), 6.99 - 6.90 (m, 2H), 6.06 - 5.97 (m, 1H), 4.07 -4.02 (m, 2H), 3.37 - 3.34 (m, 2H), 3.07 - 2.99 (m, 2H), 2.88 - 2.81 (m, 2H), 2.63 - 2.53 (m, 6H), 2.39 (s, 3H), 1.19 - 1.14 (m, 6H); LCMS [M+H]+ 605.4

Example 163: N-[4-fluoro-5-[l-[(2-methyl-l, 3-oxazol-5-yl)methyl] -3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00445] The procedure was similar to Example 148 using 2-methyloxazole-5-carbaldehyde and N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide to give the title compound in 35 % yield. ¾ NMR (500MHz,

METHANOL-d4) δ = 7.96 - 7.91 (m, 1H), 7.82 - 7.74 (m, 1H), 6.99 - 6.97 (m, 1H), 6.96 - 6.93 (m, 1H), 6.93 - 6.91 (m, 1H), 6.05 - 5.99 (m, 1H), 3.80 - 3.75 (m, 2H), 3.28 - 3.21 (m, 2H), 3.06 - 2.99 (m, 2H), 2.81 (t, J=5.7 Hz, 2H), 2.62 - 2.53 (m, 6H), 2.49 - 2.45 (m, 3H), 2.41 - 2.38 (m, 3H), 1.19 - 1.16 (m, 6H); LCMS [M+H]+ 603.5

Example 164: N-[4-fluoro-5-[ 1 -[(1 -methylpyrazol-4-yl)methyl] -3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00446] The procedure was similar to Example 148 using 1-methyl-lH-pyrazole-4-carbaldehyde and N-(4-fluoro-5-(l ,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide to give the title compound in 68 % yield. H NMR (500MHz, METHANOL-d4) δ = 7.94 (s, 1H), 7.77 (br d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 6.96 - 6.92 (m, 1H), 6.91 (s, 1H), 6.02 (br s, 1H), 3.90 (s, 3H), 3.64 (s, 2H), 3.26 - 3.20 (m, 2H), 3.05 - 2.98 (m, 2H), 2.83 - 2.76 (m, 2H), 2.62 - 2.50 (m, 6H), 2.37 (s, 3H), 1.16 (d, J=6.0 Hz, 6H); LCMS [M+H]+ 602.5.

Example 165: N-[4-fluoro-5-[l -[( 4-morpholin-4-ylphenyl)methyl ]-3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00447] The procedure was similar to Example 148 using 4-mo holinobenzaldehyde and N-(4-fluoro-5-(l ,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide to give the title compound in 45 % yield. H NMR (500MHz, METHANOLS) δ = 7.98 - 7.91 (m, 1H), 7.83 - 7.74 (m, 1H), 7.35 - 7.26 (m, 2H), 7.01 - 6.97 (m, 2H), 6.96 - 6.92 (m, 1H), 6.91 - 6.89 (m, 1H), 6.11 - 5.92 (m, 1H), 3.87 - 3.83 (m, 4H), 3.69 - 3.63 (m, 2H), 3.27 - 3.21 (m, 2H), 3.19 - 3.15 (m, 4H), 3.05 - 2.98 (m, 2H), 2.83 - 2.76 (m, 2H), 2.62 - 2.50 (m, 6H), 2.39 - 2.36 (m, 3H), 1.18 - 1.14 (m, 6H); LCMS [M+H]+ 683.5

Example 166: N-[4-fluoro-5-[l-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-3, 6-dihydro-2H-pyridin-4-ylJ-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4- (trifluoromethyl)-lH-pyridine-3-carboxamide


[00448] The procedure was similar to Example 148 using 4-(4-methylpiperazin-l-yl)benzaldehyde and N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide to give the title compound in 22 % yield. H NMR (500MHz, METHANOL-d4) δ = 8.01 - 7.89 (m, 1H), 7.82 - 7.72 (m, 1H), 7.34 - 7.27 (m, 2H), 7.02 - 6.98 (m, 2H), 6.96 - 6.92 (m, 1H), 6.92 - 6.88 (m, 1H), 6.07 - 5.94 (m, 1H), 3.73 - 3.66 (m, 2H), 3.28 - 3.22 (m, 6H), 3.06 - 2.98 (m, 2H), 2.85 - 2.78 (m, 2H), 2.70 - 2.65 (m, 4H), 2.62 - 2.50 (m, 6H), 2.38 (d, J=8.9 Hz, 6H), 1.18 - 1.14 (m, 6H); LCMS [M+H]+ 696.5

Example 167: N-[4-fluoro-5-[ 1 -(oxan-4-ylmethyl)-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00449] The procedure was similar to Example 148 using tetrahydro-2H-pyran- 4-carbaldehyde and N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide to give the title compound in 88 % yield. ¾ NMR (500MHz, METHANOL-d4) δ = 7.98 - 7.90 (m, 1H), 7.85 - 7.74 (m, 1H), 6.98 - 6.93 (m, 1H), 6.93 - 6.89 (m, 1H), 6.08 - 5.95 (m, 1H), 4.00 - 3.93 (m, 2H), 3.51 - 3.43 (m, 2H), 3.28 - 3.22 (m, 2H), 3.07 - 2.98 (m, 2H), 2.84 - 2.77 (m, 2H), 2.65 - 2.52 (m, 6H), 2.46 - 2.42 (m, 2H), 2.40 - 2.36 (m, 3H), 2.02 - 1.90 (m, 1H), 1.79 - 1.73 (m, 2H), 1.34 - 1.30 (m, 2H), 1.18 - 1.15 (m, 6H); LCMS [M+H]+ 606.5.

Example 168: 3, 5-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]phenyl]benzamide


Step 1: Preparation of (R)-l-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine


[00450] A solution of l-bromo-2,4-difluoro-5-nitrobenzene (2.7 mL, 21 mmol) in toluene (5 mL) was added drop wise to a rapidly stirring mixture of (3R)-(+)-3-(dimethylamino)pyrrolidine (2.4 g, 21 mmol) and potassium carbonate (1.4 g, 10 mmol) in toluene (50 mL) at room temperature. After stirring for 20 minutes the reaction was warmed to 45 °C for 30 minutes. After the reaction was cooled to room temperature the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [1-10% MeOH/DCM + 0.5% NH4OH] afforded (R)- 1 -(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (6.4 g, 91 %). LCMS [M+H]+: 332.1.

Step 2: Preparation of (R)-l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin


[00451] A vial was charged with (R)-l-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.50 g, 1.50 mmol), 2-(4^ο ^1ίηο^ιιη^ίη6-5-boronic acid pinacol ester (0.48 g, 1.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (12 mL) and 2 M aqueous sodium carbonate (4 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 85 °C for 3 h. After cooling to room temperature the reaction mixture was concentrated onto celite and flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (R)-l-(5-fluoro-4-(2-mo holinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.61 g, 97 %). LCMS [M+H]+: 417.3.

Step 3: Preparation of (R)-l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin- -a


[00452] A mixture of (R)-l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.61 g, 1.5 mmol) and tin(II) chloride (0.93 g, 4.9 mmol) in ethanol (12 mL) was heated to 75 °C for 1 h. The reaction mixture was concentrated onto celite and purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (R)-l-(2-amino-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3 -amine (0.54 g, 90 %). LCMS [M+H]+: 387.2.

Step 4: Preparation of (R)-3,5-dichloro-N-(2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluoro-5-(2-morpholinopyrimidi -5- enyl)benzamide

[00453] To a solution of 3,5-dichlorobenzoic acid (0.025 g, 0.13 mmol) in

DCM (1 mL) was added propylphosphonic anhydride (50% solution) (0.08 mL, 0.13 mmol) and triethylamine (0.03 mL, 0.19 mmol). After mixing the clear solution was transferred by pipette to a suspension of (R)-l-(2-amino-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3 -amine (0.025 g, 0.07 mmol) in DCM (1 mL) at room temperature. After stirring for 18 h at room temperature the reaction was concentrated onto celite and purified by flash chromatography [0.5 - 10% MeOH/DCM + 0.5% NH4OH] to afford the title compound (R)-3,5-dichloro-N-(2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluoro-5-(2-mo holinopyrimidin-5-yl)phenyl)benzamide (0.021 g, 55 %). l NMR (500MHz, DMSO-d6) δ = 10.17 (s, 1H), 8.52 (s, 2H), 7.99 (d, J=1.8 Hz, 2H), 7.89 (t, J=1.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.67 (d, J=14.1 Hz, 1H), 3.75 - 3.72 (m, 4H), 3.70 - 3.66 (m, 4H), 3.44 - 3.40 (m, 1H), 3.19 (t, J=8.7 Hz, 1H), 2.65 - 2.61 (m, 1H), 2.13 - 2.05 (m, 7H), 1.71 - 1.62 (m, 1H); LCMS [M+H]+: 559.3.

Example 169: 3, 5-dichloro-N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[( 3R)-3-(dimethylamino)pyrrolidin-l-yl]phenyl]benzamide


[00454] The title compound was prepared similar to the sequence described above for the preparation of Example 168 using 4-(morpholino)phenylboronic acid in place of 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester in Step 2. H NMR

(500MHz, DMSO-d6) δ = 10.13 (s, 1H), 7.99 (s, 2H), 7.89 (s, 1H), 7.37 (br d, J=8.3 Hz, 2H), 7.23 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.81 (br s, 1H), 6.68 - 6.56 (m, 2H), 3.78 - 3.73 (m, 4H), 3.41 - 3.39 (m, 2H), 3.19 (br t, J=8.9 Hz, 1H), 3.16 -3.12 (m, 4H), 2.13 - 2.05 (m, 9H), 1.72 - 1.62 (m, 1H); LCMS [M+H]+: 557.3.

Example 170: N-[5-(5-cyano-6-morpholin-4-ylpyridin-3-yl)-4-fluoro-2-[(3R, 5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00455] The title compound was prepared according a procedure similar to

Example 31 using 3-cyano-2-mo holinopyridine-5-boronic acid, pinacol ester. H NMR (500 MHz, MeOD) δ 8.57 (s, IH), 8.15 (d, J = 2.2 Hz, IH), 7.96 (s, IH), 7.91 (d, J = 8.3 Hz, IH), 7.09 (d, J = 12.2 Hz, IH), 6.91 (s, IH), 3.85 - 3.82 (m, 4H), 3.76 - 3.73 (m, 4H), 3.07 (d, J = 11.2 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.55 (dt, J = 6.4, 4.2 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); LCMS [M+l]+ = 614.39.

Example 171: N-[4-fluoro-5-(5-methyl-6-morpholin-4-ylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo m


[00456] The title compound was prepared using a procedure similar to Example

31 using 4-(3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine. XH NMR (500 MHz, MeOD) δ 8.27 (s, IH), 7.96 (s, IH), 7.91 (d, J = 8.2 Hz, IH), 7.74 (s, IH), 7.07 (d, J = 12.1 Hz, IH), 6.91 (s, IH), 3.87 - 3.84 (m, 4H), 3.20 - 3.17 (m, 4H), 3.07 (d, J = 11.2 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.55 (ddd, J = 10.4, 6.2, 3.1 Hz, 2H), 2.37 (s, 6H), 1.16 (d, J = 6.1 Hz, 6H); iyF NMR (471 MHz, MeOD) δ -63.78, -120.54; LCMS HSS [M+l]+ = 603.26.

Example 172: N-[5-(2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-4-fluoro-2-[(3R,5S)- 3,4,5-trimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00457] The title compound was prepared by a procedure similar to Example

31 using 2,3-dihydropyrrolo[2,3-b]pyridine-5-boronic acid, pinacol ester. H NMR (500 MHz, MeOD) δ 7.95 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 7.03 (d, J = 12.1 Hz, 1H), 6.90 (s, 1H), 3.65 (t, J = 8.5 Hz, 2H), 3.12 (t, J = 8.4 Hz, 2H), 3.04 (d, J = 10.9 Hz, 2H), 2.60 (t, J = 11.1 Hz, 2H), 2.54 (ddd, J = 9.8, 7.5, 2.5 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); 19F NMR (471 MHz, MeOD) δ -63.78 (s), -120.60 (s); LCMS HSS [M+l]+ = 545.33.

Example 173: N-[4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]-5-[5- (Mfluoromethyl)pyridin-3-yl]phenyl]-6 >xo-4-(Mfluoromethyty


[00458] The procedure followed was similar to that used in Example 39 to give, after deprotection of the silyloxy intermediate, the title compound in 91% yield. XH NMR (500MHz, METHANOL-d4) δ = 9.07 - 9.00 (m, 1H), 8.94 - 8.86 (m, 1H), 8.37 - 8.32 (m, 1H), 8.03 - 7.96 (m, 2H), 7.20 - 7.12 (m, 1H), 6.97 - 6.91 (m, 1H), 3.17 - 3.11 (m, 2H), 2.70 - 2.63 (m, 2H), 2.62 - 2.54 (m, 2H), 2.42 - 2.37 (m, 3H), 1.22 - 1.16 (m, 6H); LCMS [M+H]+ 572.5.

Example 174: N-[5-[5-(tert-butylcarbamoyl)pyridin-3-yl]-4-fluoro-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00459] The procedure followed was similar to that used in Example 39 to give, after deprotection of the silyloxy intermediate, the title compound in 84% yield. XH NMR (500MHz, METHANOL-d4) δ = 8.90 - 8.81 (m, 2H), 8.35 - 8.30 (m, 1H), 8.04 - 7.93 (m, 2H), 7.18 - 7.08 (m, 1H), 6.96 - 6.87 (m, 1H), 3.16 - 3.05 (m, 2H), 2.70 - 2.61 (m, 2H), 2.61 - 2.52 (m, 2H), 2.41 - 2.35 (m, 3H), 1.51 - 1.47 (m, 9H), 1.21 - 1.15 (m, 6H); LCMS [M+H]+ 603.7

Example 175: 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide


[00460] The title compound (beige solid, 36.8 mg, 59%) was prepared using a procedure similar that of Example 34 using 3-chloro-5-(trifluoromethyl)benzoic acid (45 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.45 (s, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.60 (d, J=0.7 Hz, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.06 (d, J=l l. l Hz, 1H), 3.94 - 3.86 (m, 4H), 3.86 - 3.79 (m, 4H), 2.92 (br d, J=l l . l Hz, 2H), 2.74 (br t, J=10.9 Hz, 2H), 2.52 -2.42 (m, 2H), 2.39 (s, 3H), 1.20 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 607.3.

Example 176: 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide


[00461] The title compound (beige solid, 38.4 mg, 63%) was prepared by a procedure similar to Example 34 using 3-fluoro-5-trifluoromethylbenzoic acid (42 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.44 (s, 1H), 8.66 - 8.63 (m, 1H), 8.58 (d, J=1.5 Hz, 2H), 7.94 - 7.88 (m, 2H), 7.56 (br d, J=7.7 Hz, 1H), 7.04 (d, J=l l . l Hz, 1H), 3.91 - 3.86 (m, 4H), 3.82 - 3.78 (m, 4H), 2.90 (br d, J=11.0 Hz, 2H), 2.72 (t, J=11.0 Hz, 2H), 2.47 - 2.40 (m, 2H), 2.37 (s, 3H), 1.18 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 591.4.

Example 177: N-[4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[(3R)-3- (dimethylamino)pyrrolidin-l-yl]phenyl]-lH-pyrazole-4-carboxamide


[00462] The title compound was prepared similar to the sequence described above for the preparation of Example 168 using lH-pyrazole-4-carboxylic acid in place of 3,5- dichlorobenzoic acid in Step 4. ¾ NMR (500MHz, DMSO-d6) δ = 13.21 (br s, 1H), 9.47 (s, 1H), 8.38 - 8.25 (m, 1H), 8.15 - 7.97 (m, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.17 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 6.81 (s, 1H), 6.66 - 6.59 (m, 2H), 3.78 - 3.73 (m, 4H), 3.23 (t, J=8.7 Hz, 1H), 3.16 - 3.12 (m, 4H), 2.63 - 2.59 (m, 1H), 2.12 (s, 3H), 2.11 - 2.02 (m, 7H), 1.73 - 1.61 (m, 1H), 1.57 - 1.46 (m, 1H); LCMS [M+H]+: 479.3.

Example 178: N-[4-fluoro-5-(5-methylpyridin-3-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00463] The procedure used was similar to Example 39 to give, after deprotection of the silyloxy intermediate, the title compound in 91% yield. H NMR (500MHz, METHANOL-d4) δ = 9.07 - 9.00 (m, 1H), 8.94 - 8.86 (m, 1H), 8.37 - 8.32 (m, 1H), 8.03 - 7.96 (m, 2H), 7.20 - 7.12 (m, 1H), 6.97 - 6.91 (m, 1H), 3.17 - 3.11 (m, 2H), 2.70 - 2.63 (m, 2H), 2.62 - 2.54 (m, 2H), 2.42 - 2.37 (m, 3H), 1.22 - 1.16 (m, 6H); LCMS [M+H]+ 572.5.

Example 179: N-[5-(5-carbamoylpyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-carb


[00464] TFA (2 ml) was added to a solution of N-(5-(5-(tert-butylcarbamoyl)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (Example 174) in DCM (2 ml) at RT and the mixture was heated at 50 °C for 30 min. The reaction

mixture was concentrated and heated with methylsulfonic acid (10 eq) in toluene at 100 °C. Complete disappearance of the intermediate and formation of the desired product was observed after 30 min. The reaction mixture was concentrated to dryness, the residue was dissolved in MeOH and passed through a cation exchange resin cartridge (Isolute SCX-2 500 mg, 6ml) to collect the title compound as a beige powder (6.5 mg, 27 %). ¾ NMR (500MHz, METHANOL-d4) δ = 8.95 - 8.88 (m, 1H), 8.83 - 8.74 (m, 1H), 8.38 - 8.32 (m, 1H), 7.93 - 7.83 (m, 2H), 7.09 - 7.01 (m, 1H), 6.86 - 6.79 (m, 1H), 3.10 - 2.99 (m, 2H), 2.66 - 2.54 (m, 4H), 2.42 - 2.30 (m, 3H), 1.15 - 1.07 (m, 6H); 19F NMR (471MHz, METHANOL-d4) δ = -63.78 (s, IF), -120.49 (s, IF)

Example 180: N-[4-fluoro-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]-5-[5- (trifluoromethyl)pyridin-3-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethy

carboxamide


[00465] Cesium carbonate (8.55 mg, 0.026 mmol) was added to a solution of N- (4-fluoro-5-(5-(trifluoromethyl)pyridin-3-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (Example 173, 15 mg, 0.026 mmol) and iodomethane (2.451 μΐ, 0.039 mmol) in DMF (l.ml) at RT. The reaction mixture was continuously stirred at RT. After 10 min, complete conversion was observed. One minor less polar peak with the same mass was observed. While not wishing to be limited by theory, it could be the O-methylated by-product. Mass (600) corresponding to the dimethyl substituted by-product was also observed in trace amounts. The mixture was diluted with DCM (4 ml) and washed with water (6 ml). The aqueous phase was extracted with DCM (2x5ml) and the combined organic phase was washed with water, and brine, then dried with Na2S04 and concentrated onto celite. Purification by flash column chromatography on Isco (4G) column, eluting with DCM containing 0-3 % MeOH afforded the title compound as a white solid. (6 mg,

37% yield). ¾ NMR (500MHz, METHANOL-d4) δ = 8.97 - 8.87 (m, IH), 8.83 - 8.73 (m, IH), 8.25 - 8.19 (m, IH), 8.19 - 8.14 (m, IH), 7.93 - 7.84 (m, IH), 7.11 - 7.03 (m, IH), 6.88 - 6.80 (m, IH), 3.58 - 3.54 (m, 3H), 3.09 - 2.99 (m, 2H), 2.62 - 2.45 (m, 4H), 2.37 - 2.27 (m, 3H), 1.12 - 1.07 (m, 6H); LCMS [M+H]+ 586.4.

Example 181: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-4-methyl-l,3-thiazole-2-carboxamide


[00466] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using 4-methylthiazole-2-carboxylic acid in place of 6-chloro-4-(trifluoromethyl)nicotinic acid. H NMR (500MHz, DMSO-d6) δ = 10.19 (s, IH), 8.56 (s, 2H), 8.38 (d, J=8.3 Hz, IH), 7.76 (s, IH), 7.31 (d, J=11.7 Hz, IH), 3.80 - 3.75 (m, 4H), 3.71 - 3.67 (m, 4H), 2.98 - 2.86 (m, 5H), 2.59 (br d, J=9.5 Hz, 3H), 2.28 (s, 3H), 1.04 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 512.4.

Example 182: 2-[(dimethylamino)methyl]-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l , 3-thiazole-4-carboxamide


[00467] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using 2-[(dimethylamino)methyl]-l,3-thiazole-4-carboxylic acid in place of 6-chloro-4-(trifluoromethyl)nicotinic acid. H NMR (500MHz, DMSO-d6) δ = 10.24 (s, IH), 8.56 (s, 2H), 8.49 (br d, J=8.2 Hz, IH), 8.45 (s, IH), 7.28 (br d, J=11.7 Hz, IH), 3.90 - 3.81 (m, 2H), 3.77 (br d, J=4.2 Hz, 4H), 3.70 (br d, J=4.4 Hz, 4H), 2.94 - 2.86 (m, 4H), 2.34 - 2.28 (m, 8H), 1.02 (br d, J=6.0 Hz, 3H); LCMS [M+H]+: 555.4.

Example 183: 4-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-lH-pyrazole-3-carboxamide


[00468] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using 4-chloro-lH-pyrazole-3-carboxylic acid in place of 3,5-dichlorobenzoic acid. H NMR (500MHz, DMSO-d6) δ = 9.63 (s, IH), 8.49 (d, J=1.0 Hz, 2H), 8.37 (d, J=8.4 Hz, IH), 8.05 (br s, IH), 7.18 (d, J=11.7 Hz, IH), 3.71 - 3.68 (m, 4H), 3.63 - 3.60 (m, 4H), 2.89 - 2.75 (m, 4H), 2.40 - 2.34 (m, 2H), 2.28 - 2.23 (m, IH), 2.19 (s, 3H), 0.94 (d, J=6.1 Hz, 3H); LCMS [M+H]+: 515.2.

Example 184: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- (dimethylamino)pyrrolidin-l-yl]phenylJ-l-methyl-6-oxo-4-(trifluoromethyl)pyridine- 3-carboxamide

[00469] l-Methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (29 mg, 0.13 mmol) was activated with HATU (49 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.023 niL, 0.13 mmol) in DMF (0.5 mL) at room temperature. This solution of activated acid was added to a stirring solution of (R)-l-(2-amino-5-fluoro-4-(2-morpholinopyrirnidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (25 mg, 0.065 mmol) [Example 168, Step C] in DMF (1 mL) at room temperature. The reaction was warmed to 40 °C for 1 h and then to 55 °C for an additional 1 h. An additional portion of activated acid was prepared and added to the reaction mixture and the reaction was heated at 55 °C overnight. The reaction mixture was concentrated onto celite and purified by flash chromatography [1-10% MeOH/DCM + 1%) NH4OH] followed by reverse phase chromatography [5-95% MeCN/water; C18 column] to afford (R)-N-(2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluoro-5-(2-mo holinopyrimidin-5-yl)phenyl)-l-methyl-6- oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (0.020 g, 52%). XH NMR (500MHz, DMSO-d6) δ = 13.95 (br. s., 1H), 9.29 (br. s., 1H), 8.59 (br. s., 1H), 8.55 (s, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.14 (d, J=12.0 Hz, 1H), 3.78 - 3.75 (m, 4H), 3.70 - 3.67 (m, 4H), 3.01 (br. s., 2H), 2.88 (br. s, 2H), 2.23 (br. s., 3H), 1.00 (br. s, 3H); LCMS [M+H]+: 590.5.

Example 185: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- (dimethylamino)pyrrolidin-l-yl]phenyl]-3-(trifluorom


[00470] The title compound was prepared similar to the procedure described above for the preparation of Example 184 using 3-(trifluoromethyl)pyrazole-4-carboxylic acid in place of l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid. XH NMR (500MHz, DMSO-d6) δ = 9.60 (s, 1H), 8.46 (s, 1H), 8.44 (s, 2H), 7.17 (d, J=8.7 Hz, 1H), 6.60 (d, J=14.1 Hz, 1H), 3.68 - 3.64 (m, 4H), 3.62 - 3.59 (m, 4H), 3.30 (br dd, J=3.2, 6.7 Hz, 4H), 3.14 (t, J=8.8 Hz, IH), 2.55 - 2.49 (m, 4H), 2.02 (s, 6H), 2.00 - 1.95 (m, IH), 1.64 - 1.55 (m, IH); LCMS [M+H]+: 549.4.

Example 186: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenyl]-3-(trifluoromethyl)benzamide


[00471] The title compound (beige solid, 51.0 mg, 87%) was prepared by a procedure similar to Example 34 using 3-(trifluoromethyl)benzoic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimiώn-5-yl)-2-((3S,5R)-3,4,5-tximethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.41 (s, IH), 8.67 (d, J=8.2 Hz, IH), 8.58 (d, J=1.2 Hz, 2H), 8.18 (d, J=7.8 Hz, IH), 8.14 (s, IH), 7.86 (d, J=7.8 Hz, IH), 7.70 (t, J=7.8 Hz, IH), 7.03 (d, J=11.2 Hz, IH), 3.91 - 3.85 (m, 4H), 3.83 - 3.77 (m, 4H), 2.91 (br d, J=11.0 Hz, 2H), 2.71 (t, J=11.0 Hz, 2H), 2.49 - 2.40 (m, 2H), 2.37 (s, 3H), 1.17 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 573.3.

Example 187: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenyl]-4-(trifluoromethyl)pyrimidine-5-carboxamide


[00472] The title compound (beige solid, 39.0 mg, 65%) was prepared through a procedure similar to Example 34 using 4 rifluoromethyl-pyrimidine-5-carboxylic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-

trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.50 (s, 1H), 9.15 (s, 1H), 8.83 (s, 1H), 8.61 - 8.54 (m, 3H), 7.06 (d, J=l l.l Hz, 1H), 3.90 - 3.85 (m, 4H), 3.83 - 3.78 (m, 4H), 2.81 (br d, J=10.9 Hz, 2H), 2.65 (br t, J=10.8 Hz, 2H), 2.33 - 2.21 (m, 5H), 1.12 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 575.4.

Example 188: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenylJ-4-(trifluoromethyl)-l,3-thiazole-5-carboxamide


[00473] The title compound (beige solid, 42.3 mg, 72%) was prepared by a procedure similar to Example 34 using 4-(trifluoromethyl)-l,3-thiazole-5-carboxylic acid (39 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFODR-d) δ = 9.19 (br s, 1H), 8.94 (s, 1H), 8.60 - 8.54 (m, 3H), 7.07 (d, J=l l. l Hz, 1H), 3.92 - 3.84 (m, 4H), 3.83 - 3.77 (m, 4H), 2.82 (br d, J=10.8 Hz, 2H), 2.66 (br t, J=10.8 Hz, 2H), 2.43 - 2.30 (m, 5H), 1.14 (d, J=6.2 Hz, 6H); LCMS [M+ H]+580.3.

Example 189: 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-5-(trifluoromethyl)benzamide

[00474] The title compound (pale beige solid, 53.6 mg, 89%) was prepared by a procedure similar to Example 34 using 2-fluoro-5-(trifluoromethyl)benzoic acid (42 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrirnidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.84 (br d, J=12.7 Hz, IH), 8.73 (d, J=8.3 Hz, IH), 8.59 (d, J=l . l Hz, 2H), 8.54 (dd, J=2.0, 6.9 Hz, IH), 7.86 - 7.80 (m, IH), 7.38 (dd, J=8.9, 10.9 Hz, IH), 7.05 (d, J=11.2 Hz, IH), 3.91 - 3.86 (m, 4H), 3.83 - 3.77 (m, 4H), 2.89 (br d, J=10.8 Hz, 2H), 2.67 (br t, J=10.8 Hz, 2H), 2.53 - 2.45 (m, 2H), 2.38 (s, 3H), 1.16 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 591.4.

Example 190: 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] ' -5-methoxybenzamide


[00475] The title compound (beige solid, 48.4 mg, 87%) was prepared by a procedure similar to Example 34 using 3-fluoro-5-methoxybenzoic acid (34 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimiώn-5-yl)-2-((3S,5R)-3,4,5-tximethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, IH), 8.63 (d, J=8.2 Hz, IH), 8.57 (s, 2H), 7.28 (br s, IH), 7.16 (br d, J=8.7 Hz, IH), 7.01 (d, J=11.2 Hz, IH), 6.83 (td, J=2.1, 10.1 Hz, IH), 3.90 (s, 3H), 3.89 - 3.85 (m, 4H), 3.82 - 3.78 (m, 4H), 2.90 (br d, J=11.0 Hz, 2H), 2.68 (t, J=10.9 Hz, 2H), 2.49 - 2.39 (m, 2H), 2.37 (s, 3H), 1.16 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 553.4.

Example 191: 3, 5-dichloro-N-[4-fluoro-5-(4-morpholin-4-ylphenyl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl] phenyl] benzamide


[00476] The title compound (pale beige solid, 43.1 mg, 75%) was prepared by a procedure similar to Example 34 using 3,5-dichlorobenzoic acid (38 mg, 0.2 mmol) substituting 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline as the aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.30 (s, 1H), 8.63 (d, J=8.3 Hz, 1H), 7.80 (d, J=1.7 Hz, 2H), 7.59 - 7.51 (m, 3H), 7.02 - 6.94 (m, 3H), 3.93 - 3.85 (m, 4H), 3.28 - 3.18 (m, 4H), 2.90 (br d, J=11.0 Hz, 2H), 2.71 (t, J=10.9 Hz, 2H), 2.52 - 2.41 (m, 2H), 2.38 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 571.3.

Example 192: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-l-methylpyrazole-3-carboxamide


[00477] The title compound was prepared similar to the procedure described for the preparation of Example 78 using 1 -methyl- lH-pyrazole-3-carboxylic acid as the acylating agent. l NMR (500MHz, DMSO-d6) δ = 9.75 (br s, 1H), 8.55 (br s, 2H), 8.47 - 8.41 (m, 1H), 7.90 (br s, 1H), 7.30 - 7.21 (m, 1H), 6.77 (br s, 1H), 3.97 (br s, 3H), 3.79 - 3.75 (m, 4H), 3.71 - 3.68 (m, 4H), 2.91 (br s, 5H), 2.29 (br s, 3H), 1.04 (br s, 3H); LCMS [M+H]+: 495.4.

Example 193: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-lH-pyrazole-3-carboxamide


[00478] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using lH-pyrazole-3-carboxylic acid in place of 3-(trifluoromethyl)pyrazole-4-carboxylic acid. l NMR (500MHz, DMSO-d6) δ = 13.70 - 13.36 (m, IH), 9.72 (br s, IH), 8.56 (br s, 2H), 8.48 (br d, J=4.0 Hz, IH), 7.93 (br s, IH), 7.25 (br d, J=l l . l Hz, IH), 6.80 (br s, IH), 3.80 - 3.76 (m, 4H), 3.71 - 3.67 (m, 4H), 2.97 - 2.85 (m, 5H), 2.28 (br s, 3H), 1.03 (br s, 3H); LCMS [M+H]+: 481.4.

Example 194: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-2-methyl-l,3-thiazole-4-carboxamide


[00479] The title compound was prepared similar to the procedure described for Example 78 using 2-methyl-l,3-thiazole-4-carboxylic acid hydrochloride as the carboxylic acid acylating agent. XH NMR (500MHz, DMSO-d6) δ = 10.27 (s, IH), 8.56 (s, 2H), 8.50 (d, J=8.6 Hz, IH), 8.32 (s, IH), 7.28 (d, J=l 1.6 Hz, IH), 3.79 - 3.76 (m, 4H), 3.71 - 3.68 (m, 4H), 2.95 - 2.87 (m, 4H), 2.78 (s, 3H), 2.56 (br d, J=l l. l Hz, 4H), 2.29 (s, 3H), 1.04 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 512.2.

Example 195: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-2-methyl-l,3-thiazole-5-carboxamide


[00480] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using 2-methyl-l,3-thiazole-5-carboxylic acid as acylating agent. XH NMR (500MHz, DMSO-d6) δ = 9.59 (s, 1H), 8.48 (s, 2H), 8.31 (br s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.03 (d, J=12.3 Hz, 1H), 3.70 - 3.67 (m, 4H), 3.62 - 3.59 (m, 4H), 2.99 - 2.90 (m, 2H), 2.79 - 2.68 (m, 2H), 2.64 (s, 3H), 2.27 - 2.21 (m, 1H), 2.13 (s, 3H), 0.89 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 512.2.

Example 196: N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


-butyl (S)-3-methylpiperazine-l-carboxylate


[00481] To a stirred solution of 2- methyl piperazine (lOg, lOOmmol, leq) in ethanol (200mL) was added DIPEA (43.5mL, 250mmol, and the reaction mixture stirred for 10 min.. To this Boc anhydride (21.8mL, lOOmmol, leq) was added at 0°C and the resulting reaction mixture was stirred at room temperature overnight. The progress of reaction was monitored by TLC, which indicated formation of nonpolar spot. The reaction mixture was concentrated and dissolved in DCM (200mL) then washed with water (2 x 80mL) followed by brine solution. The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude tert-butyl (S)-3-methylpiperazine-l-carboxylate (20g, crude yield 100%) as a yellow liquid. TLC: MeOH : DCM (0.5: 9.5); R,= 0.3.

Step 2: tert-butyl (S)-3,4-dimethylpiperazine-l-carboxylate

Boc

I

[00482] To a stirred solution of tert-butyl (S)-3-methylpiperazine-l-carboxylate

(50 g, 250 mmol, leq) in DCM: AcOH (10: 3, 500 mL) was added 37% HCHO (40.5 mL, 500 mmol, 2 eq) at 0°C and the resulting reaction mixture was stirred at room temperature for 3h. NaCNBH3 (31.5 g, 500 mmol, 2 eq) was added portion wise at 0°C and the resulting reaction mixture was stirred at room temperature for 2h. The progress of reaction was monitored with TLC, which indicated formation of nonpolar spot. The reaction mixture was basified with sat. aq, NaHCC solution and extracted with DCM (2 x 150 mL). The combined organic layer was washed with water, followed by brine solution and dried over Na2S04 then concentrated under reduced pressure to afford tert-butyl (S)-3,4-dimethylpiperazine-l-carboxylate (55g, crude) as colorless liquid. TLC system: MeOH : DCM (1 : 9); Rf.: 0.4.

Step 3: (S)-l ,2-dimethylpiperazine


[00483] To a stirred solution of tert-butyl (S)-3,4-dimethylpiperazine-l-carboxylate (50 g, 233 mol, 1 eq) in DCM (500 mL) was added TFA (156 mL, 2097.3 mmol, 9 eq) at 0°C and the resulting reaction mixture was stirred at room temperature for 16h. The progress of reaction was monitored with TLC, which indicated formation of

polar spot. The reaction mixture was evaporated under reduced pressure to crude residue, which was basified with NH3 in THF and excess THF then was concentrated under reduced pressure, followed by dilution with DCM (150 mL) and filtration. The filtrate was concentrated under reduced pressure to afford crude (S)-l,2-dimethylpiperazine (55 g, crude) as a colorless liquid. TLC system: MeOH: DCM (1 : 5); Rf :0.1.

Step 4: l-bromo-2, 4-difluoro-5-nitrobenzene


[00484] To a stirred suspension of 1 -bromo-2,4-difluorobenzene (50 g, 259 mmol, leq) in cold H2SO4 (187.6 mL) was added cone. HNO3 (165.5 mL) in a dropwise manner keeping the internal temp 20°C then stirred for 10 min. at 0°C. Then the reaction mixture was poured into a mixture of diethyl ether (250 mL) and ice water (250 mL) with vigorous stirring. The organic layer was separated and the aqueous layer was again extracted with Et20 (250 mL). The combined organic layer was washed with sat. sodium bicarbonate (2X 200 mL) followed by sat. brine (2X 200 mL) solution. The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude product which was purified by column chromatography (silica gel, 100-200 mesh) using 0-15% EtOAc in pet ether as an eluent to afford l-bromo-2,4-difluoro-5-nitrobenzene (52 g, 72%) as a yellow color liquid. TLC System: EtOAc: pet ether (3: 7); Rf: 0.4


Step 5: (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l, 2-dimethylpiperazine

[00485] To a stirred solution of (S)-l, 2-dimethylpiperazine (45g, 190.6mmol, leq) in EtOH (450mL) was added TEA (106.9mL, 762.7mmol, 4eq) under argon for 20min., then followed by addition of l-bromo-2,4-difluoro-5-nitrobenzene (47.8g,

286.0mmol, 1.5eq) at RT under argon atm and heated to 85°C for 16h. TLC analysis indicated formation of less polar spot, then the reaction mixture was cooled to RT and solvent was evaporated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 100-200 mesh) using 0-30% EtOAc in pet ether as an eluent to afford (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (42g, 92%) as a yellow solid. LCMS: [M+H]+ 332.0.

Step 6: (S)-5-bromo-2-(3, 4-dimethylpiperazin-l-yl)-4-fluoroaniline


[00486] To a stirred solution of (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (32 g, 96.67 mmol, leq) in EtOH: water (1 : 1, 640 mL) was added NH4C1 (31g, 96.67mmol, 6eq) followed by Fe powder (32.3 g, 96.67 mmol, 6 eq) at RT under argon atm., and heated to 80°C for 16h. TLC analysis indicated formation of polar spot, then the reaction mixture was cooled to RT then filtered through a celite pad and washed with MeOH (2X lOOmL). The filtrate was concentrated under reduced pressure to crude product. The crude compound was purified by column chromatography (neutral alumina) using 100% DCM as an eluent affording (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline (10.5 g, 48% yield) as pale yellow semi-solid. LCMS: [M+H]+ 302.17.

Step 7: (S)-N-(5-bromo-2-(3, 4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00487] Propylphosphonic anhydride solution (2.81 ml, 4.71 mmol) was added dropwise to a mixture of (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline

(0.890 g, 2.95 mmol) and pyridine (0.949 ml, 11.78 mmol) in dry tetrahydrofuran

(THF) (14.73 ml) under N2 at RT. After 1.5 h of stirring, a pale yellow solution was obtained. Then (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline (0.890 g, 2.95 mmol) was added as a solid and the reaction mixture was heated at 50 °C. The crude product was allowed to cool to RT, THF was removed and the residue was partitioned between ethyl acetate (25 mL) and sodium bicarbonate sat solution (25 mL). The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (25 mL). The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound (1.36 g, 89%). LCMS [M+l]+ = 591.22 g/mol.

Step 8: N-[5-( 6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00488] In a 5 mL microwave vial 2-acetamidopyridine-5-boronic acid, pinacol ester (0.034 g, 0.131 mmol), (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.05183 g,

0.088 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.20 mg, 8.76 μηιοΐ) and potassium phosphate tribasic reagent grade (0.037 g, 0.175 mmol) were dissolved in water (0.175 ml) / 1,4-dioxane (1.577 ml) (9 : 1 mixture) to give a white suspension.

The suspension was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 110 °C. The solvent was evaporated and 15 mL of CH2C12 were added. The suspension was sonicated and extracted from water (15 mL). The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the protected intermediate. The product was dissolved in 2 mL of DCM and trifiuoroacetic acid (0.101 ml, 1.314 mmol) was added. The purple solution was stirred for 1 h and the solvent was evaporated. The residue was purified using a cation exchange column eluting with MeOH:NH4OH. XH NMR (500 MHz, MeOD-d4) δ 8.37 (s, 1H), 8.08 (d, J= 8.6 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J= 7.7 Hz, 2H), 7.00 (d, J= 12.1 Hz, 1H), 6.81 (s, 1H), 3.02 (dq, J = 11.6, 2.0 Hz, 1H), 2.97 (dt, J = 11.6, 2.2 Hz, 1H), 2.87 - 2.80 (m, 2H), 2.50 - 2.42 (m, 2H), 2.32 (ddd, J = 9.4, 6.4, 2.7 Hz, 1H), 2.27 (s, 3H), 2.10 (s, 3H), 1.03 (d, J= 6.3 Hz, 3H); LCMS [M+l]+ = 547.28.

Example 197: N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00489] The title compound was prepared similar to the sequence described above for the preparation of Example 196 using 2-cyanopyrimidine-5-boronic acid pinacol ester in place of 2-acetamidopyridine-5-boronic acid, pinacol ester. 1H NMR (500 MHz, MeOD) δ 9.14 (d, J = 0.7 Hz, 2H), 8.05 (d, J = 8.1 Hz, 1H), 7.97 (s, 1H), 7.18 (d, J = 12.2 Hz, 1H), 6.92 (s, J = 4.4 Hz, 1H), 3.21 - 3.17 (m, 1H), 3.14 (dt, J = 12.0, 2.7 Hz, 1H), 2.98 - 2.91 (m, 2H), 2.61 - 2.52 (m, 2H), 2.42 (ddd, J = 9.6, 6.3, 2.9 Hz, 1H), 1.13 (d, J= 6.4 Hz, 3H); LCMS [M+l]+ = 516.29.

Example 198: N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyrid^

[00490] The title compound was prepared similar to the sequence described above for the preparation of Example 196 using 2-cyanopyrimidine-5-boronic acid pinacol ester in place of 2-acetamidopyridine-5-boronic acid, pinacol ester. H NMR (500 MHz, MeOD) 5 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.76 (dq, J = 8.7, 0.8 Hz, 1H), 6.99 (d, J = 12.0 Hz, 1H), 6.82 (s, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.05 (d, J = 7.1 Hz, 2H), 3.01 (dq, J = 11.3, 2.0 Hz, 1H), 2.96 (dt, J = 11.4, 2.1 Hz, 1H), 2.87 - 2.82 (m, 2H), 2.49 - 2.42 (m, 2H), 2.33 (ddd, J = 9.6, 6.5, 3.0 Hz, 1H), 2.28 (s, 2H), 1.21 (ddd, J = 12.9, 7.7, 4.1 Hz, 1H), 1.03 (d, J = 6.3 Hz, 3H), 0.53 -0.49 (m, 2H), 0.27 (q, J = 4.7 Hz, 2H); LCMS [M+l]+ = 560.30.

Example 199: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-ylj 'phenyl] '-2-methyl-4-(trifluoromethyl)-l,3-thiazole-5-carboxamide


[00491] The title compound was prepared according to a procedure similar to

Example 78 using 2-methyl-4-(trifluoromethyl)-l,3-thiazole-5-carbonyl chloride as acylating agent. XH NMR (500MHz, DMSO-d6) δ = 9.96 (s, 1H), 8.46 (s, 2H), 7.70 (br d, J=7.0 Hz, 1H), 7.05 (br d, J=11.5 Hz, 1H), 3.71 - 3.67 (m, 4H), 3.63 - 3.59 (m, 4H), 2.98 - 2.86 (m, 2H), 2.81 - 2.67 (m, 5H), 2.36 (br t, J=10.5 Hz, 1H), 2.31 - 2.24 (m, 1H), 2.19 - 2.12 (m, 4H), 0.93 (d, J=6.1 Hz, 3H); LCMS [M+H]+: 580.2.

Example 200: 3, 5-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-ylJphenylJbenzamide

[00492] The title compound was prepared using a procedure similar to Example

78 with 3,5-dichlorobenzoic acid as acylating agent. H NMR (500MHz, DMSO-d6) δ = 9.79 (s, IH), 8.49 (d, J=l. l Hz, 2H), 7.92 - 7.80 (m, 3H), 7.73 (d, J=8.6 Hz, IH), 7.05 (d, J=12.3 Hz, IH), 3.71 - 3.66 (m, 4H), 3.63 - 3.59 (m, 5H), 2.96 (br t, J=9.0 Hz, 2H), 2.82 - 2.66 (m, 2H), 2.20 (dt, J=2.8, 11.0 Hz, IH), 2.16 - 2.07 (m, 4H), 0.90 (d, J=6.4 Hz, 3H); LCMS [M+H]+: 559.1.

Example 201: N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine


[00493] The title compound (brown solid, 37.4 mg, 61%) was prepared through a procedure similar to that of Example 40 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 3-fluoro-4-morpholinophenylboronic acid (45 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 7.97 (s, IH), 7.92 (d, J=8.3 Hz, IH), 7.33 (d, J=8.7 Hz, IH), 7.30 (d, J=14.2 Hz, IH), 7.12 (t, J=8.7 Hz, IH), 7.05 (d, J=12.4 Hz, IH), 6.93 (s, IH), 3.92 - 3.83 (m, 4H), 3.18 - 3.11 (m, 4H), 3.08 (br d, J=10.9 Hz, 2H), 2.69 - 2.54 (m, 4H), 2.40 (s, 3H), 1.19 (d, J=6.0 Hz, 6H); LCMS [M + H]+ 606.3.

Example 202: N-[4-fluoro-5-[2-[(2R, 6SJ-2, 6-dimethylmorpholin-4-yl]pyrimidin-5-yl]- 2-[(3R)-3,4-dimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00494] The title compound (light brown solid, 48.3 mg, 77%) was prepared in a manner similar to that described in Example 40 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin- 1 -yl)-4-fluorophenyl)-6-oxo-4-(tafluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (49.1 mg, 0.1 mmol) and (2-((2S,6R)-2,6-dimethylmo holino)pyrimidin-5-yl)boronic acid (47 mg, 0.2 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 8.71 (s, IH), 8.57 (d, J=1.0 Hz, 2H), 8.47 (d, J=8.2 Hz, IH), 7.89 (s, IH), 7.06 (d, J=l l. l Hz, IH), 7.02 (s, IH), 4.64 (dd, J=1.5, 13.2 Hz, 2H), 3.69 (ddd, J=2.4, 6.3, 10.5 Hz, 2H), 3.02 - 2.87 (m, 3H), 2.83 (br d, J=l l. l Hz, IH), 2.68 (dd, J=10.6, 13.2 Hz, 2H), 2.61 (br t, J=10.6 Hz, IH), 2.42 - 2.32 (m, 4H), 2.28 - 2.18 (m, IH), 1.30 (d, J=6.2 Hz, 6H), 1.11 (d, J=6.2 Hz, 3H); LCMS [M+ H]+ 604.3.

Example 203: 4-fluoro-N-[4-fluoro-5-[2-(4-methyl-l, 4-diazepan-l-yl)pyrimidin-5-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide


[00495] To a mixture of 2-chloropyrimidine-5-boronic acid (48 mg, 0.3 mmol) and 1-methylhomopiperazine (0.039 mL, 0.315 mmol) in EtOH (2 mL) was added

triethylamine (0.070 mL, 0.5 mmol). The resulting mixture was stirred at 75 °C for 1.5 h. Solvents were removed to give crude (2-(4-methyl-l,4-diazepan-l-yl)pyrimidin-5-yl)boronic acid as a yellow oil. LCMS [M + H]+ 237.4. The title compound (off white solid, 31.4 mg, 50%) was prepared using a procedure similar to that of Example 29 using crude (2-(4-methyl-l,4-diazepan-l-yl)pyrimidin-5-yl)boronic acid (0.3 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-fluoro-2-(trifluoromethyl)benzamide (50.5 mg, 0.1 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 8.60 - 8.52 (m, 4H), 7.66 (dd, J=5.3, 8.4 Hz, IH), 7.50 (dd, J=2.4, 8.8 Hz, IH), 7.38 (dt, J=2.3, 8.1 Hz, IH), 7.00 (d, J=l l. l Hz, IH), 4.02 - 3.95 (m, 2H), 3.87 (t, J=6.4 Hz, 2H), 2.83 (br d, J=11.0 Hz, 2H), 2.76 - 2.69 (m, 2H), 2.65 - 2.56 (m, 4H), 2.40 (s, 3H), 2.30 - 2.18 (m, 5H), 2.08 -2.00 (m, 2H), 1.10 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 618.6.

Example 204: N-[ 4-fluoro-5-(4-morpholin-4-ylphenyl)-2-[ (3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6 >xo-4-(trifluoromethyl)pyridine-3-carboxamide


Step 1: Preparation of 6-fluoro-4'-morpholino-4-((3S,5R)-3, 4,5-trimethylpiperazin-l-yl)-[l, 1 '-biphenyl] -3-amine


[00496] To a 20 mL microwave vial charged with 5-bromo-4-fluoro-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (1.265 g mg, 4 mmol), 4-

(morpholino)phenylboronic acid (1.242 g, 6.0 mmol), and Pd(dppf)Cl2 (220 mg, 0.3 mmol, 7.5 mol%) was added dioxane (12 mL), followed by 1 M aq K3PO4 (6 mL, 6 mmol). The resulting mixture was irradiated in a microwave at 110 °C for 2 h. After quenching with sat. brine (20 mL), it was extracted with EtOAc (30 mL x 2). The combined extracts were concentrated and purified by Biotage SNAP KP-Sil 50 g (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-8%). Fractions showing product gave light brownish clear needle crystals (1.320 g, yield 82%) of the desired product. LCMS[M + H]+ 399.3.

Step 2: N-( 6-fluoro-4 '-morpholino-4-( { 3S, 5R)-3, 4, 5-trimethylpiperazin-l -yl)-[l, 1 '-biphenyl]-3-yl)-l-methyl-6 >xo-4-(trifluoromethyl)-l, 6-dihydro


[00497] The title compound (yellow solid, 19.9 mg, 32%) was prepared through a procedure similar to Example 34 using l -methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (44 mg, 0.2 mmol) and 6-fluoro-4'-morpholino-4-((3 S ,5R)-3 ,4,5 -trimethylpiperazin- 1 -yl)-[ 1 , 1 '-bi phenyl] -3 -amine (40 mg, 0.1 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 8.71 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=7.5 Hz, 2H), 7.02 - 6.94 (m, 4H), 3.92 - 3.85 (m, 4H), 3.64 (s, 3H), 3.26 - 3.19 (m, 4H), 2.81 (br d, J=11.0 Hz, 2H), 2.65 (br t, J=10.8 Hz, 2H), 2.33 (s, 5H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 602.4.

Example 205: N-[5-(5-cyanopyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00498] The title compound was prepared using a procedure similar to that described in Example 39 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-mme

l-yl)phenyl)-4-(mfluoromethyl)-6-(2-(ta (50 mg, 0.083 mmol), 3-cyanopyridine-5-boronic acid pinacol ester (19.00 mg, 0.083 mmol) and [Ι,Γ-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.10 mg, 0.017 mmol) to give, after deprotection of the silyoxy intermediate, 25.5 mg (94% yield for the last step) of the title compound. ¾ NMR (500 MHz, METHANOL-d4) δ = 9.15 - 8.83 (m, 2H), 8.52 - 8.30 (m, 1H), 8.14 - 7.90 (m, 2H), 7.27 - 7.08 (m, 1H), 7.02 - 6.85 (m, 1H), 3.20 - 3.10 (m, 2H), 2.77 - 2.57 (m, 4H), 2.50 - 2.37 (m, 3H), 1.26 - 1.15 (m, 6H); LCMS [M+H]+ 529.2

Example 206: N-[5-(5-chloropyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00499] A procedure similar to that of Example 39 using N-(5-bromo-4-fluoro- 2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol), 3-chloropyridine-5-boronic acid (19.49 mg, 0.124 mmol) to give the silyoxy intermediate which was deprotected using TFA and purified by standard methods to give the title compound in 89% yield. XH NMR (500 MHz, METHANOL-d^ δ = 8.73 - 8.65 (m, 1H), 8.61 - 8.52 (m, 1H), 8.15 - 8.07 (m, 1H), 8.01 - 7.94 (m, 2H), 7.21 - 7.09 (m, 1H), 6.96 - 6.91 (m, 1H),

3.20 - 3.08 (m, 2H), 2.71 - 2.62 (m, 4H), 2.47 - 2.40 (m, 3H), 1.20 (br d, J=4.9 Hz, 6H); LCMS [M+H]+ 538.2.

Example 207: N-[5-(2 yclohexyloxypyridin-3-yl)-4-fluoro-2-[(3R, 5SJ-3, 4, 5- Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridim


[00500] A procedure similar to that of Example 39 employing N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (50 mg, 0.083 mmol) and 2-cyclohexyloxypyridine-3-boronic acid, pinacol ester (37.6 mg, 0.124 mmol) was used. Deprotection of the N-(5-(2-(cyclohexyloxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide intermediate with TFA and purification by standard procedures gave the title compound in 97% yield for the last step. H NMR (500MHz, METHANOL-d4) δ = 8.20 - 8.07 (m, 1H), 8.03 - 7.80 (m, 2H), 7.74 - 7.62 (m, 1H), 7.14 - 6.97 (m, 2H), 6.96 - 6.89 (m, 1H), 5.19 - 5.05 (m, 1H), 3.17 - 3.04 (m, 2H), 2.75 - 2.57 (m, 4H), 2.52 - 2.35 (m, 3H), 2.00 - 1.89 (m, 2H), 1.79 - 1.68 (m, 2H), 1.62 - 1.51 (m, 3H), 1.49 . 1.40 (m, 2H), 1.38 - 1.28 (m, 2H), 1.27 - 1.14 (m, 6H); LCMS [M+H]+ 602.5

Example 208: N-[4-fluoro-5-[l-[2-(4-methoxyphenyl)acetyl]-3, 6-dihydro-2H-pyridin- 4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00501] To N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol obtained from Example 148) and N,N-diisopropylethylamine (0.021 ml, 0.118 mmol) in DCM (3 ml) at RT was added 4-methoxy phenyl acetyl chloride (9.75 μΐ, 0.065 mmol). The milky reaction mixture became a clear solution. It was stirred at RT. Complete disappearance of the starting material and formation of the desired product was observed after 20 min at rt. The reaction was worked up at this point and purified using standard methods to give the title compound (31.5 mg, 77% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.89 - 7.77 (m, 1H), 7.66 - 7.55 (m, 1H), 7.15 - 7.01 (m, 2H), 6.88 - 6.75 (m, 4H), 5.96 -5.75 (m, 1H), 4.19 - 4.09 (m, 2H), 3.72 - 3.59 (m, 7H), 2.97 - 2.85 (m, 2H), 2.54 -2.39 (m, 5H), 2.30 - 2.23 (m, 4H), 1.09 - 1.03 (m, 6H); LCMS [M+H]+ 656.6.

Example 209: N-[4-fluoro-5-[6-(2-methoxyethoxy)pyridin-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


Step 1: Preparation of N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00502] To a solution of N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (505 mg, 1 mmol) in DMF (10 mL) was added cesium carbonate (326 mg, 1 mmol). After stirring at rt for 10 min, iodomethane (68 μί, 1.1 mmol) was added. The resulting mixture was stirred at rt for 30 min. then H20 (50 mL) was

added slowly with stirring and an abundance of white precipitate formed. After stirring at rt for 10 min, it was filtered and washed with H20 (10 mL), then dried to give the title compound as a light beige solid (417 mg, 78%). LCMS [M + H]+ 519.2.

Step 2: N-(4-fluoro-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2-( (3S, 5RJ-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00503] The title compound (grey solid, 41.2 mg, 67%) was prepared similar to the Suzuki coupling procedure described in Example 31 using N-(5-bromo-4-fluoro-2-((3 S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (56 mg, 0.2 mmol). l NMR (500MHz, CHLOROFORM-d) δ = 8.71 (s, IH), 8.47 (d, J=8.2 Hz, IH), 8.35 (s, IH), 7.87 (s, IH), 7.78 (br d, J=8.7 Hz, IH), 7.02 (d, J=10.4 Hz, IH), 6.97 (s, IH), 6.88 (d, J=8.7 Hz, IH), 4.57 - 4.49 (m, 2H), 3.81 - 3.74 (m, 2H), 3.64 (s, 3H), 3.46 (s, 3H), 2.81 (br d, J=11.0 Hz, 2H), 2.64 (br t, J=10.8 Hz, 2H), 2.37 - 2.27 (m, 5H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 592.4.

Example 210: N-[4-fluoro-5-(2^yrrolidin-l-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

[00504] The title compound (grey solid, 50.6 mg, 84%) was prepared using a procedure similar to Example 29 with N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and 2-(pyrrolidin-l-yl)pyrimidine-5-boronic acid pinacol ester (55 mg, 0.2 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.72 (s, 1H), 8.54 (s, 2H), 8.45 (d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.01 (d, J=10.5 Hz, 1H), 6.97 (s, 1H), 3.68 - 3.60 (m, 7H), 2.80 (br d, J=10.9 Hz, 2H), 2.63 (br t, J=10.8 Hz, 2H), 2.37 - 2.26 (m, 5H), 2.08 - 1.99 (m, 4H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 588.4.

Example 211 : N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-3-(trifluoromethyl)thiophene-2-carboxamide


[00505] The title compound (beige solid, 36.1 mg, 62%) was prepared similar to Example 34 using 4-(trifluoromethyl)-l,3-thiazole-5-carboxylic acid (39 mg, 0.2 mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.13 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.56 (d, J=1.2 Hz, 2H), 7.54 (d, J=5.1 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 7.04 (d, J=11.2 Hz, 1H), 3.90 - 3.83 (m, 4H), 3.83 - 3.76 (m, 4H), 2.85 (br d, J=10.8 Hz, 2H), 2.65 (t, J=10.9 Hz, 2H), 2.46 - 2.37 (m, 2H), 2.34 (s, 3H), 1.14 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 579.3.

Example 212: 3, 5-dichloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]benzamide


[00506] The title compound (beige solid, 49.8 mg, 83%) was prepared in a manner similar to that described in Example 34 using 3,5-dichloro-4-fluorobenzoic acid (42 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.25 (s, IH), 8.58 - 8.54 (m, 3H), 7.88 (d, J=6.0 Hz, 2H), 7.02 (d, J=l l . l Hz, IH), 3.91 - 3.85 (m, 4H), 3.82 - 3.78 (m, 4H), 2.89 (br d, J=11.0 Hz, 2H), 2.71 (t, J=10.9 Hz, 2H), 2.47 - 2.40 (m, 2H), 2.38 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 591.3.

Example 213: 2, 3-dichloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00507] The title compound (beige solid, 45.5 mg, 77%) was prepared by a procedure similar to that of Example 34 using 2,3-dichlorobenzoic acid (38 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.91 (s, IH), 8.63 (d, J=8.2 Hz, IH), 8.58 (s, 2H), 7.60 (dd, J=8.0, 9.1 Hz, IH), 7.61 (dd, J=7.9, 12.2Hz, IH), 7.36 (t, J=7.8 Hz, IH), 7.01 (d, J=11.2 Hz, 1H), 3.91 - 3.85 (m, 4H), 3.82 - 3.78 (m, 4H), 2.88 (br d, J=11.0 Hz, 2H), 2.64 (t, J=10.9 Hz, 2H), 2.39 - 2.29 (m, 5H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M+ H]+573.3.

Example 214: N-[4-fluoro-5-[3-[[methyl(oxetan-3-yl)aminoJmethylJphenylJ-2-[(3R)- 3,4-dimethylpiperazin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00508] (S)-N-(4-(3,4-dimethylpiperazin-l -yl)-6-fluoro-3'-formyl-[ 1 , Γ-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (116 mg, 0.225 mmol), (S)-N-(4-(3,4-dimethylpiperazin-l-yl)-6-fluoro-3'-formyl-[l, r-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (116 mg, 0.225 mmol) and acetic acid, glacial, 99.8% (53.9 mg, 0.898 mmol) were mixed in anhydrous DCE. A cloudy solution was obtained. After 5-10 min, Sodium triacetoxyborohydride (143 mg, 0.674 mmol) was added and the reaction mixture was stirred at RT overnight. LCMS showed complete disappearance of the starting material and formation of the desired product. The reaction mixture was quenched with sat aq NaHCCb solution. The organic phase was separated, the aqueous phase was extracted with DCM, the combined organic phase was washed with brine, then dried over Na2S04 and concentrated to obtain the crude. The product was purified using silica gel chromatography (4 G column), eluting with DCM containing 0-6 % DCM. The appropriate fractions were combined and concentrated to afford the desired product as a white foam (71 mg, 51 % yield). XH NMR (500MHz, METHANOL-d4) δ = 8.25 - 8.19

(m, 1H), 7.95 - 7.87 (m, 1H), 7.86 - 7.79 (m, 1H), 7.44 - 7.41 (m, 1H), 7.40 - 7.37 (m, 1H), 7.37 - 7.32 (m, 1H), 7.29 - 7.24 (m, 1H), 7.07 - 7.01 (m, 1H), 6.86 - 6.81 (m, 1H), 4.56 - 4.51 (m, 2H), 4.50 - 4.45 (m, 2H), 3.70 - 3.58 (m, 1H), 3.47- 3.39 (m, 2H), 3.31 -3.25 (m, 1H), 3.18 - 3.10 (m, 2H), 3.04 - 2.91 (m, 3H), 2.78 - 2.68 (m, 1H), 2.68 - 2.58 (m, 3H), 2.09 - 1.98 (m, 3H), 1.24 -1.21 (m, 3H); LCMS [M+H]+ 588.

Example 215: N-[5-(5-ethoxypyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00509] The procedure was similar to Example 39 using N-(5-bromo-4-fluoro-2- ((3 S,5R)-3,4,5 -trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (30 mg, 0.050 mmol), 3-(Cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (27.3 mg, 0.099 mmol) to give the intermediate N-(5-(5-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide which was deprotected by TFA and purified by standard methods to give the title compound (5.0 mg, Yield = 71% for the last step). l NMR (500MHz, METHANOL-d4) δ = 8.22 - 8.17 (m, 1H), 8.16 - 8.08 (m, 1H), 7.93 - 7.88 (m, 1H), 7.87 - 7.80 (m, 1H), 7.50 - 7.44 (m, 1H), 7.10 - 7.00 (m, 1H), 6.86 - 6.79 (m, 1H), 3.90 - 3.83 (m, 2H), 3.16 - 3.08 (m, 2H), 3.01 - 2.81 (m, 2H), 2.73 - 2.65 (m, 2H), 2.63 - 2.43 (m, 3H), 1.23 - 1.18 (m, 7H), 0.59 - 0.52 (m, 2H), 0.33 - 0.27 (m, 2H); LCMS [M+H]+ 574.6.

Example 216: 4-(difluoromethyl)-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3,4-dimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxopyridine-3-carboxamide


[00510] The title compound was prepared similar to the procedure described above for the preparation of Example 78 using l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid as the acylating agent. H NMR (500MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.45 (s, 2H), 8.23 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.02 (d, J=12.2 Hz, 1H), 6.80 (s, 1H), 3.71 - 3.66 (m, 4H), 3.63 - 3.59 (m, 4H), 3.46 (s, 3H), 3.01 - 2.91 (m, 2H), 2.78 - 2.66 (m, 2H), 2.35 - 2.27 (m, 2H), 2.20 - 2.09 (m, 4H), 0.90 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 590.3.

Example 217: N-[5-(6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide


Step 1: 5-bromo-2-methoxyisonicotinaldehyde


[00511] To a solution of DiPA (30.6mL, 212.76mmol, 2eq) in dry THF (100 mL) was added n-BuLi (2.5M in n-hexane, 84.8 mL, 212.76 mmol, 2eq) at -78°C and allowed to warm up to -30°C over 30min. To freshly prepared LDA was added a solution of 5-bromo-2-methoxypyridine Exact Mass: 186.96 (2 X 20 g, 106.38 mmol, leq) in dry THF

(400 mL) at -78°C under an argon arm and maintained for lh at the same temperature before being quenched with DMF (15.7mL, 212.76mmol, 2eq) added dropwise and stirred at the same temperature for 10 mins. TLC analysis indicated formation of polar spots. Then, the reaction mixture was quenched with sat.NH4Cl (150mL) and extracted with EtOAc (2 X 200 ml) and washed with water and brine. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give crude product of 5-bromo-2-methoxypyridine. TLC: 10% EtOAc in pet ether; Rf-: 0.6

Step 2: methyl 4-formyl-6-methoxynicotinate


[00512] To a stirred solution of 5-bromo-2-methoxypyridine (2 X 20g, 93.45 mmol, leq) in methanol (200 mL) was added TEA (65.27 ml, 462.27 mmol, 5eq) at RT in a steel bomb degassed with argon for 10 mins, then Pd2(dppf)Cl2DCM(2.28g, 2.8 mmol, 0.03 eq) was added and the reaction mixture heated to 70°C under 250 Psi (CO gas) for 16 h. TLC analysis indicated formation of polar spots. The reaction mixture was filtered through a celite bed washed with methanol; then the filtrate was evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (230-400 mesh) using 0-5% EtOAc in pet ether as an eluent to give methyl 4-formyl-6-methoxynicotinate (8.2 g, 43.9%) as an off white solid. TLC system: 20% EtOAc in pet ether; Rf: 0.6.

Step 3: methyl 4-(difluoromethyl)- -methoxynicotinate


[00513] To a stirred solution of methyl 4-formyl-6-methoxynicotinate (2X8g,

41.0mmol, leq) in DCM (80mL) was added DAST (10.8mL, 81.98mmol, 2eq) at -78°C under argon then slowly warmed to RT and stirred for 16h. TLC analysis indicated formation of less polar spots. The reaction mixture was cooled to 0°C, quenched with satd. aq.NaHC03 solution, extracted with DCM (2 X 200ml), and washed with water (2 X lOOmL) and brine (2 X lOOmL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give crude product of methyl 4-(difluoromethyl)-6-methoxynicotinate (8g, crude) as an off white solid. The crude product was used without further purification. TLC: 20% EtOAc in pet ether; Rf: 0.7

Step 4: methyl 4-(difluoromethyl)- opyridine-3-carboxylate


[00514] To a stirred solution of methyl 4-(difluoromethyl)-6-methoxynicotinate

(16g, 73.7 mmol, leq) in ACN (160 mL) was added Nal (33.13 g, 22.1 mmol, 2eq) followed by TMS-C1 (28.1 mL, 22.1 mmol, 3 eq) dropwise at rt under argon then slowly warmed to 80°C and stirred for 2h. TLC analysis indicated formation of polar spots. The reaction mixture was cooled to rt and poured into ice water. Isolation of the product gave methyl 4-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (14g, 78.6%) as an off white solid. The crude product was used without further purification. TLC: 70% EtOAc in pet ether; Rf: 0.3

Step 5: methyl 4-(difluoromethyl)-l-methyl-6-oxo-l, 6-dihydropyridine-3-carboxylate


[00515] To a stirred solution of methyl 4-(difiuoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (14 g, 68.96 mmol, leq) in DMF (140 mL) was added Cs2C03 (33.62 g, 103.44 mmol, 1.5eq) followed by CH3I (4.16 mL, 82.69 mmol, 1.2eq) dropwise at RT under argon then stirred for lh. TLC analysis indicated formation of less polar spots. The reaction mixture was at rt poured into ice water. The solids were collected by suction filtration and dried under vacuum to give methyl 4-(difiuoromethyl)-l -methyl-6-oxo-l ,6-dihydropyridine-3-carboxylate (13g, 87.2%) as an off white solid. The crude product was used without further purification. TLC: 5% EtOAc in pet ether; Rf: 0.6

Step 6: 4-(difluoromethyl)-l-methyl- -oxo-l,6-dihydropyridine-3-carboxylic acid


[00516] To a stirred solution of methyl 4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (13g, 59.9 mmol, leq) in MeOH: THF: H20 (50mL:

50mL: 30mL) was added LiOH (5.02 g, 119.81 mmol, 2 eq) at RT stirred for 16h.

TLC analysis indicated formation of polar spot. The solvent was evaporated under reduced pressure, the reaction mixture was cooled to 0°C, acidified with 2N HC1, extracted with EtOAc (2 X 200mL) and washed with water (2X100mL) and brine

(2X100mL). Combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give crude product. The crude product was washed with n-pentane to obtain pure 4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid (10 g, 82.6%) as an off white solid. LCMS: [M+H]+: 203.95:

Step 7: (S)-N-(5-bromo-2-(3, 4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide


[00517] To a stirred solution of 4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid (8 g, 39.40 mmol, leq) in DMF (80 mL) under argon atm was added DIPEA (21.7mL, 118.2 mmol, 3 eq), HATU (44.9g, 118.2 mmol, 3 eq) and then (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline (11.94 g, 39.4 mmol, leq, preparation described in Example 196) at 0°C and then was stirred for 16 h. TLC analysis indicated formation of nonpolar spots. The reaction mixture was diluted with ice water (200mL) and extracted with EtOAc (2 X 500mL). The organic layer was washed with brine and dried over Na2S04 and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (neutral alumina) using 0-5% MeOH in EtOAc as an eluent to afford (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l -yl)-4-fluorophenyl)-4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxarnide (5.5g, 50%) as a pale brown solid.; LCMS: [M+H]+ 487.25.

Step 8: N-[5-( 6-acetamidopyridin-3-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide


[00518] The title compound was prepared through a procedure similar to that described in the final step of Example 100 using 2-acetamidopyridine-5-boronic acid, pinacol ester and (S)-4-(difluoromethyl)-N-(2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-moφholinopyrirnidin-5-yl)phenyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide to give the title compound which was purified using standard methods. H NMR (500 MHz, MeOD) δ 8.47 (s, 1H), 8.30 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.28 (t, J= 55.1 Hz, 1H), 7.09 (d, J= 12.1 Hz, 1H), 6.82 (s, 1H), 3.65 (s, 3H), 3.14 (dd, J= 11.7, 2.2 Hz, 1H), 3.08 (d, J = 11.6 Hz, 1H), 2.93 (ddd, J = 11.6, 10.0, 2.4 Hz, 2H), 2.52 (ddd, J = 14.1, 13.6, 6.3 Hz, 2H), 2.41 - 2.36 (m, 1H), 2.35 (s, 3H), 2.20 (s, 3H), 1.11 (d, J= 6.3 Hz, 3H); LCMS [M+l]+ = 543.30.

Example 218: N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-ylJphenylJ-4-(difluoromethyl)-l-methyl-6-oxopyridine-3-carboxamide


[00519] The title compound was prepared using a procedure similar to Example

217 using 2-cyanopyrimidine-5-boronic acid pinacol ester and (S)-N-(5-bromo-2- (3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(difluoromethyl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide in the final step. H NMR (500 MHz, MeOD) δ 9.04

(s, 2H), 8.19 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 55.0 Hz, 1H), 7.07 (d, J =

12.6 Hz, 1H), 6.72 (s, 1H), 3.55 (s, 3H), 3.11 (dq, J = 11.6, 2.2 Hz, 1H), 3.05 (dt, J = 11.9, 2.4 Hz, 1H), 2.86 (t, J = 11.6 Hz, 1H), 2.82 (dt, J = 11.5, 2.1 Hz, 1H), 2.50 -2.45 (m, 1H), 2.42 (td, J = 11.4, 2.9 Hz, 1H), 2.31 - 2.27 (m, 1H), 2.25 (s, 3H), 1.01 (d, J= 6.3 Hz, 3H); LCMS [M+l]+ = 512.30.

Example 219: N-[5-[6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3


[00520] The title compound was prepared similar to the sequence described above for the preparation of Example 196 using 6-(dimethylamino)pyridine-3-boronic acid pinacol ester in place of 2-acetamidopyridine-5-boronic acid, pinacol ester. H NMR (500 MHz, MeOD) δ 8.25 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 6.75 (d, J = 9.0 Hz, 1H),

3.12 (s, 6H), 3.09 (dq, J = 11.3, 1.9 Hz, 1H), 3.04 (dt, J = 11.5 Hz, 1H), 2.97 - 2.90 (m, 2H), 2.55 (ddd, J = 11.4, 10.3, 3.9 Hz, 2H), 2.44 - 2.40 (m, 1H), 2.38 (s, 3H),

1.13 (d, J= 6.3 Hz, 3H); LCMS [M+l]+ = 533.29.

Example 220: N-[5-[5-cyano-6-(dimethylamino)pyridin-3-yl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(M uoromethyl)-lH-pyridine-3-car^


[00521] The procedure was similar to Example 39 using 3-cyano-2-(N,N-dimethylamino)pyridine-5-boronic acid, pinacol ester (0.034 g, 0.125 mmol),N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)- 6-(2-(trimethylsilyl)ethoxy)nicotinamide (0.05033 g, 0.083 mmol) to give, after deprotection of the silyloxy coupled product 38.3 mg (77% yield) the title compound. XH NMR (500 MHz, MeOD) δ 8.49 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.96 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 12.2 Hz, 1H), 6.91 (s, 1H), 3.33 (s, 6H), 3.06 (d, J = 11.2 Hz, 2H), 2.61 (t, J = 11.1 Hz, 2H), 2.57 - 2.51 (m, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); LCMS [M+l]+ = 572.34.

Example 221 : N-[5-[6-(dimethylamino)-5-fluoropyridin-3-yl]-4-fluoro-2-[(3R, 5SJ-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00522] The title compound was prepared by a procedure similar to that of

Example 39 using 2-(N,N-dimethylamino)-3-fluoropyridine-5-boronic acid pinacol ester hydrochloride (0.039 g, 0.129 mmol),N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (0.05214 g, 0.086 mmol) to give the title compound (14 mg, 29% yield). XH NMR (500 MHz, MeOD) δ 8.12 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 14.9 Hz, 1H), 7.06 (d, J = 12.2 Hz, 1H), 6.91 (s, 1H), 3.13 (d, J = 2.0 Hz, 6H), 3.06 (d, J = 11.1 Hz, 2H), 2.61 (t, J = 11.1 Hz, 2H), 2.56 (dt, J = 9.8, 6.5 Hz, 2H), 2.38 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); 19F NMR (471 MHz, MeOD) δ -63.79 (s), -120.46 (s), -131.66 (s); LCMS [M+l]+ = 565.34.

Example 222: N-[5-(5-chloro-6-morpholin-4-ylpyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^

[00523] The title compound was prepared similar to the sequence described above for the preparation of Example 39 using 5-chloro-6-moφholinopyridin-3-ylboronic acid (0.032 g, 0.130 nimol),N-(5¾omo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(†jimethylsilyl)ethoxy)nicotinamide (0.05251 g, 0.087 mmol) to give the title compound (14 mg, 26% yield). H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 3.87 - 3.84 (m, 4H), 3.41 - 3.39 (m, 4H), 3.07 (d, J= 11.2 Hz, 2H), 2.62 (t, J = 11.1 Hz, 2H), 2.55 (dd, J = 12.6, 6.7 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J = 6.1 Hz, 6H); LCMS [M+l]+ = 623.27.

Example 223: N-[5-(2, 3-dihydro-[l , 4 ]dioxino[2, 3-b Jpyridin- 7-yl) -4-fluoro-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00524] The procedure used was similar to Example 39 except using 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (0.033 g, 0.125 mmol) and N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(†jifluoromethyl)-6-(2-(†jimethylsilyl)ethoxy)nicotinamide (0.05027 g, 0.083 mmol) to give after deprotection of the silyloxy coupled intermediate the title compound (41 mg, 85% yield). ¾ NMR (500 MHz, MeOD) δ 7.95 (s, 1H), 7.89 (d, J= 7.6 Hz, 2H), 7.50 (s,

1H), 7.07 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 4.49 (dd, J = 5.0, 3.1 Hz, 2H), 4.33 (dd, J = 5.0, 3.1 Hz, 2H), 3.07 (d, J = 11.2 Hz, 2H), 2.62 (t, J= 11.1 Hz, 2H), 2.56 (dt, J= 9.6, 6.2 Hz, 2H), 2.37 (s, 3H), 1.16 (d, J= 6.1 Hz, 6H); LCMS [M+H]+ = 562.26.

Example 224: 2-(difluoromethyl)-N-(2-( (S)-3, 4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-((S)-2-methylmorpholino)pyrimidi - -yl)phenyl)-4-fluorobenzamide


[00525] The title compound (formic acid salt, white solid, 46.9 mg, 41%) was prepared according to a procedure similar to Example 31 using crude (S)-(2-(2-methylmo holino)pyrimidin-5-yl)boronic acid (0.555 mmol + 0.278 mmol) and (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-2-(difluoromethyl)-4-fluorobenzamide (prepared as described in Example 62) in dioxane (0.185 mmol). H NMR (500MHz, METHANOL-d4) δ = 8.57 (br s, 2H), 8.36 (br dd, J=1.7, 2.8 Hz, 1H), 7.96 (br d, J=8.1 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.56 (br d, J=9.3 Hz, 1H), 7.50 -7.26 (m, 2H), 7.19 (d, J=11.9 Hz, 1H), 4.65 - 4.54 (m, 2H), 3.99 (br d, J=11.6 Hz, 1H), 3.68 - 3.58 (m, 2H), 3.48 - 3.38 (m, 1H), 3.31 - 3.25 (m, 2H), 3.22 - 3.04 (m, 4H), 2.94 - 2.83 (m, 1H), 2.82 - 2.71 (m, 4H), 1.37 - 1.30 (m, 3H), 1.25 (d, J=6.1 Hz, 3H); LCMS [M + H]+ 573.3

Example 225: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-(3, 3, 4-trimethylpiperazin-l-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

Step 1: Preparation of 5-bromo-4-fluoro-2-(3,3,4-trimethylpiperazin-l-yl)aniline


[00526] To a suspension of K2CO3 (566 mg, 4.09 mmol, 0.525 equiv.) in toluene (20 mL) was added 1,2,2-trimethyl-piperazine (1.00 g, 7.8 mmol), followed by dropwise addition of a solution of 1 -bromo-2,4-difluoro-5 -nitrobenzene (0.98 mL, 7.8 mmol) in toluene (3 mL) over 2 min. The resulting mixture was stirred at rt for 30 min, then 45 °C for 1.5 h resulting in an abundance of yellow precipitate. After diluting with H20 (20 mL) to dissolve the insoluble salts, it was extracted with EtOAc (20 mL x 2). The combined extracts were concentrated and dried under vacuum to give the nitro intermediate as an orange red oil. LCMS [M + H]+ 346.2. To a solution of the above orange oil in MeOH (30 mL) was added a suspension of Raney-Nickel (334 mg, 3.9 mmol) in MeOH (5 mL), followed by hydrazine monohydrate (1.14 mL, 23.4 mmol) dropwise over 2 min. After addition, the reaction mixture was stirred at rt for 30 min. Additional Raney-Nickel (334 mg, 3.9 mmol) in MeOH (5 mL) and hydrazine monohydrate (1.14 mL, 23.4 mmol) were added, followed by THF (15 mL) to make a clear solution. The resulting mixture was heated at 60 °C for 30 min. Additional THF (10 mL) and hydrazine monohydrate (0.38 mL, 7.8 mmol) were added and it was heated at 60 °C for 30 min. After filtration, the filtrate was concentrated to give a dark brown liquid which was purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-10%) to give the title compound as a beige solid (1.796 g, 68%). LCMS [M + H]+ 316.2.

Step 2: Preparation of N-(5-bromo-4-fluoro-2-(3,3,4-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide


[00527] The title compound (beige solid, 1.303 g, 70%) was prepared by a method similar to that of Example 29 Step 3 using 5-bromo-4-fluoro-2-(3,3,4-trimethylpiperazin-l-yl)aniline. LCMS [M + H]+ 505.2.

Step 3: Preparation of N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-(3,3, 4-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00528] The title compound (white solid, 36.3 mg, 61%) was prepared using a procedure similar to the final step of Example 31 using N-(5-bromo-4-fluoro-2-(3,3,4-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (58 mg, 0.2 mmol). XH NMR (500 MHz, METHANOL-d4) δ = 8.56 (s, 2H), 8.09 (s, IH), 7.91 (br d, J=8.2 Hz, IH), 7.13 (d, J=12.1 Hz, IH), 6.93 (s, IH), 3.88 - 3.82 (m, 4H), 3.80 - 3.74 (m, 4H), 3.10 - 2.99 (m, 2H), 2.85 - 2.75 (m, 2H), 2.70 (s, 2H), 2.33 (s, 3H), 1.13 (s, 6H); LCMS [M + H]+ 590.3.

Example 226: N-[4-fluoro-5-(2-morpholin-4-ylpyridin-4-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylj phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

Step 1 : N-(5-bromo-4-fluoro-2-( ( 3S, 5RJ-3, 4, 5-trimethylpiperazin-l -yl)phenyl)-l -methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00529] To a stirred solution of l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (2.1g, 9.50mmol, leq, from Example 93) in DMF (30 mL) was added HATU (10.83 g, 28.50 mmol, 3eq) at 0°C under argon atmosphere followed by DIPEA (5.2mL, 28.50mmol, 3eq) and stirred for 15 min at the same temp. Then, 5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (2.99g, 9.50mmol, leq) was added at 0°C and allowed to remain at RT over 32h. TLC analysis indicated formation of polar spot. The reaction mixture was diluted with water (300mL) and extracted with DCM (3X100mL). The organic layer was washed with water (2X200mL) and dried over Na2S04 and concentrated under reduced pressure to give crude product. Crude product was purified by column chromatography (Neutral Alumina) using 0-30% EtOAc in Methanol as an eluent and gave (1.5g, 30.48%) as an off white solid. LCMS: [M+H]+ 221.95.

Step 2: N-[4-fluoro-5-(2-morpholin-4-ylpyridin-4-yl)-2-[(3R,5S)-3,4,5-trimethylpipe l-yl]phenylJ-l-methyl-6 >xo-4-(trifluoromethyl)pyridme-3-carboxamide

[00530] The title compound (white solid, 21.2 mg, 35%) was prepared according to a procedure similar to that of Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and 2-morpholinopyridine-4-boronic acid, pinacol ester (58 mg, 0.2 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.68 (s, 1H), 8.51 (d, J=8.1 Hz, 1H), 8.25 (d, J=5.1 Hz, 1H), 7.88 (s, 1H), 7.01 (d, J=11.4 Hz, 1H), 6.99 - 6.97 (m, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 3.89 - 3.82 (m, 4H), 3.65 (s, 3H), 3.59 - 3.53 (m, 4H), 2.82 (br d, J=10.9 Hz, 2H), 2.64 (br t, J=10.9 Hz, 2H), 2.37 - 2.27 (m, 5H), 1.14 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 603.4.

Example 227: N-[4-fluoro-5-(4^yrrolidin-l-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenylJ-l-methyl-6 >xo-4-(trifluoromethyl)pyridme-3-carboxamide


[00531] The title compound (yellow solid, 37.5 mg, 64%) was prepared by a procedure similar to that of Example 29 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (55 mg, 0.2 mmol). l NMR (500MHz, CHLOROFORM-d) δ = 8.72 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.48 (br d,

J=7.5 Hz, 2H), 7.01 - 6.94 (m, 2H), 6.62 (d, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.34 (br t, J=6.4 Hz, 4H), 2.81 (br d, J=\ 1.0 Hz, 2H), 2.64 (br t, J=10.9 Hz, 2H), 2.36 - 2.27 (m, 5H), 2.07 - 1.99 (m, 4H), 1.13 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 586.3.

Example 228: N-[5-[4-(cyclopropylmethoxy)phenyl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


[00532] The title compound (white solid, 37.0 mg, 63%) was prepared in a manner similar to Example 31 using N-(5-bromo-4-fiuoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and 4-(cyclopropylmethoxy)phenylboronic acid (38 mg, 0.2 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.71 (s, 1H), 8.47 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.6 Hz, 2H), 7.01 - 6.95 (m, 4H), 3.85 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 2.81 (br d, J=10.9 Hz, 2H), 2.64 (t, J=10.9 Hz, 2H), 2.35 - 2.28 (m, 5H), 1.35 - 1.25 (m, 1H), 1.13 (d, J=6.2 Hz, 6H), 0.70 - 0.63 (m, 2H), 0.40 - 0.35 (m, 2H); LCMS [M + H]+ 587.4.

Example 229: 2, 3-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide

[00533] The title compound (white solid, 37.0 mg, 63%) was prepared through a procedure similar to that of Example 31 using N-(5-bromo-4-fiuoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (51.9 mg, 0.1 mmol) and 4-(cyclopropylmethoxy)phenylboronic acid (38 mg, 0.2 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.71 (s, 1H), 8.47 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.6 Hz, 2H), 7.01 - 6.95 (m, 4H), 3.85 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 2.81 (br d,

J=10.9 Hz, 2H), 2.64 (t, J=10.9 Hz, 2H), 2.35 - 2.28 (m, 5H), 1.35 - 1.25 (m, 1H), 1.13 (d, J=6.2 Hz, 6H), 0.70 - 0.63 (m, 2H), 0.40 - 0.35 (m, 2H); LCMS [M + H]+ 587.4.


[00534] The title compound (light beige solid, 46.8 mg, 84%) was prepared in a procedure similar to that of Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2,3-difluorobenzoyl chloride (19 μί, 0.15 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.74 (br d, J=12.1 Hz, 1H), 8.72 (d, J=8.2 Hz, 1H), 8.58 (s, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.31 - 7.26 (m, 1H), 7.04 (d, J=11.4 Hz, 1H), 3.90 -3.86 (m, 4H), 3.82 - 3.79 (m, 4H), 2.89 (br d, J=10.9 Hz, 2H), 2.67 (t, J=10.8 Hz, 2H), 2.55 - 2.46 (m, 2H), 2.38 (s, 3H), 1.16 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 541.3.

Example 230: 2-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]benzamide


[00535] The title compound (light beige solid, 23.6 mg, 70%) was prepared by a procedure similar to that of Example 78 using (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-mo holinopyrirnidin-5-yl)aniline (23 mg, 0.06 mmol) and 2-chloro-4-fluorobenzoylchloride (12 μί, 0.09 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ =

9.20 (s, IH), 8.68 (d, J=8.2 Hz, IH), 8.59 (s, 2H), 7.85 (dd, J=6.0, 8.7 Hz, IH), 7.25 (dd, J=2.4, 8.3 Hz, IH), 7.15 (t, J=8.2 Hz, IH), 7.04 (d, J=11.2 Hz, IH), 3.91 - 3.86 (m, 4H), 3.82 - 3.78 (m, 4H), 3.01 - 2.85 (m, 4H), 2.60 (t, J=10.6 Hz, IH), 2.42 (dt, J=3.2, 11.0 Hz, IH), 2.35 (s, 3H), 2.26 (br s, IH), 1.09 (d, J=6.2 Hz, 3H); LCMS [M + H]+ 543.4.

Example 231 : N-[5-(l-cyclopentyl-3, 6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00536] The procedure used was similar to Example 148 using N-(4-fluoro-5- (l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (34 mg, 0.057 mmol) and cyclopentanone (7.59 μΐ, 0.085 mmol) to give, after isolation of the product combined and concentrated to afford the title compound as a yellow powder (28 mg, 77% yield) of the title compound. XH NMR (500MHz, METHANOL-d4) δ = 8.02 - 7.93 (m, IH), 7.84 - 7.75 (m, IH), 6.98 - 6.92 (m, IH), 6.91 - 6.87 (m, IH), 6.09 - 5.99 (m, IH), 3.43 - 3.38 (m, 2H), 3.07 - 2.99 (m, 2H), 2.97 - 2.90 (m, 2H), 2.89 - 2.81 (m, IH), 2.68 - 2.62 (m, 2H), 2.62 - 2.56 (m, 2H), 2.56 - 2.49 (m, 2H), 2.39 - 2.36 (m, 3H), 2.09 - 2.01 (m, 2H), 1.83 - 1.75 (m, 2H), 1.71 - 1.63 (m, 2H), 1.61 - 1.52 (m, 2H), 1.18 - 1.15 (m, 6H); LCMS [M+H]+ 576.5

Example 232: N-[4-fluoro-5-[l-[l-(4-methoxyphenyl)ethyl]-3, 6-dihydro-2H-pyridin- 4-yl]-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00537] The procedure used was similar to that of Example 148 using N-(4-fluoro- 5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (40 mg, 0.067 mmol), 4'-methoxyacetophenone 99% (15.09 mg, 0.100 mmol) and Titanium(IV) isopropoxide (0.060 ml, 0.201 mmol) which were mixed in anhydrous THF. The reaction mixture was heated at 75°C for 6h. The reaction mixture was then cooled to RT and EtOH (2 ml) and sodium borohydride (10.14 mg, 0.268 mmol) were added in sequence. The mixture was then allowed to stir at room temperature for 16 h. The workup and isolation using standard methods provided the title compound (7 mg, 14% yield). H NMR (500MHz, METHANOL-d4) δ = 7.94 - 7.84 (m, 1H), 7.77 - 7.68 (m, 1H), 7.43 - 7.31 (m, 2H), 7.04 - 6.92 (m, 3H), 6.85 - 6.78 (m, 1H), 5.98 - 5.87 (m, 1H), 4.46 - 4.36 (m, 1H), 3.86 - 3.76 (m, 1H), 3.76 - 3.72 (m, 3H), 3.71 - 3.63 (m, 1H), 3.47 - 3.26 (m, 4H), 3.19 - 3.12 (m, 2H), 2.89 - 2.81 (m, 2H), 2.80 - 2.77 (m, 3H), 2.76 - 2.69 (m, 2H), 1.73 - 1.65 (m, 3H), 1.30 (d, J=6.4 Hz, 6H); LCMS [M+H]+ 642.6

Example 233: N-[5-( l-butan-2-yl-3, 6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-


[00538] The procedure was similar to Example 148 using N-(4-fluoro-5- (l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-

oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol) and 2-butanone (7.94 μΐ, 0.089 mmol) to give the title compound (9 mg, 24 % yield). H NMR (500MHz, METHANOL-d4) δ = 8.83 - 8.30 (m, 2H), 7.93 (br s, 1H), 7.90 -7.80 (m, 1H), 7.03 (br d, J=12.3 Hz, 1H), 6.94 (br s, 1H), 6.09 (br s, 1H), 3.90 (br s, 2H), 3.58 - 3.41 (m, 3H), 3.15 - 3.05 (m, 2H), 2.95 - 2.84 (m, 2H), 2.83 - 2.73 (m, 2H), 2.72 - 2.63 (m, 2H), 2.51 (s, 3H), 2.02 - 1.88 (m, 1H), 1.73 - 1.61 (m, 1H), 1.44 -1.38 (m, 3H), 1.28 - 1.21 (m, 6H), 1.13 - 1.05 (m, 3H); LCMS [M+H]+ 564.5

Example 234: N-[4-fluoro-5-( 6-morpholin-4-ylpyridin-3-yl)-2-[( 3RJ-3- (dimethylamino)pyrrolidin-l-yl]phenyl]-6 >xo-4-(trifluom

carboxamide


Step 1: (R)-l-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylpyrrolidin-3-amine


[00539] A mixture of (R)-l-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3 -amine (0.65 g, 2.0 mmol) and SnCl2 (0.93 g, 4.9 mmol) in EtOH (8 mL) was heated to 75 °C 4 h. After cooling to room temperature the reaction mixture was concentrated onto celite. Purification by flash chromatography [1-20% MeOH/DCM] afforded (R)-l-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylpyrrolidin-3 -amine (0.61 g, 95 %). LCMS [M+H]+: 302.3.

Step 2: (R)-N-(5-bromo-2-(3-(dimethylamino)pyrrolidin-l -yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide


[00540] 4-(Trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinic acid (0.30 g,

0.99 mmol) was activated with HATU (0.38 g, 0.99 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.1 mmol) in DMF (1 mL) at room temperature. The solution of activated acid was added to a solution of (R)-l-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylpyrrolidin-3-amine (0.250 g, 0.827 mmol) in DMF (3 mL) and the reaction was heated to 55 °C for 18 h. After cooling to room temperature the reaction was partitioned between H20 and DCM. The layers were separated and the aqueous layer was extracted with an additional portion of DCM. The combined organics were washed with water, IN NaOH (Aq.), brine and dried over magnesium sulfate. After removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [0-5% MeOH/DCM] afforded (R)-N-(5-bromo-2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.12 g, 24 %). LCMS [M+H]+: 591.2.

Step 3: (R)-N-(2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluoro-5-(6-m

yl)phenyl)-6-oxo-4-(trifluorometh -l,6-dihydropyridine-3-carboxamide


[00541] A microwave vial was charged with (R)-N-(5-bromo-2-(3- (dimethylamino)pyrrolidin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-

(trimethylsilyl)ethoxy)nicotinamide (0.058 g, 0.098 mmol), 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- yridin-2-yl]-mo holine (0.043 g, 0.15 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.007 g, 0.01 mmol) and K3PO4 (0.042 g, 0.20 mmol). The vial was sealed with a septum cap and evacuated and backfilled with nitrogen. 1,4-Dioxane (1.5 mL) and H20 (0.15 mL) were added via syringe and the vial was evacuated and backfilled with nitrogen an additional time. The reaction was irradiated to 110 °C for 1.5 h. The reaction mixture was concentrated onto celite and purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded the silyl protected biaryl as a clear amber film. The silyl protected product of the Suzuki coupling was dissolved in DCM (2 mL) and treated with trifluoroacetic acid (0.75 mL) at room temperature. After stirring for 1 h at room temperature the volatiles were removed in vacuo and the pure product was isolated by a catch and release protocol using a PoraPak Rxn CX ion exchange cartridge. Lyophilization afforded the title compound (R)-N-(2-(3-(dimethylamino)pyrrolidin-l-yl)-4-fluoro-5-(6-mo holinopyridin-3-yl)phenyl)-6-oxo-4- trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (0.017 g, 30%). ¾ NMR (500MHz, DMSO-d6) δ = 9.71 (s, 1H), 8.18 (s, 1H), 7.89 (br s, 1H), 7.59 (br d, J=9.7 Hz, 1H), 7.21 (br d, J=8.8 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 6.71 (s, 1H), 6.58 (d, J=14.2 Hz, 1H), 3.66 - 3.62 (m, 4H), 3.42 - 3.38 (m, 4H), 3.34 - 3.30 (m, 2H), 3.17 (br d, J=8.4 Hz, 1H), 2.08 (s, 6H), 2.03 - 1.96 (m, 1H), 1.63 (quin, J=9.9 Hz, 1H); LCMS [M+H]+: 575.3.

Example 235: N-[4-fluoro-5-[l-(oxetan-3-yl)-3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00542] The procedure used was similar to that of Example 148 using N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (33 mg, 0.055 mmol), and oxetan-3-one (4.18 mg, 0.058 mmol) to give after workup the title compound (31 mg, 95% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.93 (s, 1H), 7.79 (br d, J=7.9 Hz, 1H), 6.97 - 6.94 (m, 1H), 6.92 (s, 1H), 6.03 (br s, 1H), 4.78 - 4.67 (m, 4H), 3.70 (t, J=6.5 Hz, 1H), 3.16 - 3.08 (m, 2H), 3.04 (br d, J=9.8 Hz, 2H), 2.65 - 2.55 (m, 8H), 2.40 (s, 3H), 1.21 - 1.16 (m, 6H); LCMS [M+H]+ 564.6

Example 236: N-[4-fluoro-5-piperidin-4-yl-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: tert-butyl 4-(2-fluoro-5-(4-(trifluoromethyl)-6-(2- ( trimethylsilyl)ethoxy)nicotinamido)-4-( ( 3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)piperidine-l-carboxylate


[00543] A solution of tert-butyl 4-(2-fluoro-5-(4-(trifluoromethyl)-6-(2

(trimethylsilyl) ethoxy) nicotinamido)-4-((3 S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-5,6-dihydropyridine-l(2H)-carboxylate (310 mg, 0.438 mmol) in MeOH was subjected to hydrogenation using palladium on carbon, 10% catalyst cartridge at

RT, under 1 atm. pressure, on an H-cube. The mixture was concentrated to dryness to afford a white foam (301 mg, 97 %). XH NMR (500MHz, METHANOL-d4) δ = 8.47 -8.35 (m, 1H), 7.77 - 7.66 (m, 1H), 7.07 - 6.99 (m, 1H), 6.89 - 6.78 (m, 1H), 4.51 -4.42 (m, 2H), 4.18 - 4.07 (m, 2H), 2.97 - 2.90 (m, 1H), 2.89 - 2.85 (m, 2H), 2.84 -2.67 (m, 2H), 2.52 - 2.42 (m, 2H), 2.40 - 2.31 (m, 2H), 2.26 - 2.20 (m, 3H), 1.77 -1.66 (m, 2H), 1.62 - 1.51 (m, 2H), 1.40 - 1.37 (m, 9H), 1.11 - 1.07 (m, 2H), 1.05 -1.02 (m, 6H), 0.05 - 0.04 (m, 9H); LCMS [M+H]+ 710.6.

Step 2: N-(4-fluoro-5-(piperidin-4-yl)-2-( ( 3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00544] TFA (2 ml) was added to a solution of tert-butyl 4-(2-fluoro-5-(4- (trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamido)-4-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)piperidine-l-carboxylate in DCM (6 ml) at RT and the reaction mixture was stirred at RT for 10 min. The mixture was concentrated to dryness, then the residue was dissolved in MeOH and passed through a cation exchange resin cartridge (Porapak Rxn CX 20 cc). The desired product as a free base was isolated as an off white powder. (210 mg, 94 %). ¾ NMR (500MHz, METHANOL-d4) δ = 8.10 (s, 1H), 7.86 (br d, J=7.7 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.78 - 6.72 (m, 1H), 3.44 -3.39 (m, 2H), 3.21 - 3.11 (m, 1H), 3.09 - 3.01 (m, 2H), 3.01 - 2.95 (m, 2H), 2.60 - 2.54 (m, 2H), 2.53 - 2.47 (m, 2H), 2.39 - 2.34 (m, 3H), 2.04 - 1.98 (m, 2H), 1.96 - 1.86 (m, 2H), 1.15 (d, J=6.1 Hz, 6H); LCMS [M+H]+ 510.5.

Example 237: N-[4-fluoro-5-( 5-hydroxypyridin-3-yl)-2-[( 3R)-3-(dimethylamino)pyrrolidin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00545] Examples 237 and 238 were isolated from a single reaction performed using a procedure similar to Example 234 Step 3 using 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine in place of 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-moφholine and separating the two products by chromatography. ¾ NMR (500MHz, DMSO-d6) δ = 11.81 - 11.62 (m, IH), 9.66 (br s, IH), 8.00 (br s, IH), 7.61 - 7.55 (m, IH), 7.42 (br s, IH), 7.21 (br d, J=8.9 Hz, IH), 6.68 - 6.59 (m, J=14.2 Hz, 2H), 6.41 (d, J=9.5 Hz, IH), 3.24 - 3.19 (m, IH), 2.14 (s, 6H), 2.09 - 2.03 (m, IH), 1.73 - 1.64 (m, IH), 1.23 (s, IH); LCMS [M+H]+: 506.2

Example 238: N-[5-[6-(cyclopropylmethoxy)pyridin-3-ylJ-4-fluoro-2-[(3R)-3- (dimethylamino)pyrrolidin-l-ylJphenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00546] ¾ NMR (500MHz, DMSO-d6) δ = 12.54 (br s, IH), 9.77 (br s, IH), 8.22

(s, IH), 7.97 (br s, IH), 7.78 (br d, J=8.2 Hz, IH), 7.29 (br d, J=8.7 Hz, IH), 6.89 (d, J=8.6 Hz, IH), 6.74 (br s, IH), 6.66 (d, J=14.2 Hz, IH), 4.12 (d, J=7.1 Hz, 2H), 3.42 -3.37 (m, 4H), 3.26 - 3.21 (m, IH), 2.15 (s, 6H), 2.09 - 2.03 (m, IH), 1.74 - 1.64 (m, IH), 1.29 - 1.22 (m, IH), 0.58 - 0.53 (m, 2H), 0.36 - 0.31 (m, 2H); LCMS [M+H]+: 560.3.

Example 239: N-[4-fluoro-5-( 5-morpholin-4-ylpyridin-3-yl)-2-[( 3R)-3, 4-dimethylpiperazin-1 -yl ]phenyl] -6-oxo-4-( lrifluoromethyl)-lH-pyridine-3-carboxamide


[00547] The procedure used was similar that used in the last step of Example

196 using 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine (0.040 g, 0.138 mmol),(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.05432 g, 0.092 mmol) to give 18 mg (34% yield) of the title compound. H NMR (500 MHz, MeOD) δ 8.31 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 3.83 - 3.79 (m, 4H), 3.55 - 3.52 (m, 4H), 3.11 (d, J = 11.7 Hz, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.96 (dd, J = 20.2, 10.7 Hz, 2H), 2.60 (dd, J = 21.9, 11.5 Hz, 2H), 2.50 (s, 1H), 2.42 (s, 3H), 1.15 (d, J= 6.2 Hz, 3H); LCMS [M+l]+ = 575.42.

Example 240: N-[4-fluoro-5-(2-propan-2-yloxypyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine


[00548] The title compound (18 mg, 38% yield) was prepared similar to the sequence described above for the preparation of Example 196 using (2-isopropoxypyrimidin-5-yl)boronic acid (0.024 g, 0.130 mmol),(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.05144 g, 0.087 mmol). XH NMR (500 MHz,

MeOD) δ 8.73 (s, 2H), 7.97 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 12.0 Hz, 1H), 6.91 (s, 1H), 5.37 (sep, J = 6.2 Hz, 1H), 3.11 (dd, J = 26.9, 10.8 Hz, 2H), 2.96 (t, J = 8.9 Hz, 2H), 2.59 (t, J = 10.7 Hz, 2H), 2.47 (s, 1H), 2.40 (s, 3H), 1.14 (d, J = 6.0 Hz, 3H); LCMS [M+l]+ = 549.09.

Example 241: N-[5-(2, 3-dihydro-[l, 4]dioxino[2, 3-b]pyridin-7-yl)-4-fluoro-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-


[00549] The title compound (22.5 mg, 45% yield) was prepared similar to the sequence described above for the preparation of Example 196 using 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (0.035 g, 0.132 mmol),(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (0.05200 g, 0.088 mmol). XH NMR (500 MHz, MeOD) δ 7.97 (s, 1H), 7.92 - 7.89 (m, 2H), 7.49 (s, 1H), 7.09 (d, J = 12.1 Hz, 1H), 6.91 (s, 1H), 4.49 (dd, J = 5.0, 3.1 Hz, 2H), 4.33 (dd, J = 4.9, 3.1 Hz, 2H), 3.13 (d, J = 11.7 Hz, 1H), 3.08 (d, J = 11.5 Hz, 1H), 2.97 (dd, J = 19.7, 10.3 Hz, 2H), 2.61 (dd, J = 21.5, 11.1 Hz, 2H), 2.51 (s, 1H), 2.42 (s, 3H), 1.15 (d, J = 6.2 Hz, 3H); LCMS HSS [M+l]+ = 548.26.

Example 242: N-[4-fluoro-5-[l-(l-methylpiperidin-4-yl)-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00550] A procedure similar to that of Example 148 using N-(4-fluoro-5- (l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (40 mg, 0.067 mmol), N-methyl-4-piperidone 97% (0.012 ml, 0.100 mmol) gave the title compound (14 mg, 31 % yield). XH NMR (500MHz, METHANOL-d4) δ = 7.86 - 7.79 (m, 1H), 7.71 - 7.61 (m, 1H), 6.85 - 6.80 (m, 1H), 6.80 - 6.77 (m, 1H), 5.99 - 5.86 (m, 1H), 3.29 - 3.25 (m, 2H), 3.07 - 3.01 (m, 2H), 2.93 - 2.86 (m, 2H), 2.82 - 2.75 (m, 2H), 2.53 - 2.40 (m, 7H), 2.38 - 2.31 (m, 3H), 2.30 - 2.23 (m, 5H), 1.99 - 1.89 (m, 2H), 1.67 - 1.58 (m, 2H), 1.07 - 1.03 (m, 6H); LCMS [M+H]+ 605.5.

Example 243: N-[5-[ 1 -(2,2-dimethylpropanoyl)-3, 6-dihydro-2H-pyridin-4-yl] -4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00551] To a solution of N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (27 mg, 0.053 mmol) and N,N-diisopropylethylamine (10.66 μΐ, 0.061 mmol) in DCM (3 ml) at RT was added trimethylacetyl chloride (6.87 μΐ, 0.056 mmol). After 10 min, the reaction mixture was quenched with water (2 ml), worked up and the crude product purified to provide the title compound (15 mg, 45% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.94 (s, 1H), 7.78 (br d, J=8.2 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.94 - 6.91 (m, 1H), 6.05 (br s, 1H), 4.28 (br s, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.04 (br d, J=10.3 Hz, 2H), 2.64 - 2.55 (m, 6H), 2.42 -2.38 (m, 3H), 1.35 - 1.33 (m, 9H), 1.19 - 1.16 (m, 6H); LCMS [M+H]+ 592.6

Example 244: N-[5-[l-(2, 2-dimethylpropanoyl)piperidin-4-yl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-


[00552] To a solution of N-(4-fluoro-5-(piperidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.049 mmol) and N,N-diisopropylethylamine (9.83 μΐ, 0.056 mmol) in DCM (3 ml) at RT was added trimethylacetyl chloride (6.34 μΐ, 0.052 mmol). The mixture became a clear solution. It was stirred at RT. Complete disappearance of the starting material and formation of the desired product was observed after 4 min at rt. The reaction was quenched with water (2 ml) after 10 min. The organic phase was separated, the aqueous phase was extracted with DCM (2 ml), and the combined organic phase was washed with, saturated NaHCCb sola, brine, then dried over Na2S04 and concentrated onto celite. It was then purified by sgc (4 g column), eluting with DCM containing 0-8 % MeOH. The desired fractions were combined and concentrated to afford the title compound as a white powder (26 mg, 85% yield). H

NMR (500MHz, METHANOL-d4) δ = 7.98 - 7.93 (m, 1H), 7.80 - 7.72 (m, 1H), 6.99 -6.94 (m, 1H), 6.94 - 6.91 (m, 1H), 4.66 - 4.55 (m, 2H), 3.23 - 3.11 (m, 1H), 3.06 - 2.91 (m, 4H), 2.63 - 2.51 (m, 4H), 2.43 - 2.37 (m, 3H), 1.96 - 1.88 (m, 2H), 1.74 - 1.65 (m, 2H), 1.35 - 1.32 (m, 10H),1.18 - 1.15 (m, 6H); LCMS [M+H]+ 594.7.

Example 245: N-[4-fluoro-5-(l-pyrimidin-2-yl-3, 6-dihydro-2H-pyridin-4-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00553] To a solution of N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol) and 2-bromopyrimidine 95% (10.34 mg, 0.065 mmol) in ethanol (3 ml) at RT was added N,N-diisopropylethylamine (0.021 ml, 0.118 mmol). The reaction mixture was heated at 80 °C. Complete disappearance of the starting material and formation of the desired product were observed after 4 min. The organic phase was separated, the aqueous phase was extracted with DCM (2 ml), the combined organic phase was washed with saturated NaHCCb soln., brine, then dried over Na2S04 and concentrated onto celite. It was purified by sgc (4 g column), eluting with DCM containing 0-6 % MeOH. The desired fractions were combined and concentrated to afford the title compound as an off white powder (26 mg, 71 %). XH NMR (500MHz, METHANOL-d4) δ = 8.43 -8.31 (m, 2H), 7.95 (s, 1H), 7.80 (br d, J=8.1 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.92 (s, 1H), 6.63 (t, J=4.8 Hz, 1H), 6.13 (br s, 1H), 4.37 (br d, J=2.8 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H), 3.03 (br d, J=10.9 Hz, 2H), 2.62 - 2.52 (m, 6H), 2.38 (s, 3H), 1.17 (d, J=6.0 Hz, 6H), 1.00 (d, J=6.6 Hz, 1H); LCMS [M+H]+ 586.

Example 246: N-[4-fluoro-5-[2-[(2R, 6SJ-2, 6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

[00554] The title compound (pale beige solid, 37.1 mg, 73%) was prepared by a procedure similar to Example 226 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (42 mg, 0.08 mmol) and (2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-5-yl)boronic acid (38 mg, 0.16 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.73 (s, IH), 8.54 (s, 2H), 8.46 (d, J=8.2 Hz, IH), 7.87 (s, IH), 7.02 (d, J=10.4 Hz, IH), 6.97 (s, IH), 4.62 (dd, J=1.3, 13.0 Hz, 2H), 3.73 - 3.63 (m, 5H), 2.80 (br d, J=10.9 Hz, 2H), 2.70 - 2.59 (m, 4H), 2.37 - 2.26 (m, 5H), 1.28 (d, J=6.2 Hz, 6H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 632.5.

Example 247: N-[4-fluoro-5-(3-fluoro-4-morpholin-4-ylphenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


[00555] The title compound (pale beige solid, 35.8 mg, 72%) was prepared by a procedure similar to Example 226 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)- 1 -methyl-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (42 mg, 0.08 mmol) and 3-fluoro-4-morpholinophenylboronic acid (36 mg, 0.16 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.70 (s, IH), 8.48 (d, J=8.3 Hz, IH), 7.87 (s, IH), 7.32 (s, IH), 7.30 (d, J=7.7 Hz, IH), 7.02 - 6.96 (m, 3H), 3.93 - 3.87 (m, 4H), 3.65 (s, 3H),

3.18 - 3.11 (m, 4H), 2.82 (br d, J=11.0 Hz, 2H), 2.64 (br t, J=10.8 Hz, 2H), 2.37 -2.27 (m, 5H), 1.13 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 620.4.

Example 248: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide


[00556] To a solution of 4-fluoro-5-(2-mo holino yrimidin-5-yl)-2-((3S,5R)- 3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) in dioxane (2 mL) was added 4-fluoro-2-(trifluoromethyl)benzoyl chloride (17 μί, 0.11 mmol). The mixture was heated at 110 °C for 30 min, and EtsN (0.028 mL, 0.2 mmol) was added and the resulting mixture was heated at 110 °C for 10 min. Additional dioxane (3 mL) was added and the mixture was heated at 110 °C for 30 min. After quenching with sat. NaHC03 (3 mL), the reaction was extracted with DCM (5 mL) and the organic layer was loaded on Biotage samplet and purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-10%) to give the title compound as a brown solid (23.9 mg, 39%). ¾ NMR (500MHz, CHLOROFORM-d) δ = 8.62 - 8.54 (m, 4H), 7.66 (dd, J=5.3, 8.3 Hz, 1H), 7.50 (dd, J=2.3, 8.8 Hz, 1H), 7.39 (dt, J=2.2, 8.1 Hz, 1H), 7.01 (d, J=11.2 Hz, 1H), 3.90 - 3.86 (m, 4H), 3.82 - 3.78 (m, 4H), 2.84 (br d, J=l l.l Hz, 2H), 2.72 - 2.56 (m, 2H), 2.38 - 2.20 (m, 5H), 1.12 (br d, J=5.6 Hz, 6H); LCMS [M+ H]+ 591.4.

Example 249: N-[4-fluoro-5-( I -methylsulfonyl-2, 5-dihydropyrrol-3-yl)-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-carb


[00557] To a mixture of N-(5-(2,5-dihydro-lH-pyrrol-3-yl)-4-fluoro-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.051 mmol) and N,N-diisopropylethylamine (0.018 ml, 0.101 mmol) in DCM (3 ml) at RT, was added methanesulfonyl chloride (3.92 μΐ, 0.051 mmol). It was stirred at RT. Formation of the desired product along with some di-substituted by-product and starting material was observed even after 20 min at rt. No change between 20 min and 45 min was observed. Therefore, 0.5 eq of methanesulfonyl chloride was added stirring at RT continued. The mixture was quenched with MeOH and concentrated onto celite, then purified by sgc eluting with DCM containing 0-6 % MeOH and 0-0.6 % NH40H. The desired fractions were combined and concentrated to afford the title compound as a white powder (16 mg, 53% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.89 - 7.81 (m, 1H), 7.73 -7.62 (m, 1H), 6.94 - 6.85 (m, 1H), 6.83 - 6.76 (m, 1H), 6.27 - 6.19 (m, 1H), 4.50 -4.40 (m, 2H), 4.30 - 4.19 (m, 2H), 3.00 - 2.90 (m, 2H), 2.87 - 2.79 (m, 3H), 2.54 -2.38 (m, 4H), 2.30 - 2.22 (m, 3H), 1.10 - 1.02 (m, 6H); LCMS [M+H]+ 572.4.

Example 250: 3, 5-dichloro-N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00558] The title compound (off white solid, 23.0 mg, 40%) was prepared according to a sequence similar to that described hereinabove using 5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (38.4 mg, 0.1 mmol) and 3,5-dichlorobenzoyl chloride (21 μί, 0.15 mmol). XH NMR (500MHz, CHLOROFORM-d) δ = 9.27 (s, IH), 8.61 (d, J=8.2 Hz, IH), 8.37 (s, IH), 7.83 - 7.77 (m, 3H), 7.57 (s, IH), 7.02 (d, J=l l. l Hz, IH), 6.85 (d, J=8.6 Hz, IH), 4.19 (d, J=7.1 Hz, 2H), 2.91 (br d, J=l l. l Hz, 2H), 2.73 (t, J=10.9 Hz, 2H), 2.52 - 2.42 (m, 2H), 2.39 (s, 3H), 1.37 - 1.28 (m, IH), 1.19 (d, J=6.2 Hz, 6H), 0.67 -0.61 (m, 2H), 0.41 - 0.36 (m, 2H); LCMS [M + H]+ 557.4.

Example 251 : 2-chloro-N-[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-fluoro-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-4-fluorobenzamide


[00559] The title compound (white solid, 44.4 mg, 81%) was prepared in a sequence similar that described hereinabove using 5-(6-(cyclopropylmethoxy)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (38.4 mg, 0.1 mmol) and 2-chloro-4-fluorobenzoylchloride (20 μί, 0.15 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, IH), 8.68 (d, J=8.3 Hz, IH), 8.37 (s, IH), 7.85 (t, J=7.5 Hz, IH), 7.80 (d, J=8.4 Hz, IH), 7.24 (dd, J=2.4, 8.4 Hz, IH), 7.14 (t, J=8.1 Hz, IH), 7.02 (d, J=11.2 Hz, IH), 6.85 (d, J=8.6 Hz, IH), 4.19 (d, J=7.2 Hz, 2H), 2.88 (br d, J=11.0 Hz, 2H), 2.65 (t, J=10.9 Hz, 2H), 2.42 - 2.31 (m, 5H), 1.37 - 1.28 (m, IH), 1.13 (d, J=6.2 Hz, 6H), 0.67 - 0.61 (m, 2H), 0.40 - 0.35 (m, 2H); LCMS [M + H]+ 541.2.

Example 252: N-[5-( l-acetyl-3, 6-dihydro-2H-pyridin-4-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00560] To a solution of N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2- ((3 S,5R)-3,4,5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol) and N,N-diisopropylethylamine (0.021 ml, 0.118 mmol) in DCM (3 mL) at RT, was added 4-methoxybenzoyl chloride, 99% (8.55 μΐ, 0.062 mmol). The reaction mixture was stirred at RT. Complete disappearance of the starting material and formation of the desired product was observed after 4 min. The reaction was quenched with water (2 ml) after 10 min. The organic phase was separated, the aqueous phase was extracted with DCM (2 ml), the combined organic phase was washed with satd. NaHC03 soln., brine, then dried over Na2S04 and concentrated onto celite. It was then purified on Isco column (4 g), eluting with DCM containing 0-8 % MeOH. The desired fractions were combined and concentrated to afford the title compound as a white powder (23 mg, 58 %)19F NMR (471MHz, METHANOL-d4) δ = -63.83 (s, IF), -117.61 (s, IF); LCMS [M+H]+ 642.5

Example 253: ethyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonylJaminoJ-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-3, 6-dihydro-2H-pyridine-l-carboxylate

[00561] To a solution of N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2- ((3S,5R)-3,4,5 rimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50 mg, 0.099 mmol) and N,N-diisopropylethylamine (0.034 ml, 0.197 mmol) in dichloromethane (DCM) (3 ml) at RT was added ethyl chloroformate (0.011 ml, 0.118 mmol). The milky reaction mixture became a clear solution. It was stirred at RT. Complete disappearance of the starting material and formation of the desired product was observed after 20 min at RT. The reaction was quenched with water (2 mL), the organic phase was separated, the aqueous phase was extracted with DCM (2 x 2 ml), the combined organic phase was washed with brine, then dried over Na2S04 and concentrated onto celite. It was purified on Isco column (4 g), eluting with DCM containing 0-6 % MeOH to collect the title compound as a white powder (44 mg, 73 %)} NMR (500MHZ, METHANOLS) δ = 7.94 (s, 1H), 7.77 (br d, J=8.1 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.92 (s, 1H), 6.00 (br s, 1H), 4.21 -4.16 (m, 2H), 4.16 - 4.07 (m, 2H), 3.68 (br s, 2H), 3.03 (br d, J=10.5 Hz, 2H), 2.63 -2.50 (m, 6H), 2.39 (s, 3H), 1.33 - 1.30 (m, 3H), 1.20 - 1.15 (m, 6H), 0.94 - 0.94 (m, 1H); LCMS [M+H]+ 580.46

Example 254: 2-methylpropyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonylJaminoJ-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-ylJphenylJ-3, 6-dihydro-2H-pyridine-l-carboxylate


[00562] The procedure used was similar to that of Example 253 using N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol) and isobutyl chloroformate (7.73 μΐ, 0.059 mmol) to give, after workup and purification, the title compound as a white powder (25.5 mg, 67% yield). H

NMR (500MHz, METHANOL-d4) δ = 7.94 - 7.87 (m, 1H), 7.78 - 7.68 (m, 1H), 6.94 - 6.90 (m, 1H), 6.90 - 6.87 (m, 1H), 6.04 - 5.89 (m, 1H), 4.19 - 4.06 (m, 2H), 3.92 -3.87 (m, 2H), 3.73 - 3.60 (m, 2H), 3.02 - 2.97 (m, 2H), 2.58 - 2.46 (m, 6H), 2.37 -2.33 (m, 3H), 2.01 - 1.89 (m, 1H), 1.15 - 1.11 (m, 6H), 0.98 - 0.94 (m, 6H), 0.85 -0.85 (m, 1H); LCMS [M+H]+ 608.45

Example 255: N-[5-[l-(3,3-dimethylbutanoyl)-3, 6-dihydro-2H-pyridin-4-yl]-4-fluoro- 2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00563] The procedure used was similar to Example 253 using N-(4-fluoro-5- (l,2,3,6 etrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (29.5 mg, 0.058 mmol) and N,N-diisopropylethylamine (0.013 ml, 0.073 mmol) and 3,3-dimethylbutyryl chloride (8.48 μΐ, 0.061 mmol). The workup and purification provided the title compound as a white powder (25 mg, 68% yield). lU NMR (500MHz, METHANOL-d4) δ = 7.99 - 7.91 (m, 1H), 7.84 - 7.71 (m, 1H), 6.98 - 6.94 (m, 1H), 6.94 - 6.90 (m, 1H), 6.08 - 5.97 (m, 1H), 4.34 - 4.27 (m, 1H), 4.26 - 4.20 (m, 1H), 3.87 - 3.78 (m, 2H), 3.08 - 3.01 (m, 2H), 2.64 - 2.51 (m, 6H), 2.45 - 2.40 (m, 2H), 2.39 - 2.37 (m, 3H), 1.19 - 1.15 (m, 6H), 1.11 - 1.07 (m, 9H); LCMS [M+H]+ 606.5

Example 256: N-[5-[l-(3, 3-dimethylbutanoyl)piperidin-4-yl]-4-fluoro-2-[(3R, 5S)-3, 4,5-Mmethylpiperazin-l-yl]phenyl]-6-oxo-4-(Mfluoromethyl)-lH-pyrid^

[00564] To a mixture of N-(4-fluoro-5-(piperidin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (26.5 mg, 0.052 mmol) and N,N-diisopropylethylamine (0.011 ml, 0.065 mmol) in DCM (3 ml) at RT was added 3,3-dimethylbutyryl chloride (7.59 μΐ, 0.055 mmol). A workup and purification provided the title compound as a white powder (26 mg, 74% yield). XH NMR (500MHz, METHANOL-d4) δ = 8.00 - 7.90 (m, 1H), 7.81 - 7.70 (m, 1H), 6.99 - 6.94 (m, 1H), 6.94 - 6.90 (m, 1H), 4.82 - 4.73 (m, 1H), 4.28 - 4.19 (m, 1H), 3.29 - 3.21 (m, 1H), 3.17 - 3.09 (m, 1H), 3.02 - 2.94 (m, 2H), 2.77 - 2.69 (m, 1H), 2.63 - 2.51 (m, 4H), 2.49 - 2.44 (m, 1H), 2.40 - 2.37 (m, 3H), 2.36 - 2.29 (m, 1H), 1.95 - 1.86 (m, 2H), 1.78 - 1.70 (m, 1H), 1.69 - 1.62 (m, 1H), 1.18 - 1.14 (m, 6H), 1.08 (s, 9H); LCMS [M+H]+ 608.45

Example 257: N-[4-fluoro-5-( 5-fluoropyridin-3-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00565] The title compound was prepared similar to the procedure described above for the final coupling and deprotection steps in the preparation of Example 31 using 6-fluoropyridine-3-boronic acid pinacol ester. H NMR (500MHz, DMSO-d6) δ = 12.81 - 12.30 (m, 1H), 9.59 (s, 1H), 8.36 (s, 1H), 8.16 - 8.06 (m, 1H), 7.92 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.32 (dd, J=2.7, 8.6 Hz, 1H), 7.08 (d, J=12.5 Hz, 1H), 6.81 (s, 1H), 3.06 (br d, J=11.0 Hz, 2H), 2.49 - 2.43 (m, 2H), 2.20 (s, 3H), 1.01 (d, J=6.0 Hz, 6H); LCMS [M+H]+: 522.5.

Example 258: N-[2-[4-(dimethylamino)piperidin-l-yl]-4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00566] The title compound was prepared similar to the sequence described above for the preparation of Example 234 using 4-(dimethylamino)piperidine in place of (R)-N-ethyl-N-methylpyrrolidin-3-amine in Step 1. H NMR (500MHz, DMSO-d6) δ = 9.55 (s, 1H), 8.52 (s, 2H), 7.90 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.07 (d, J=12.3 Hz, 1H), 6.81 (s, 1H), 3.78 - 3.74 (m, 4H), 3.69 - 3.66 (m, 4H), 3.19 (br d, J=11.6 Hz, 2H), 2.67 - 2.58 (m, 3H), 2.24 (br s, 6H), 1.87 - 1.76 (m, 2H), 1.58 (br dd, J=3.1, 11.7 Hz, 2H); LCMS [M+H]+: 590.5.

Example 259: N-[2-[4-[2-(dimethylamino)ethylJpiperazin-l-ylJ-4-fluoro-5-(2-morpholm-4-ylpyrimidin-5-yl)phenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo mide


[00567] The title compound was prepared similar to the procedure described above for the preparation of Example 234 using l-(2-dimethylaminoethyl)piperazine in place of (R)-N-ethyl-N-methylpyrrolidin-3-amine in Step 1. 'll NMR (500MHZ, DMSO-d6) δ = 9.54 (s, IH), 8.53 (d, J=1.0 Hz, 2H), 7.92 (s, IH), 7.75 (d, J=8.7 Hz, IH), 7.09 (d, J=12.2 Hz, IH), 6.81 (s, IH), 3.78 - 3.73 (m, 4H), 3.70 - 3.65 (m, 4H), 2.90 (br s, 4H), 2.60 - 2.54 (m, 4H), 2.48 - 2.39 (m, 4H), 2.21 (br s, 6H); LCMS [M+H]+: 619.5.

Example 260: N-[2-[2-[(dimethylamino)methyl]morpholin-4-yl]-4-fluoro

4-ylpyrimidin-5-yl)phenyl]-6 >xo-4-(trifluoromethyl)-lH-pyridim


[00568] The title compound was prepared similar to the sequence described above for the preparation of Example 234 using dimethyl ^ο ηο1ίη-2^^6^1-3ηιίη6 in place of (R)-N-ethyl-N-methylpyrrolidin-3-amine in Step 1. H NMR (500MHz, DMSO-d6) δ = 9.58 (s, IH), 8.53 (d, J=0.9 Hz, 2H), 7.95 (s, IH), 7.77 (d, J=8.4 Hz, IH), 7.10 (d, J=12.1 Hz, IH), 6.81 (s, IH), 3.85 (br d, J=11.4 Hz, IH), 3.77 - 3.74 (m, 4H), 3.73 - 3.70 (m, IH), 3.69 - 3.67 (m, 4H), 3.08 (br d, J=11.4 Hz, IH), 2.99 (br d, J=11.7 Hz, IH), 2.77 (dt, J=2.6, 11.4 Hz, IH), 2.63 (br d, J=1.7 Hz, IH), 2.48 (br d, J=1.6 Hz, IH), 2.36 (br d, J=1.8 Hz, IH), 2.13 (br s, 6H); LCMS [M+H]+: 606.4.

Example 261 : N-[4-fluoro-5-( 5-pyrrolidin-l -ylpyridin-3-yl)-2-[( 3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carbo


[00569] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 6-(pyrrolidin-l-yl)pyridine-3-boronic acid, pinacol ester (34.0 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) to give the title compound (37 mg, 79%). XH NMR (500MHz, DMSO-d6) δ = 12.66 - 12.44 (m, 1H), 9.49 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.76 - 7.69 (m, 1H), 7.61 (br d, J=8.7 Hz, 1H), 7.00 (br d, J=12.5 Hz, 1H), 6.81 (s, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.41 (br s, 6H), 3.06 -2.97 (m, 1H), 2.44 (br d, J=9.3 Hz, 1H), 2.36 (br dd, J=1.8, 3.5 Hz, 1H), 1.99 - 1.89 (m, 5H), 1.14 (d, J=13.2 Hz, 2H), 1.01 (br d, J=5.0 Hz, 6H); LCMS [M+H]+: 573.5.

Example 262: N-[5-(5-cyano-6-pyrrolidin-l-ylpyridin-3-yl)-4-fluoro-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00570] The title compound was prepared similar to the sequence described for the preparation of Example 100 using 3-cyano-2-pyrrolidinopyridine-5-boronic acid, pinacol ester (37.1 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) to give the title compound (32 mg 64% yield). XH NMR (500MHz, DMSO-d6) δ = 12.66 - 12.49 (m, 1H), 9.55 (s, 1H), 8.46 (d, J=1.7 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.02 (d, J=12.5 Hz, 1H), 6.81 (s, 1H), 3.71 (br t, J=6.5 Hz, 5H), 3.02 (br d, J=11.2 Hz, 2H), 2.47 - 2.40 (m, 2H), 2.38 - 2.28 (m, 2H), 2.19 (br s, 3H), 1.95 (td, J=3.4, 6.3 Hz, 5H), 1.00 (br d, J=6.0 Hz, 6H); LCMS [M+H]+: 598.5.

Example 263: N-[5-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00571] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2,2-difiuoro-benzo[l,3]dioxole-5-boronic acid (25.01 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) to give the title compound (40.2 mg, 80% yield). XH NMR (500MHz, DMSO-d6) δ = 12.77 - 12.43 (m, 1H), 9.55 (s, 1H), 7.91 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.59 - 7.46 (m, 2H), 7.31 (d, J=8.6 Hz, 1H), 7.04 (d, J=12.5 Hz, 1H), 6.80 (s, 1H), 3.04 (br d, J=10.9 Hz, 2H), 2.48 - 2.43 (m, 2H), 2.38 - 2.31 (m, 2H), 2.19 (s, 3H), 1.01 (d, J=6.1 Hz, 6H); LCMS [M+H]+: 583.0.

Example 264: 3-chloro-4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00572] The title compound (beige solid, 49.8 mg, 83%) was prepared by a procedure similar to that of Example 34 using 3,5-dichloro-4-fluorobenzoic acid (42 mg, 0.2 mmol) and 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.25 (s, 1H), 8.58 - 8.54 (m, 3H), 7.88 (d, J=6.0 Hz, 2H), 7.02 (d, J=l l . l Hz, 1H), 3.91 - 3.85 (m, 4H), 3.82 - 3.78 (m, 4H), 2.89 (br d, J=11.0 Hz, 2H), 2.71 (t, J=10.9 Hz, 2H), 2.47 - 2.40 (m, 2H), 2.38 (s, 3H), 1.18 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 591.3.

Example 265: 3-chloro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l -yljphenyl] ' -5-methoxybenzamide


[00573] The title compound (white solid, 42.2 mg, 76%) was prepared by a procedure similar to Example 34 using 3-chloro-5-methoxybenzoic acid (37 mg, 0.2 mmol) and 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.24 (s, 1H), 8.62 (d, J=8.3 Hz, 1H), 8.57 (s, 2H), 7.42 (s, 1H), 7.39 (s, 1H), 7.10 (t, J=2.0 Hz, 1H), 7.01 (d, J=11.2 Hz, 1H), 3.90 (s, 3H), 3.89 -3.86 (m, 4H), 3.82 - 3.78 (m, 4H), 2.91 (br d, J=l l. l Hz, 2H), 2.69 (t, J=11.0 Hz, 2H), 2.52 - 2.41 (m, 2H), 2.38 (s, 3H), 1.17 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 569.3.

Example 266: 3-chloro-2, 4-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]benzamide


[00574] The title compound (off-white solid, 46.6 mg, 79%) was prepared by a procedure similar to that of Example 34 using 3-chloro-2,4-difluorobenzoic acid (39 mg, 0.2 mmol) and 4-fluoro-5-(2-moφholino yrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 9.78 (br d, J=12.5 Hz, 1H), 8.70 (d, J=8.2 Hz, 1H), 8.58 (s, 2H), 8.14 (q, J=7.7 Hz, 1H), 7.19 (br t, J=8.1 Hz, 1H), 7.04 (d, J=l l. l Hz, 1H), 3.87 (br d, J=3.8 Hz, 4H), 3.81 (br d, J=4.4 Hz, 4H), 2.88 (br d, J=l l. l Hz, 2H), 2.68 (br t, J=10.8 Hz, 2H), 2.55 - 2.45 (m, 2H), 2.38 (s, 3H), 1.16 (d, J=6.1 Hz, 6H); LCMS [M + H]+ 575.4.

Example 267: N-[4-fluoro-5-(l-methyl-3, 6-dihydro-2H-pyridin-4-yl)-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00575] The procedure followed was similar to Example 148 using N-(4-fluoro- 5-(l,2,3,64etrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (30 mg, 0.059 mmol) and paraformaldehyde (3.55 mg, 0.118 mmol) to give, after workup and purification, 3.5 mg (10% yield) of the title compound. XH NMR (500MHz, METHANOL-d4) δ = 7.90 -7.85 (m, 1H), 7.72 - 7.64 (m, 1H), 6.86 - 6.79 (m, 1H), 6.78 - 6.72 (m, 1H), 5.93 - 5.88 (m, 1H), 3.11 - 3.06 (m, 2H), 2.93 - 2.87 (m, 2H), 2.68 - 2.61 (m, 2H), 2.52 - 2.49 (m, 2H), 2.48 - 2.43 (m, 2H), 2.42 - 2.37 (m, 2H), 2.34 - 2.30 (m, 3H), 2.26 - 2.23 (m, 3H), 1.04 (br d, J=6.0 Hz, 6H); LCMS [M+H]+ 522.46.

Example 268: N-[4-fluoro-2-(8-methyl-3, 8-diazabicyclo[3.2.1 ]octan-3-yl)-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6 >xo-4-(trifluoromethyl)-lH-pyridine-3

[00576] The title compound was prepared similar to the procedure described above for the preparation of Example 234 using 8 -methyl -3,8 -diaza-bicyclo[3.2.1]octane dihydrochloride in place of (R)-N-ethyl-N-methylpyrrolidin-3-amine in Step 3. XH NMR (500MHz, DMSO-d6) δ = 9.42 (s, IH), 8.53 (s, 2H), 8.07 (s, IH), 7.66 (br d, J=8.4 Hz, IH), 7.07 (d, J=12.5 Hz, IH), 6.83 (s, IH), 3.78 - 3.73 (m, 4H), 3.70 - 3.65 (m, 4H), 3.13 (br s, H), 2.96 - 2.81 (m, 4H), 2.22 (s, 3H), 1.95 -1.82 (m, 2H), 1.75 (br d, J=7.1 Hz, 2H); LCMS [M+H]+: 588.4.

Example 269: N-[5-( 5 yano-4-methylpyridin-3-yl)-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 -4-(Mfluoromethyl)-lH-pyridine-


[00577] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 4-methyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (30.2 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) to give the title compound (41.2 mg, 92% yield). XH NMR (500MHz, DMSO-d6) δ = 9.59 (s, IH), 8.55 (s, IH), 8.08 (s, IH), 7.90 (s, IH), 7.65 (br d, J=8.1 Hz, IH), 7.11 (d, J=11.7 Hz, IH), 6.80 (s, IH), 3.10 (br d, J=10.8 Hz, 2H), 2.96 (s, 2H), 2.27 (s, 3H), 2.22 (br s, 3H), 1.14 (d, J=13.2 Hz, 4H), 1.02 (br d, J=5.9 Hz, 6H); LCMS [M+H]+: 543.2.

Example 270: N-[4-fluoro-5-( I -pyridin-2-yl-3, 6-dihydro-2H-pyridin-4-yl)-2-[( 3R, 5S)- 3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH^yridine-3-carboxamide


[00578] Copper (I) iodide (1.013 mg, 5.32 μηιοΐ) was added to a mixture of 2-chloropyridine 99% (6.50 μΐ, 0.069 mmol), N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,54rimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (27 mg, 0.053 mmol) and N,N-diisopropylethylamine (0.028 ml, 0.160 mmol) in ethylene glycol (1.5 ml). The mixture was heated in a microwave reactor at 180 °C for lh. The mixture was quenched and worked up in a similar manner to Example 148 to provide the title compound as a yellow powder (8.5 mg, 26 %). XH NMR (500MHz, METHANOL-d4) δ = 7.99 (dd, J=1.2, 4.9 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.73 - 7.67 (m, 1H), 7.51 - 7.45 (m, 1H), 6.87 - 6.83 (m, 1H), 6.82 - 6.79 (m, 1H), 6.76 - 6.71 (m, 1H), 6.60 - 6.52 (m, 1H), 6.08 - 6.01 (m, 1H), 4.04 - 3.99 (m, 2H), 3.75 - 3.70 (m, 2H), 2.95 - 2.90 (m, 2H), 2.55 - 2.43 (m, 6H), 2.29 - 2.27 (m, 3H), 1.06 (d, J=5.9 Hz, 6H); LCMS [M+H]+ 585.5.

Example 271: N-[4-fluoro-5-[l-(5-methylpyrimidin-2-yl)-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00579] In a small reaction vessel N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (26 mg, 0.051 mmol) and 2-chloro-5-methylpyrimidine (7.57 mg, 0.059 mmol) in ethanol (3 ml) were combined at ambient temperature, and N,N-diisopropylethylamine (0.018 ml, 0.102 mmol) was added. The mixture was heated for 3 h at 150 °C, and the standard workup and purification provided (12 mg (36% yield) of the title compound. l NMR (500 MHz, METHANOL-d4) δ = 8.31 - 8.19 (m, 2H), 7.94 (s, 1H), 7.85 - 7.72 (m, 1H), 6.98 -6.94 (m, 1H), 6.92 (s, 1H), 6.12 (br s, 1H), 4.33 (br d, J=2.7 Hz, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.04 (br d, J=10.5 Hz, 2H), 2.64 - 2.54 (m, 6H), 2.39 (s, 3H), 2.17 (s, 3H), 1.20 - 1.16 (m, 6H); LCMS [M+H]+ 600.4

Example 272: N-[4-fluoro-5-[6-[(2R, 6S)-2, 6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-f(3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: (2S, 6RJ-2, 6-dimethyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine


[00580] To a 20 mL microwave vial charged with 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.968 g, 4 mmol), cis-2,6-dimethylmorpholine (0.54 mL, 4.4 mmol) and Hunig base (1.39 mL, 8 mmol) was added NMP (2 mL). The resulting solution was heated at 140 °C for 2 h. After

removing Hunig base, the mixture was purified by flash chromatography (gradient: EtO Ac/hex 0-100%) to give the title compound as a crystalline beige solid (485 mg, yield 38%). LCMS for boronic acid [M + H]+ 237.2.

Step 2: N-(5-(6-((2S, 6R)-2, 6-dimethylmorpholino)pyridin-3-yl)-4-fluoro-2-((3S,5R)-3, 4, 5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(trifluoromethyl)-l , 6-dihydropyridine-3-carboxamide


[00581] The title compound (off-white solid, 34.2 mg, 54%) was prepared by a procedure similar to that described in Example 31 using N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and (2S,6R)-2,6-dimethyl-4-(5-(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (63 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.97 (s, 1H), 7.92 (br d, J=8.3 Hz, 1H), 7.78 (br d, J=9.2 Hz, 1H), 7.07 (d, J=12.1 Hz, 1H), 6.95 - 6.89 (m, 2H), 4.16 (br d, J=11.6 Hz, 2H), 3.74 (ddd, J=2.3, 6.3, 10.3 Hz, 2H), 3.07 (br d, J=10.4 Hz, 2H), 2.68 - 2.57 (m, 4H), 2.53 (dd, J=10.8, 12.6 Hz, 2H), 2.41 (s, 3H), 1.26 (d, J=6.2 Hz, 6H), 1.19 (br d, J=5.6 Hz, 6H); LCMS [M + H]+ 617.5.

Example 273: N-[4-fluoro-5-[2-[(2R, 6S)-2, 6-dimethylmorpholin-4-yl]pyrimidin-5-yl]-2-[(3R)-3, 4-dimethylpiperazin-l -yljphenyl] -1 -methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


Step 1: (S)-N-(5-bromo-2-(3, 4-dimethylpiperazin-l-yl)-4-fluorophenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00582] stirred solution of l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (5g, 22.62mmol, leq) in DMF (50mL) was added HATU(25.79g, 67.87mmol, 3eq) at 0°C under argon atmosphere followed by DIPEA (11.82mL, 67.87mmol, 3eq) and stirred for 15min at the same temperature. Then, (S)-5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluoroaniline (2.99g, 24.88mmol, l. leq) was added at 0°C and the reaction mixture was allowed to remain at RT over 48h. TLC analysis indicated formation of polar spot. The reaction mixture was diluted with water (300mL) and extracted with EtOAc (3X100mL). The organic layer was washed with ice water (2X200mL) and dried over Na2S04 then concentrated under reduced pressure to give crude product. Crude product was purified by column chromatography (Neutral Alumina) using 0-60% EtOAc in petroleum ether as an eluent to provide (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (4g, 35%) as an off white solid. LCMS [M + H]+ 505.23.

Step 2: N-(4-fluoro-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2-( (3S, 5R)-3, 4, 5-trimethylpiperazin-l-yl)phenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00583] The title compound (white solid, 47.4 mg, 77%) was prepared by a procedure similar to that of Example 31 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1 -yl)-4-fiuorophenyl)- 1 -methyl-6-oxo-4-(mfluoromethyl)- 1 ,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and (2-((2S,6R)-2,6-dimethylmoφholino)pyrimidin-5-yl)boronic acid (47 mg, 0.2 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 8.74 (br s, IH), 8.54 (s, 2H), 8.46 (br d, J=7.8 Hz, IH), 7.88 (s, IH), 7.03 (d, J=\ 1.1 Hz, IH), 6.97 (s, IH), 4.65 - 4.58 (m, 2H), 3.72 - 3.63 (m, 5H), 3.02 - 2.84 (m, 3H), 2.80 (br d, J=10.9 Hz, IH), 2.70 - 2.54 (m, 3H), 2.43 - 2.28 (m, 4H), 2.20 (br s, IH), 1.28 (d, J=6.2 Hz, 6H), 1.09 (br d, J=6.1 Hz, 3H); LCMS [M+ H]+618.4.

Example 274: N-[4-fluoro-5-[l-(6-methoxypyrimidin-4-yl)-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00584] microwave vial charged with N-(4-fluoro-5-(l, 2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25.5 mg, 0.050 mmol) and 4-iodo-6-methoxy pyrimidine (13.64 mg, 0.058 mmol) in ethanol (3 ml) at RT, was added N,N-diisopropylethylamine (0.018 ml, 0.100 mmol) . The mixture was heated at 130 °C for 3 h. The reaction was worked up and the product was purified by sgc to

afford the title compound (19 mg, 58 % yield). 1H NMR (500 MHz, METHANOL-d4) δ = 8.26 - 8.21 (m, 1H), 7.98 - 7.93 (m, 1H), 7.85 - 7.76 (m, 1H), 6.99 - 6.94 (m, 1H), 6.94 - 6.90 (m, 1H), 6.12 (br s, 1H), 6.04 (s, 1H), 4.26 - 4.16 (m, 2H), 4.00 - 3.88 (m, 5H), 3.03 (br d, J=11.0 Hz, 2H), 2.65 - 2.52 (m, 6H), 2.38 (s, 3H), 1.19 - 1.15 (m,6H); LCMS [M+H]+ 616.6

Example 275: N-[5-[l-(5-chloropyrimidin-2-yl)-3, 6-dihydro-2H-pyridin-4-yl] -4-fluoro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00585] To a microwave vial charged with N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25.5 mg, 0.050 mmol) and 2,5-dichloropyrimidine (8.61 mg, 0.058 mmol) in ethanol (3 ml) at RT, was added N,N-diisopropylethylamine (0.018 ml, 0.100 mmol) . The mixture was heated at 90 °C for 2 h. 95 % conversion to the desired product was observed after 2 h. Standard workup and purification yielded the title compound (23 mg, 69% yield). H NMR (500 MHz, METHANOL-d4) δ = 8.25 - 8.18 (m, 2H), 7.87 - 7.79 (m, 1H), 7.73 - 7.62 (m, 1H), 6.87 - 6.82 (m, 1H), 6.81 - 6.78 (m, 1H), 6.04 - 5.96 (m, 1H), 4.30 - 4.22 (m, 2H), 3.97 - 3.90 (m, 2H), 2.96 - 2.89 (m, 2H), 2.52 - 2.40 (m, 6H), 2.28 - 2.25 (m, 3H), 1.07 - 1.03 (m, 6H); LCMS [M+H]+ 620.

Example 276: ethyl 2-[4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-3, 6-dihydro-2H-pyridin-l-ylJpyrimidine-4-carboxylate


[00586] A small microwave flask was charged with N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25. mg, 0.049 mmol) and methyl 2-chloropyrimidine-4-carboxylate (9.78 mg, 0.057 mmol) in ethanol (3 ml) at RT, followed by N,N-diisopropylethylamine (0.017 ml, 0.099 mmol). The mixture was heated at 90 °C for 72 h. A standard workup and purification yielded the title compound (16 mg, 47 % yield). XH NMR (500MHz, METHANOL-d4) δ = 8.61 -8.57 (m, 1H), 8.06 - 7.95 (m, 1H), 7.87 - 7.77 (m, 1H), 7.22 - 7.14 (m, 1H), 7.09 -7.01 (m, 1H), 6.99 - 6.90 (m, 1H), 6.21 - 6.11 (m, 1H), 4.49 - 4.40 (m, 4H), 4.17 -4.10 (m, 2H), 3.24 - 3.10 (m, 4H), 2.86 - 2.78 (m, 2H), 2.78 - 2.70 (m, 3H), 2.66 -2.59 (m, 2H), 1.45 - 1.40 (m, 3H), 1.36 - 1.32 (m, 6H); LCMS [M+H]+ 658.4.

Example 277: N-[4-fluoro-2-[3-(methylamino)pyrrolidin-l-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenylJ-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


Step 1: tert-butyl (l-(4-bromo-5-fluoro-2-nitrophenyl)pyrrolidin-3-yl) (methyl)carbamate


[00587] A suspension of 3-N-boc-3-(methylamino)pyrrolidine (1.33 g, 6.64 mmol) and K2CO3 (0.459 g, 3.32 mmol) in toluene (10 ml) was stirred for 5 min at room temperature. Then a solution of 1 -bromo-2,4-difiuoro-5 -nitrobenzene (1.580 g, 6.64 mmol) in toluene (1 ml) was added dropwise from a pipette (2 ml of toluene were used to rinse the vial) and the reaction was stirred at 50 °C for 3 h 30 min. Then the reaction mixture was partitionned into water and DCM and the product was extracted by DCM (3x20mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by flash chromatography [0-10% MeOH/DCM] to afford the desired tert-butyl (l-(4-bromo-5-fluoro-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (2.17 g, 5.19 mmol, 78 % yield) as an orange oil. LCMS [M+H]+ 418.2.

Step 2: tert-butyl (l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)pyrrolidin-3-yl)(me


[00588] A 100 mL RBF was charged with a mixture of tert-butyl (l-(4-bromo-5-fluoro-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (2.17 g, 5.19 mmol), XPhos (0.049 g, 0.104 mmol), XPhos (0.049 g, 0.104 mmol) and XPhos (0.049 g, 0.104 mmol). Then 1,4-dioxane (50 ml) and sodium carbonate solution (2 M) (2.75 mL) were added via syringe and the vial was flushed with argon. The reaction was stirred at 90 °C overnight. Then the reaction mixture was partitionned into water and DCM and the product was

extracted by DCM (3x50mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by Flash chromatography [0-10% MeOH/DCM] to afford the desired tert-butyl (l-(5-fiuoro-4-(2-moφholinopyrimidin-5-yl)-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (1.21 g, 2.415 mmol, 46.6 % yield) as a dark orange oil. LCMS [M+H]+ 503.4.

Step 3: tert-butyl (l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate


[00589] A mixture of tert-butyl (l-(5-fluoro-4-(2-mo holinopyrimidin-5-yl)-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (1.8598 g, 3.70 mmol) and tin(II) chloride, 98% (2.105 g, 11.10 mmol) in a mixture of EtOH (10 ml) and MeOH (10 ml) was heated to 90 °C for 3 h. Then the reaction mixture was concentrated onto celite and purified by flash [0.5-10% MeOH/DCM] to afford the tert-butyl (l-(2-amino-5-fluoro-4-(2-moφholinopyrirnidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (0.94 g, 1.990 mmol, 53.8 % yield) as a yellow solid. LCMS [M+H]+ 473.2.

Step 4: tert-butyl (l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-(4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamido)phenyl)pyrrolidin-3-yl)(methyl)carbamate


[00590] Propylphosphonic anhydride solution (0.189 ml, 0.317 mmol) was added dropwise to a mixture of 4-(trifluoromethyl)-6-(2-

(trimethylsilyl)ethoxy)nicotinic acid (72 mg, 0.234 mmol) and pyridine (5.24 ml, 65.1 mmol) in DCM (2 ml) under N2 atmosphere at room temperature. After 15 minutes of stirring at 50 °C a solution of tert-butyl (l-(2-amino-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.212 mmol) in 2mL of DCM was added and the reaction mixture was heated at 50 °C overnight. The reaction mixture was then concentrated onto celite and purified by flash chromatography [0-10% MeOH/DCM] to afford the tert-butyl (l-(5-fluoro-4-(2-mo holinopyrimidin-5-yl)-2-(4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamido)phenyl)pyrrolidin-3-yl)(methyl)carbamate (161 mg, 0.211 mmol, 100 % yield) as an off-white powder. LCMS [M+H]+ 762.5.

Step 5: N-(4-fluoro-2-(3-(methylamino)pyrrolidin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l, 6-dihydropyridine-3-carboxamide


[00591] To a solution of tert-butyl (l-(5-fluoro-4-(2-mo holinopyrimidin-5-yl)-2- (4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamido)phenyl)pyrrolidin-3-yl)(methyl)carbamate (161 mg, 0.211 mmol) in DCM (3 ml) was added trifluoroacetic acid (2 ml, 26.1 mmol). The reaction mixture was stirred at 60 °C for 50 minutes. Then the TFA and solvent were removed under vacuum and the crude material was purified by flash chromatography [0-40% DCM/MeOH] to afford the N-(4-fluoro-2-(3- (methylalnino)pylτolidin-l-yl)-5-(2-mo holinopyrimidin-5-yl)phenyl)-6-oxo-4- (trifluoromethyl)-l,6-a^hydropyridine-3-carboxarnide (6.4 mg, 0.011 mmol, 5.39 % yield) as a white powder (yield for 2 steps). ¾ NMR (500MHz, DMSO-d6) δ = 9.79 (br s, 1H), 8.49 (s, 2H), 7.98 (br s, 1H), 7.29 (br d, J=8.6 Hz, 1H), 6.75 (s, 1H), 6.62 (d,

J=14.1 Hz, 1H), 3.75 - 3.71 (m, 4H), 3.69 - 3.65 (m, 4H), 3.46 (br dd, J=5.6, 9.2 Hz, 1H),

3.41 - 3.38 (m, 1H), 3.18 - 3.13 (m, 1H), 3.10 (br dd, J=4.5, 9.7 Hz, 1H), 2.26 (s, 3H),

2.03 - 1.94 (m, 1H), 1.76 - 1.66 (m, 1H), 1.23 (s, 1H); LCMS [M+H]+ 562.3.

Example 278: N-[2-[3-[(dimethylamino)methyl]pyrrolidin-l-yl]-4-fluoro-5-(2-m

4-ylpyrimidin-5-yl)phenylJ-6 >xo-4-(trifluoromethyl)-lH^yridme-3-carboxamide


[00592] The title compound was prepared similar to the procedure described above for the preparation of Example 234 using N,N-dimethyl(3-pyrrolidinyl)methanamine in place of (R)-N-ethyl-N-methylpyrrolidin-3-amine in Step 1. ¾ NMR (500MHz, DMSO-d6) δ = 9.81 (s, 1H), 8.50 (s, 2H), 7.95 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J=14.1 Hz, 1H), 3.76 - 3.70 (m, 4H), 3.69 - 3.65 (m, 4H), 3.10 (br dd, J=7.1, 9.3 Hz, 1H), 2.44 - 2.33 (m, 1H), 2.24 (br s, 2H), 2.16 (br s, 6H), 1.98 (qd, J=6.0, 11.8 Hz, 1H), 1.64 - 1.52 (m, 1H); LCMS [M+H]+: 590.4.

Example 279: N-[4-fluoro-5-[2-(4-methylpiperazin-l-yl)pyrimidin-5-yl]-2-[(3R)-3, 4-dimethylpiperazin-l-ylj 'phenyl]-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide


[00593] The title compound (light beige solid, 44.2 mg, 72%) was prepared by a procedure similar to Example 273 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l,6-ihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 2-(4-methylpiperazin-l-yl)pyrimidine-5-boronic acid pinacol ester (61 mg, 0.2 mmol). ¾ NMR (500MHz, METHANOL-d4) δ = 8.57 - 8.53 (m, 2H), 8.26 (s, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.11 (br d, J=10.9 Hz, 1H), 6.95 (s, 1H), 3.97 - 3.85 (m, 4H), 3.66 (s, 3H), 3.14 - 3.03 (m, 2H), 3.00 - 2.87 (m, 2H), 2.61 - 2.49 (m, 6H), 2.43 -2.34 (m, 7H), 1.13 (d, J=6A Hz, 3H); LCMS [M+ H]+ 603.4.

Example 280: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-ylJphenyl]-3-hydroxy-5-(trifluoromethyl)benzamide


[00594] To a 25 niL RBF was charged with 3-hydroxy-5- (trifluoromethyl)benzoic acid (41 mg, 0.2 mmol) was added thionyl chloride (0.364 mL, 5 mmol). The resulting suspension was heated at 80 °C for 1 h (very insoluble, tumed clear in about 15 min). The solvents were evaporated to give a light yellow oil which was treated with DCM (5 mL), 4-fluoro-5-(2-mo holinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and Et3N (42 μί, 0.3 mmol). The resulting dark brown suspension was stirred at rt for 30 min and purified by flash chromatography and prep-HPLC to give the title compound as a beige solid (formic acid salt, 2.6 mg, 4%). XH NMR (500MHz, METHANOL-d4) δ = 8.58 (s, 2H), 8.50 (br s, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.29 (s, 1H), 7.14 (d, J=11.9 Hz, 1H), 3.88 - 3.83 (m, 4H), 3.80 - 3.76 (m, 4H), 3.17 (br d, J=10.6 Hz, 2H), 2.83 - 2.71 (m, 4H), 2.53 (s, 3H), 1.24 (d, J=5.9 Hz, 6H); LCMS [M + H]+ 589.4.

Example 281 : N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-ylJphenylJ-3-hydroxybenzamide


[00595] To a solution of N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-3-methoxybenzamide (21.4 mg, 0.04 mmol) in DCM (1 mL) at 0 °C was added boron tribromide solution (1.0 M in methylene chloride, 0.2 mL, 0.2 mmol). The mixture was stirred at rt for 3 h, quenched with H20 (20 mL), sat. NaHC03 (15 mL) and extracted with DCM (30 mL x 2). The combined DCM extracts were concentrated and purified by prep-HPLC to give the title compound as off-white solid (6.6 mg, 31%). XH NMR (500MHz, METHANOL-d4) δ = 8.58 (s, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.16 (d, J=11.9 Hz, 1H), 7.06 (br d, J=7.7 Hz, 1H), 3.89 - 3.82 (m, 4H), 3.81 - 3.75 (m, 4H), 3.23 (br d, J=11.6 Hz, 2H), 3.00 (br s, 2H), 2.88 - 2.74 (m, 2H), 2.65 (s, 3H), 1.28 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 521.4.

Example 282: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-yl]phenyl]-3-hydroxyquinoline-4-carboxamide


[00596] A mixture of 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)- 3,4,5-trimethylpiperazin-l-yl)aniline (80 mg, 0.2 mmol), 3 -hydroxy quinoline-4-carboxylic acid (76 mg, 0.4mmol) and DCC (103 mg, 0.5 mmol) in DCM (6 mL) in a 30 mL vial was sealed and heated d at 45 °C for 18 h. It was loaded directly onto Biotage samplet and purified by flash chromatography (gradient: EtO Ac/hex 0-100% then MeOH/DCM 0-20%) to give the title compound as a dark yellow solid (85.6 mg, 74%). XH NMR (500MHz, METHANOL-d4) δ = 9.21 (br d, J=8.7 Hz, 1H), 8.63 (s, 2H), 8.56 (d, J=8.4 Hz, 1H), 8.53 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.07 (d, J= 12.0 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.81 - 3.76 (m, 4H), 3.44 - 3.35 (m, 2H), 3.31 - 3.25 (m, 2H), 2.79 - 2.68 (m, 5H), 1.28 (d, J=6.5 Hz, 6H); LCMS [M + H]+ 572.5.

Example 283: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3- (dimethylamino)pyrrolidin-l-yl]phenyl]-l-methyl-3-(Mfluorom


[00597] l-Methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (0.038 g,

0.194 mmol) was activated in DMF (1 ml) with HATU (0.074 g, 0.194 mmol) and N,N-diisopropylethylamine (0.034 ml, 0.194 mmol). The solution of activated acid was then added to a stirring solution of (R)-l-(2-armno-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (0.050 g, 0.129 mmol) in N,N-dimethylformamide (DMF) (1 ml) at room temperature. The reaction was warmed to 50 °C then heated at 60 °C overnight. Workup and purification using standard methods afforded the title compound (0.071 mmol, 55.0 % yield) as a tan solid. H NMR (500MHz, DMSO-d6) δ = 9.29 (s, 1H), 8.55 (d, J=0.7 Hz, 2H), 8.49 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.13 (d, J=12.2 Hz, 1H), 4.01 (s, 3H), 3.78 - 3.73 (m, 4H), 3.72 - 3.65 (m, 4H), 3.05 - 2.98 (m, 1H), 2.95 (br d, J=10.9 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.78 - 2.72 (m, 1H), 2.66 - 2.63 (m, 1H), 2.45 (br d, J=10.5 Hz, 1H), 2.37 (br d, J=1.6 Hz, 1H), 2.34 -2.27 (m, 1H), 2.25 - 2.16 (m, 4H), 0.96 (d, J=6.2 Hz, 3H); LCMS [M+H]+: 563.4.

Example 284: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-l-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide


[00598] l-Methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid (0.038 g,

0.194 mmol) was activated in DMF (1 mL) with HATU (0.074 g, 0.194 mmol) and N,N-diisopropylethylamine (0.034 ml, 0.194 mmol). The solution of activated acid was then added to a stirring solution of (S)-2-(3,4-dimethylpiperazin-l-yl)-4-fluoro-5-(2-mo holinopyrimidin-5-yl)aniline (0.050 g, 0.129 mmol) in DMF (1 ml) at room temperature. The reaction was warmed to 50 °C and monitored by LCMS [230 pm -start heating]. After heating at 60 °C overnight, workup and purification afforded the title compound (27 mg, 37% yield). ¾i NMR (500MHz, DMSO-d6) δ = 9.72 (s, IH), 8.51 (s, 2H), 8.47 (s, IH), 7.21 (d, J=8.8 Hz, IH), 6.67 (d, J=13.8 Hz, IH), 3.99 (s, 3H), 3.75 - 3.72 (m, 4H), 3.70 - 3.66 (m, 4H), 3.40 - 3.35 (m, 3H), 3.21 (t, J=8.8 Hz, IH), 2.11 (s, 6H), 2.09 - 2.03 (m, IH), 1.68 (quin, J=10.0 Hz, IH); LCMS [M+H]+: 563.5.

Example 285: N-[5-[ l-(dimethylcarbamoyl)-3, 6-dihydro-2H-pyridin-4-yl]-4-fluoro-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00599] The procedure used was similar to that of Example 253 using N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.049 mmol) and dimethylcarbamoyl chloride (4.76 μΐ, 0.052 mmol) to give after workup and purification the title compound (24 mg, 75% yield). H NMR (500MHz, METHANOL-d4) δ = 7.99 - 7.90 (m, IH), 7.82 - 7.73 (m, IH), 6.99 - 6.94 (m, IH), 6.93 - 6.90 (m, IH), 6.06 - 5.97 (m, IH), 4.01 - 3.92 (m, 2H), 3.50 - 3.46 (m, 2H), 3.06 - 2.99 (m, 2H), 2.93 - 2.87 (m, 6H), 2.65 - 2.52 (m, 6H), 2.43 - 2.36 (m, 3H), 1.21 - 1.15 (m, 6H); LCMS [M+H]+ 579.3.

Example 286: N-[4-fluoro-5-[ 1 -(pyrrolidine-1 -carbonyl)-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R, 5SJ-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00600] The procedure was similar to Example 253 using N-(4-fluoro-5- (l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.049 mmol) and 1-pyrrolidinecarbonyl chloride (5.71 μΐ, 0.052 mmol) to give, after workup and purification, the title compound (19 mg, 61% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.98 - 7.91 (m, 1H), 7.84 - 7.73 (m, 1H), 6.98 - 6.93 (m, 1H), 6.93 - 6.91 (m, 1H), 6.06 - 5.97 (m, 1H), 4.04 - 3.96 (m, 2H), 3.57 - 3.50 (m, 2H), 3.46 - 3.41 (m, 4H), 3.09 - 2.96 (m, 2H), 2.63 - 2.50 (m, 6H), 2.43 - 2.35 (m, 3H), 1.93 - 1.85 (m, 4H), 1.19 - 1.15 (m, 6H); LCMS [M+H]+ 605.4.

Example 287: N-[4-fluoro-5-[l-(4-methylpiperazine-l-carbonyl)-3, 6-dihydro-2H-pyridin-4-yl] -2-[(3R, 5S)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide


[00601] The procedure employed was similar to that of Example 253 using N- (4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l- yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.049 mmol) and 4-methyl-l-piperazinecarbonyl chloride hydrochloride (10.30 mg, 0.052 mmol) to give, after workup and purification, the title compound as a white powder (24 mg, 73% yield). XH NMR (500MHz, METHANOL-d4) δ = 7.98 - 7.90 (m, 1H), 7.83 - 7.72 (m, 1H), 6.99 - 6.93 (m, 1H), 6.93 - 6.91 (m, 1H), 6.04 - 5.97 (m, 1H), 4.03 - 3.97 (m, 2H), 3.54 - 3.49 (m, 2H), 3.38 - 3.35 (m, 4H), 3.06 - 2.99 (m, 2H), 2.64 - 2.53 (m, 6H), 2.53 - 2.47 (m, 4H), 2.41 - 2.37 (m, 3H), 2.37 - 2.33 (m, 3H), 1.17 (d, J=5.9 Hz, 6H); LCMS [M+H]+ 634.7.

Example 288: phenyl 4-[2-fluoro-5-[[6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carbonyl]amino]-4-[(3R,5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-3, 6-dihydro-2H-pyridine-l-carboxylate


[00602] The procedure was similar to that of Example 253 using N-(4-fluoro-5- (l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (25 mg, 0.049 mmol) and phenyl chloroformate (6.51 μΐ, 0.052 mmol) to give, after standard workup and purification, the title compound (23 mg, 71 % yield). H NMR (500 MHz, METHANOL-d4) δ = 7.99 - 7.93 (m, 1H), 7.86 - 7.78 (m, 1H), 7.45 - 7.37 (m, 2H), 7.29 - 7.22 (m, 1H), 7.21 - 7.11 (m, 2H), 7.03 - 6.95 (m, 1H), 6.95 - 6.90 (m, 1H), 6.12 - 6.03 (m, 1H), 4.45 - 4.17 (m, 2H), 3.98 - 3.74 (m, 2H), 3.08 - 3.01 (m, 2H), 2.71 - 2.52 (m, 6H), 2.43 - 2.36 (m, 3H), 1.21 - 1.16 (m, 6H); LCMS [M+H]+ 628.3.

Example 289: N-[4-fluoro-5-[l-[(2R, 6S)-2, 6-dimethyloxan-4-yl]-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3S, 5R)-3, 4, 5 -trimethylpiperazin-l-yl] phenyl] -6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide

[00603] The procedure followed was similar to that of Example 148 using N- (4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (30 mg, 0.059 mmol) and cis-2,6-dimethyloxan-4-one (15.15 mg, 0.118 mmol) to give, after workup and purification, the title compound (16 mg, 40% yield). H NMR (500MHz, METHANOLS) δ = 8.02 - 7.94 (m, 1H), 7.91 - 7.82 (m, 1H), 7.15 - 7.04 (m, 1H), 6.99 - 6.91 (m, 1H), 6.15 - 6.03 (m, 1H), 3.98 - 3.87 (m, 2H), 3.66 - 3.46 (m, 4H), 3.27 - 3.16 (m, 4H), 2.88 - 2.88 (m, 1H), 2.92 - 2.81 (m, 3H), 2.80 - 2.66 (m, 4H), 2.22 - 2.11 (m, 2H), 1.42 - 1.33 (m, 8H), 1.30 - 1.19 (m, 6H); LCMS [M+H]+ 620.6

Example 290: N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl) -2-[( 3R, 5S) -3, 4, 5-trimethylpiperazin-l-ylJphenyl]-4-hydroxy-2-(trifluoromethyl)benzamide


[00604] A mixture of 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)- 3,4,5-trimethylpiperazin-l-yl)aniline (80 mg, 0.2 mmol), 4-hydroxy-2-(trifluoromethyl)benzoic acid (82 mg, 0.4mmol) and DCC (103 mg, 0.5 mmol) in DCM (5 mL) in a 30 mL vial was sealed and heated d at 45 °C for 18 h. It was purified by flash chromatography and prep-HPLC to give the title compound as a beige solid (TFA salt, 23.9 mg, 17%). XH NMR (500MHz, METHANOL-d4) δ = 8.56 (s, 2H), 8.32 (br s, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.59 (br d, J=8.4 Hz, 1H), 7.23 - 7.18 (m, 2H), 7.14 (br d, J=8.3 Hz, 1H), 3.87 - 3.82 (m, 4H), 3.80 - 3.74 (m, 4H), 3.57 -3.43 (m, 2H), 3.33 - 3.28 (m, 2H), 3.01 (br t, J=12.1 Hz, 2H), 2.93 (s, 3H), 1.43 (d, J=6.4 Hz, 6H); LCMS [M + H]+ 589.4.

Example 291: 2, 3-difluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-yl]phenyl]-5-hydroxybenzamide


[00605] A mixture of 4-fluoro-5-(2-mo holino yrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (80 mg, 0.2 mmol), 2,3-difiuoro-5-hydroxybenzoic acid (70 mg, 0.4mmol) and DCC (103 mg, 0.5 mmol) in DCM (5 mL) in a 30 mL vial was sealed and heated at 45 °C ovemight (18 h). It was purified by flash chromatography and prep-HPLC to give the title compound as a light purple solid (TFA salt, 15.7 mg, 12%). ¾ NMR (500MHz, METHANOL-d4) δ = 8.59 (s, 2H), 8.31 (d, J=8.3 Hz, 1H), 7.36 (q, J=9.5 Hz, 1H), 7.25 (br d, J=11.6 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.82 - 3.75 (m, 4H), 3.58 - 3.43 (m, 2H), 3.39 (br d, J=12.8 Hz, 2H), 3.02 - 2.90 (m, 5H), 1.45 (d, J=6.5 Hz, 6H); LCMS [M+ H]+ 557.3.

Example 292: N-[5-[2-(cyclobutylmethoxy)pyridin-4-yl]-4-fluoro-2-[(3R,5S)-3,4,5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-carb


[00606] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-(cyclobutylmethoxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (33.7 mg, 0.116 mmol), N-(5-bromo-4-iluoro-2-((3 S,5R)-3,4,5 -trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide (47 mg, 0.078 mmol) to give the title compound (34.6 mg, 76% yield). ¾ NMR (500MHz, DMSO-d6) δ = 9.59 (s, IH), 8.21 (d, J=5.3 Hz, IH), 7.93 (s, IH), 7.82 (d, J=8.4 Hz, IH), 7.11 (d, J=5.4 Hz, IH), 7.03 (d, J=12.8 Hz, IH), 6.88 (s, IH), 6.81 (s, IH), 4.27 (d, J=6.8 Hz, 2H), 3.09 (br d, J=10.9 Hz, 2H), 2.70 -2.68 (m, IH), 2.73 (td, J=7.4, 14.7 Hz, IH), 2.36 (br s, 2H), 2.20 (br s, 3H), 2.12 - 2.01 (m, 2H), 1.97 - 1.74 (m, 4H), 1.01 (br d, J=5.9 Hz, 6H); LCMS [M+H]+: 588.6.

Example 293: N-[5-[2-(2, 2-dimethylpropoxy)pyridin-4-yl]-4-fluoro-2-[(3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyr


[00607] The title compound was prepared by a procedure similar to the sequence described for Example 100 using 2-(neopentyloxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (36.1 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2- ((3S,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy Nicotinamide (50 mg, 0.083 mmol) to give the title compound

(21.1 mg, 43% yield). XH NMR (500MHz, DMSO-d6) δ = 9.59 (s, IH), 8.20 (d, J=5.4

Hz, IH), 7.94 (s, IH), 7.82 (d, J=8.4 Hz, IH), 7.11 (br d, J=5.4 Hz, IH), 7.04 (d, J=12.8 Hz, IH), 6.89 (s, IH), 6.81 (s, IH), 3.99 (s, 2H), 3.09 (br d, J=10.9 Hz, 2H), 2.48 (br s, IH), 2.36 (br d, J=1.7 Hz, 2H), 2.20 (br s, 3H), 1.01 (br s, 6H), 1.00 (s, 9H); LCMS [M+H]+: 590.6.

Example 294: N-[5-[2-(diethylamino)pyrimidin-5-yl]-4-fluoro-2-[( 3R, 5S)-3, 4, 5-Mmethylpiperazin-l-yl]phenyl]-6 >xo-4-(Mfluoromethyl)-lH-pyridine-3-car^


[00608] The title compound was prepared similar to the sequence described above for the preparation of Example 100 using 2-diethylaminopyrirnidine-5-boronic acid, pinacol ester (34.3 mg, 0.124 mmol) and N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin- 1 -yl)phenyl)-4-(mfluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (50 mg, 0.083 mmol) to give the title compound (33.5 mg, 71% yield). ¾ NMR (500MHz, DMSO-d6) δ = 9.52 (s, IH), 8.46 (s, 2H), 7.90 (s, IH), 7.73 (d, J=8.7 Hz, IH), 7.03 (d, J=12.2 Hz, IH), 6.81 (s, IH), 3.62 (q, J=7.0 Hz, 4H), 3.01 (br d, J=11.0 Hz, 2H), 2.46 (br t, J=11.0 Hz, 2H), 2.35 (br d, J=6.1 Hz, 2H), 2.19 (s, 3H), 1.14 (t, J=7.0 Hz, 6H), 1.00 (d, J=6.1 Hz, 6H); LCMS [M+H]+: 576.6.

Example 295: 3-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3, 4,5-trimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide

[00609] The title compound (beige solid, 49.3 mg, 82%) was prepared by a procedure similar to that of Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) in DCM (3 mL) and 3-fluoro-2-(trifluoromethyl)benzoyl chloride (23 μί, 0.15 mmol). 'H NMR (500MHz, CHLOROFORM-d) δ = 8.58 (s, 2H), 8.51 (d, J=8.2 Hz, 1H), 8.42 (s, 1H), 7.67 (dt, J=5.0, 7.9 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.00 (d, J=11.2 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.83 - 3.78 (m, 4H), 2.85 (br d, J=l l . l Hz, 2H), 2.62 (br t, J=10.8 Hz, 2H), 2.32 - 2.18 (m, 5H), 1.12 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 591.5.

Example 296: 3, 4, 5-trifluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-f(3R, 5S)-3, 4, 5-trimethylpiperazin-l-ylJphenylJbenzamide


[00610] The title compound (tan solid, 38.3 mg, 67%) was prepared by a procedure similar to that of Example 34 using 3,4,5-trifluorobenzoic acid (35 mg, 0.2 mmol) and 4-fluoro-5-(2-moφholinopyrimidin-5-yl)-2-((3S

(40 mg, 0.1 mmol). ¾ NMR (500MHz, CHLOROFORM-d) δ = 9.20 (s, 1H), 8.60 - 8.54 (m, 3H), 7.56 (t, J=7.0 Hz, 2H), 7.03 (d, J=l l. l Hz, 1H), 3.91 - 3.84 (m, 4H), 3.84 - 3.77 (m, 4H), 2.87 (br d, J=11.0 Hz, 2H), 2.70 (t, J=10.9 Hz, 2H), 2.47 - 2.36 (m, 5H), 1.17 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 559.5.

Example 297: 2-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R, 5S)-3,4,5-trimethylpiperazin-l-yl]phenyl]-6-(trifluoromethyl)benzamide


[00611] The title compound (off-white solid, 43.0 mg, 72%) was prepared by a procedure similar to Example 34 using 4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-l-yl)aniline (40 mg, 0.1 mmol) and 2-fluoro-6-(trifiuoromethyl)benzoyl chloride (23 μί, 0.15 mmol). H NMR (500MHz, CHLOROFORM-d) δ = 8.58 (s, 2H), 8.50 (d, J=8.2 Hz, 1H), 8.44 (s, 1H), 7.63 - 7.57 (m, 2H), 7.46 - 7.40 (m, 1H), 6.98 (d, J=11.4 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.82 - 3.77 (m, 4H), 2.90 (br d, J=l l. l Hz, 2H), 2.61 (br t, J=10.8 Hz, 2H), 2.33 - 2.23 (m, 5H), 1.12 (d, J=6.2 Hz, 6H); LCMS [M + H]+ 591.5.

Example 298: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide


[00612] The title compound (formic acid salt, pale beige solid, 34.8 mg, 56%) was prepared by a procedure similar to that of Example 29 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (51 mg, 0.104 mmol) and 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (58 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.58 (s, 2H), 8.36 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.83 (dd, J=5.4, 8.4 Hz, 1H), 7.67 (dd, J=2.0, 9.0 Hz, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.20 (d, J=11.9 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.80 - 3.76 (m, 4H), 3.48 - 3.39 (m, 1H), 3.31 - 3.24 (m, 2H), 3.21 - 3.07 (m, 3H), 2.93 - 2.84 (m, 1H), 2.83 - 2.77 (m, 3H), 1.38 - 1.32 (m, 3H); LCMS [M + H]+ 577.5.

Example 299: 4-fluoro-N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R)-3, 4-dimethylpiperazin-l-yl]phenyl]-2-(trifluoromethyl)benzamide


[00613] The title compound (formic acid salt, pale beige solid, 34.8 mg, 56%) was prepared through a procedure similar to Example 31 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (51 mg, 0.104 mmol) and 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (58 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.58 (s, 2H), 8.36 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.83 (dd, J=5.4, 8.4 Hz, 1H), 7.67 (dd, J=2.0, 9.0 Hz, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.20 (d, J=11.9 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.80 - 3.76 (m, 4H), 3.48 - 3.39 (m, 1H), 3.31 - 3.24 (m, 2H), 3.21 - 3.07 (m, 3H), 2.93 - 2.84 (m, 1H), 2.83 - 2.77 (m, 3H), 1.38 - 1.32 (m, 3H); LCMS [M + H]+ 577.5.

Example 300: 3, 5-dichloro-N-[4-fluoro-2-[3-(methylamino)pyrrolidin-l-yl]-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]benzamide


Step 1: tert-butyl (l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate

[00614] A mixture of tert-butyl (l-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (1.8598 g, 3.70 mmol, prepared as shown hereinabove in Example 277) and tin(II) chloride, 98% (2.105 g, 11.10 mmol) in a mixture of ethanol (EtOH) (10 ml) and methanol (MeOH) (10 ml) was heated to 90 °C. for 3 hours. Then the reaction mixture was concentrated onto celite and purified by flash chromatography [0-30% MeOH/DCM] to afford the tert-butyl (l-(2-amino-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (0.94 g, 1.990 mmol, 53.8 % yield) as a yellow powder. LCMS [M+H]+ 473.2.

Step 2: tert-butyl (l-(2-(3,5-dichlorobenzamido)-5-fluoro-4-(2-morpholinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate


[00615] To a solution of tert-butyl (l-(2-amino-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (211 mg, 0.446 mmol) and triethylamine (0.187 ml, 1.339 mmol) in DCM (40 ml) was added 3,5-dichlorobenzoyl chloride (94 mg, 0.446 mmol). Then the reaction mixture was stirred at room temperature for 2 hours. Then the crude material was dry loaded and purified by Flash chromatography [0-10% DCM/MeOH] to afford the desired tert-butyl (l-(2-(3,5-dichlorobenzamido)-5-fluoro-4-(2-mo holinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (288 mg, 0.424 mmol, 95 % yield) as a yellow solid. H

NMR (500 MHz, DMSO-d6) δ = 10.16 (s, IH), 8.52 (s, 2H), 7.95-8.02 (m, 2H), 7.88 (s, IH), 7.34 (d, J=8.80 Hz, IH), 6.72 (d, J=13.94 Hz, IH), 5.75 (s, IH), 4.55 (br. s., IH), 3.71-3.75 (m, 5H), 3.65-3.68 (m, 4H), 3.35-3.41 (m, 2H), 3.25-3.30 (m, 2H), 2.69 (s, 3H), 1.92-2.07 (m, 2H), 1.35 (s, 9H); LCMS [M+H]+ 645.2.

Step 3: 3, 5-dichloro-N-(4-fluoro-2-(3-(methylamino)pyrrolidin-l-yl)-5-(2-morpholinopyrimidin-5-yl)phenyl)benzamide, 2Trifluoroacetic Acid, 2CF3COOH


[00616] To a solution of tert-butyl (l-(2-(3,5-dichlorobenzamido)-5-fluoro-4- (2-morpholinopyrimidin-5-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate (288 mg, 0.446 mmol) in DCM (3 mL) was added trifluoroacetic acid (2 ml, 26.1 mmol). The reaction mixture was stirred at 24 °C for 1 hour. Then the TFA and solvent were removed under vacuum and the crude material was purified by flash chromatography [0-20% DCM/MeOH] to afford the 3,5-dichloro-N-(4-fluoro-2-(3-(methylamino)pyrrolidin-l-yl)-5-(2-mo holinopyrimidin-5-yl)phenyl)benzamide (TFA salt), (77.4 mg, 0.095 mmol, 21.31 % yield) as a light brown powder. XH NMR (500MHz, DMSO-d6) δ = 10.18 (s, IH), 8.73 (br. s., 2H), 8.53 (s, 2H), 7.97-8.04 (m, 2H), 7.89 (s, IH), 7.39 (d, J=8.80 Hz, IH), 6.76 (d, J=13.82 Hz, IH), 3.78 (d, J=5.38 Hz, IH), 3.71-3.75 (m, 4H), 3.65-3.69 (m, 4H), 3.62 (dd, J=6.85, 10.76 Hz, IH), 3.43-3.49 (m, 2H), 3.39 (dd, J=5.07, 10.70 Hz, 2H), 3.31-3.37 (m, 2H), 3.17 (s, 2H), 2.58 (br. s., 3H), 2.22-2.31 (m, IH), 1.98-2.07 (m, 1H);LCMS [M+H]+ 545.3.

Example 301: N-[4-fluoro-5-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-2-[(3R)-3, 4-dimethylpiperazin-l-ylj 'phenyl] '-l-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide

[00617] The title compound (white solid, 36.9 mg, 61%) was prepared by a procedure similar to Example 273 using (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4-fluorophenyl)-l-methyl-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol) and 2-(4-methylpiperazin-l-yl)pyridine-5-boronic acid, pinacol ester (61 mg, 0.2 mmol). XH NMR (500MHz, METHANOL-d4) δ = 8.27 (s, IH), 8.17 (d, J=5.3 Hz, IH), 7.95 (d, J=7.9 Hz, IH), 7.10 (d, J=12.1 Hz, IH), 6.99 (s