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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/08—Bridged systems

Definitions

• the present application relates to compounds, to processes for their preparation, to compositions comprising them and their use for the treatment of diseases and conditions related to interactions between WDR5 and its binding partners including, but not limited to, MLL.
• Histones are 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.
• MLL Mixed Lineage Leukemia 1
• H3K4 Histone H3 Lysine 4
• 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).
• WDR5 WD repeat domain 5 protein
• ASH2L Absent, Small, or Homeotic-2-Like
• RbBP5 Retinoblastoma Binding Protein 5
• blocking the MLL1-WDR5 protein-protein interaction can specifically inhibit the activity of MLL1 H3K4 methyltransf erase activity and such inhibition has the potential for the treatment of human diseases, such as, a subset of acute leukemia, whose development and progression depend upon MLL1 activity.
• WDR5 is a common subunit of all six mammalian histone H3K4 methyltransferases [Dev. Biol., 2010,339 (2):240-249]. WDR5 has 334 amino acids and contains seven typical WD40 repeat domains, each approximately 40 amino acids [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 peptide [Nat. Struct. Mol. Biol, 2009, 16 (7):678-680].
• 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.
• VISA virus-induced signaling adapter
• 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].
• AML adult acute myeloid leukemia
• MLL1 is the human homologue of Saccharomyces cerevisiae gene
• the genes encode an enzyme to catalyze the methylation of H3K4 [Nat. Rev. Cancer., 2007, 7(l l):823-833]. Trimethylation of histone 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(l l):823-833].
• cDNA of the MLL1 gene contains -12 kb nucleotides and encodes a peptide over 4000 amino acids in length.
• 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.
• 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].
• 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 has 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.
• WRAD2 core complex
• MLL/SET1 members to bind WRAD2 for full activity is the basis of a particular drug development strategy, which seeks to disrupt the interaction 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 interaction 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].
• MLL1 -WDR5 peptidic inhibitors exhibit poor cell-based activity and lack oral bioavailability due to poor cell-permeability and their susceptibility to peptidases.
• WDR5 also plays a critical role in embryonic stem cell self-renewal
• 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.
• 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.
• 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.
• 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
• 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.
• WDR5 is believed to play an essential role in cancer stem cells
• 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. U SA., 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.
• Nanog plays a key 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 vital role in self-renewal of bladder cancer cells by regulating Nanog.
• WDR5 silencing increased cell apoptosis and decreases 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.
• 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.].
• AML Acute Myeloid Leukemia
• CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML).
• AML acute myeloid leukemia
• C/EBPa p30 CCAAT-enhancer binding protein-a
• WDR5 SET-domain/mixed-lineage leukemia histone- methyltransferase complexes.
• p30-bound genomic regions were 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 the WDR5-MLL interaction selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells revealing the mechanism of p30-dependent transformation and establish the essential p30 cofactor WDR5 as a therapeutic target in CEBPA-mutant AML [Nat Chem Biol. 2015 ;11(8): 571-8].
• MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease.
• trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict 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 [Cancer Res 2015; 75(23); 5143- 54]. For this reason, in this study, the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells were investigated. N-Myc upregulated WDR5 expression in neuroblastoma cells.
• WDR5 target genes included those with MYC- binding elements at promoters such as MDM2.
• WDR5 was demonstrated 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.
• RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis.
• a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells.
• 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 key 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, Mo/ Cell. 2015;58(3):440-52.].
• MLL binding is a desirable drug target.
• agents that bind to the WDR5 protein and compete for binding with WDR5 -interacting partners can reverse the transcriptional activities of WDR5 containing complexes.
• complementary screening approaches namely 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.
• structure-activity relationship studies demonstrated that specific chemical features contribute to longer residence times for the binding of these compounds with WDR5.
• 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.
• the present application includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:
• R 1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C3-iocycloalkyl, OR 4 , SR 4 , NR 5 R 6 , Ci-galkyleneOR 4 , Ci -6 alkyleneSR 4 and Ci -6 alkyleneNR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom;
• R 4 and R 7 are independently selected from H, Ci -6 alkyl, Ci -6 fiuoroalkyl, C(0)Ci. 6 alkyl and C(0)Ci- 6 fiuoroalkyl;
• R 5 and R 6 are independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, heterocycloalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C(0)OCi -6 alkyl, C(0)NHCi_ 6 alkyl, S0 2 Ci -6 alkyl, S0 2 HNCi -6 alkyl, Ci-ealkyleneOCi-ealkyl, Ci -6 alkyleneNHCi.
• R 8 and R 9 are independently selected from H, Ci -6 alkyl, Ci -6 fiuoroalkyl, C(0)Ci. 6 alkyl and C(0)Ci- 6 fluoroalkyl, or R 8 and R 9 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- 6 alkyl OCi- 6 alkyl, Ci- 6 fluoroalkyl and OCi- 6 fluoroalkyl;
• X 1 , X 2 , X 3 and X 4 are each independently selected from CR 10 and N;
• X 5 , X 6 and X 7 are each independently selected from CH and N;
• R 10 is selected from H, halo, CN, Ci -6 alkyl, Ci -6 fluoroalkyl, OR 11 , SR. 11 , NR 12 R 13 , R 14 , Ci -6 alkyleneR 14 , OCi -6 alkyleneR 14 , SCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 , Ci. salkyleneOR 11 , Ci-galkyleneSR 11 , OCi -6 alkyleneNR 12 R 13 , SCi -6 alkyleneNR 12 R 13 , OCi.
• R 11 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 11 is other than H, it is unsubstituted or substituted with one or more substituents selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3-
• R 12 and R 13 are each independently selected from H, Ci.i 0 alkyl, Ci.iofluoroalkyl, C(0)Ci- 6 alkyl, C(0)Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, Ce- l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 12 and R 13 are other than H they are each independently unsubstituted or substituted with one or more substituents selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci- 6 alkyl, S02Ci- 6 alkyl, C6-io
• R 12 and R 13 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, OR 15 , SR 15 , NR 16 R 17 , C 1-6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 15 , Ci_ salkyleneOR 15 , Ci -6 alkyleneSR 15 and Ci -6 alkyleneNR 16 R 17 ;
• R 14 is selected from C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -i 0 cycloalkyl, heterocycloalkyl, heteroaryl and C 6 -ioaryl, and when R 14 is other than H it is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci-galkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci.
• R 15 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl and Ci- 6 alkyleneheterocycloalkyl, and when R 15 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, Ci_ salkyl, CN, Ci -6 fluoroalkyl, OH, SH, OCi -6 alkyl, OCi -6 fluoroalkyl, SCi -6 alkyl, SCi.
• efluoroalkyl NH 2 , NHCi -6 alkyl, N(Ci -6 alkyl)(Ci -6 alkyl), C(0)Ci -6 alkyl, C(0)d. sfluoroalkyl, C(0)OH, C(0)OCi -6 alkyl, C(0)NH 2 , C(0)NHCi -6 alkyl, C(0)N(d.
• Ci- 6 alkyl (Ci- 6 alkyl), S0 2 Ci- 6 alkyl, S(0)Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci_ 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci -6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci -6 alkyleneNH 2 , Ci- 6 alkyleneNHCi- 6 alkyl and Ci-ealkyleneNi i-ealkylXCi-ealkyl);
• R 16 and R 17 are each independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C(0)Ci- 6 alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci_ 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl and when R 16 and R 17 are other than H they are each unsubstituted or substituted with one or more substituents independently selected from halo, CN, Ci- 6 alkyl, Ci- 6 fluoroalkyl, OH, SH, OCi- 6 alkyl, OCi-gfluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci.
• Ci -6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl), or
• R 16 and R 17 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- 6 alkyl, Ci- 6 fiuoroalkyl, OH, SH, OCi- 6 alkyl, OCi-gfluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci. 6 alkyl)(Ci.
• Ci -6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl); A is fluoro; and all alkyl and alkylene groups are optionally fluorosubstituted.
• the present application includes a composition comprising one or more compounds of the application and a carrier.
• 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 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.
• the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners is cancer.
• FIG. 1 illustrates WDR5 as an adaptor protein in multiple complexes and related biological processes.
• 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 Formula la, lb, Ic, Id and Ie, and pharmaceutically acceptable salts and/or solvates thereof.
• 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, Id and/or Ie, or pharmaceutically acceptable salts and/or solvates thereof.
• 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.
• suitable 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.
• 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. [0037] 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.
• 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.
• 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.
• basic nitrogen refers to a nitrogen atom that has a lone pair of electrons available to participate in an interaction with a hydrogen atom.
• the interaction is a hydrogen bond, an ionic bond or a covalent bond.
• the basic nitrogen atom will be either a primary, secondary or tertiary alkyl amine nitrogen atom, either in a linear, branched or cyclic group.
• the pKa of the conjugate acid of the basic nitrogen atom will be greater than about 8-10.
• 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 "C n i -n2 ".
• Ci-ioalkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
• 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 "C n i -n2 "-
• C 2-6 alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.
• 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 "C n i -n2 ".
• C 2 - 6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.
• fluoroalkyl refers to an alkyl group wherein one or more, including all of the hydrogen atoms are replaced by a halogen atom.
• the halogen is fluorine.
• the haloalkyl comprises at least one -CHF 2 group.
• the haloalkyl comprises at least one -CF 3 group.
• fluorosubstituted refers to a chemical group wherein one or more, including all of the hydrogen atoms, are replaced by a fluorine atom.
• 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 "C n i- n2 " ⁇
• C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
• 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.
• heterocycloalkyl 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), S0 2 , N, NH and NC 1-6 alkyl, suitably O, S, N, NH and NCi- 6 alkyl.
• 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).
• heterocycloalkyl group When a heterocycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.
• a heterocycloalkyl group contains the prefix C n i- 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.
• Heterocycloalkyl includes, monocyclic heterocycloalkyls such as but not limited to 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-
• heterocycloalkyl includes polycyclic heterocycloalkyls such as but not limited to pyrolizidinyl and quinolizidinyl.
• heterocycloalkyl includes polycyclic heterocycloalkyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include but are not limited to quinuclidinyl, diazabicyclo[2.2.1]heptyl and 7-oxabicyclo[2.2.1]heptyl.
• 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.
• heteroaryl 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), S0 2 , N, NH and NCi -6 alkyl, suitably O, S, N, NH and NCi- 6 alkyl.
• 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.
• heteroaryl group contains the prefix C n i-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.
• available refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.
• 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.
• 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- 6 alkyl.
• atmosphere refers to atmosphere
• MS mass spectrometry
• DCM as used herein refers to dichloromethane.
• DIPEA as used herein refers to ⁇ , ⁇ -diisopropyl ethylamine
• DMF as used herein refers to dimethylformamide.
• DMSO as used herein refers to dimethylsulfoxide.
• EtOAc refers to ethyl acetate.
• HATU refers to l-[Bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate.
• MeOH as used herein refers to methanol.
• MeCN as used herein refers to acetonitrile.
• HC1 as used herein refers to hydrochloric acid.
• TFA as used herein refers to trifluoroacetic acid.
• TBAF as used herein refers to tetra-n-butyl ammonium fluoride.
• CsF as used herein is cesium fluoride.
• ⁇ -wave as used herein refers to a microwave reaction vessel.
• SnAr as used herein represents nucleophilic aromatic substitution.
• LCMS as used herein refers to liquid chromatography-mass spectrometry.
• protecting group 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.
• PG protecting group
• 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.
• 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. [0076] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.
• 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.
• 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.
• 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.
• 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.
• the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form.
• 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.
• 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.
• 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.
• solvate 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”.
• 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.
• treating 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.
• a subject with early cancer can be treated to prevent progression, or alternatively 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 alternatively comprise a series of administrations.
• the compounds of the application are administered at least once a week.
• the compounds are administered to the subject from about one time per two weeks, three weeks or one month.
• the compounds are administered about one time per week to about once daily.
• 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.
• "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.
• 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.
• 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 MLL1, and in particular using a WDR5 protein inhibitor, such as a compound of the application herein described.
• 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 MLL1.
• Such biological basis includes, for example, WDR5 and/or MLL1 gene overexpression or WDR5 and/or MLL1 protein over-accumulation or over-expression of proteins that are products of or precursors to WDR5-mediated and/or MLL1 gene expression.
• 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.
• 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.
• MLL1 refers to the protein identified as GenBank Accession number NM_005933 [Proc. Natl.
• binding refers to any interaction between two entities, such as two proteins, that leads to a functional effect.
• an 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.
• an effective amount is an amount that, for example, increases said inhibition compared to the inhibition without administration of the one or more compounds.
• effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject.
• 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.
• administered means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell, tissue, organ or subject.
• Neoplasm 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).
• 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.
• carcinoma e.g., 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 e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders
• metastatic tumors e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders
• metastatic tumors e
• the present application includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:
• R 1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C 3 -iocycloalkyl, OR 4 , SR 4 , NR 5 R 6 , Ci-galkyleneOR 4 , Ci -6 alkyleneSR 4 and Ci -6 alkyleneNR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom;
• R 4 and R 7 are independently selected from H, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C(0)Ci_ 6 alkyl and C(0)Ci- 6 fiuoroalkyl;
• R 5 and R 6 are independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, heterocycloalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C(0)OCi -6 alkyl, C(0)NHCi_
• Ci- 6 alkyl Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl), Ci- 6 alkyleneC 6 -ioaryl, Ci_
• R 5 and R 6 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- 6 alkyl, OCi- 6 alkyl, Ci- 6 fiuoroalkyl, OCi- efluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci- 6 fluoroalkyl, C(0)OCi -6 alkyl, C(0)NHCi -6 alkyl, S0 2 Ci -6 alkyl, S0 2 HNCi -6 alkyl, Ci -6 alkyleneOCi -6 alkyl, Ci -6 alkyleneNHCi -6 alkyl, Ci.
• R 8 and R 9 are independently selected from H, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C(0)Ci_ 6 alkyl and C(0)Ci -6 fluoroalkyl, or R 8 and R 9 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- 6 alkyl OCi- 6 alkyl, Ci- 6 fluoroalkyl and OCi- 6 fluoroalkyl;
• X 1 , X 2 , X 3 and X 4 are each independently selected from CR 10 and N;
• X 5 , X 6 and X 7 are each independently selected from CH and N;
• R 10 is selected from H, halo, CN, Ci -6 alkyl, Ci -6 fluoroalkyl, OR 11 , SR. 11 , NR 12 R 13 , R 14 , Ci -6 alkyleneR 14 , OCi -6 alkyleneR 14 , SCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 , Ci. salkyleneOR 11 , Ci-galkyleneSR 11 , OCi -6 alkyleneNR 12 R 13 , SCi -6 alkyleneNR 12 R 13 , OCi.
• R 11 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 11 is other than H, it is unsubstituted or substituted with one or more substituents selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3-
• R 12 and R 13 are each independently unsubstituted or substituted with one or more substituents selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci- 6 alkyl, S02Ci- 6 alkyl, C6-ioaryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci -6 alkyleneC 6 -ioaryl, Ci.
• R 12 and R 13 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, OR 15 , SR 15 , NR 16 R 17 , C 1-6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 15 , Ci_ salkyleneOR 15 , Ci -6 alkyleneSR 15 and Ci -6 alkyleneNR 16 R 17 ;
• R 14 is selected from C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -i 0 cycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and when R 14 is other than H it is unsubstituted or substituted with one or more substituents independently selected from halo, CN, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci.
• R 15 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl and Ci- 6 alkyleneheterocycloalkyl, and when R 15 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, Ci_ salkyl, CN, Ci -6 fluoroalkyl, OH, SH, OCi -6 alkyl, OCi -6 fluoroalkyl, SCi -6 alkyl, SCi.
• efluoroalkyl NH 2 , NHCi -6 alkyl, N(Ci -6 alkyl)(Ci -6 alkyl), C(0)Ci -6 alkyl, C(0)d. sfluoroalkyl, C(0)OH, C(0)OCi -6 alkyl, C(0)NH 2 , C(0)NHCi -6 alkyl, C(0)N(d. 6 alkyl)(Ci- 6 alkyl), S0 2 Ci- 6 alkyl, S(0)Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci -6 alkyleneC 6 -ioaryl, Ci.
• R 16 and R 17 are each independently selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci- 6 alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci_ 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl and when R 16 and R 17 are other than H they are each unsubstituted or substituted with one or more substituents independently selected from halo, CN, Ci- 6 alkyl, Ci- 6 fluoroalkyl, OH, SH, OCi- 6 alkyl, OCi-gfluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci.
• Ci- 6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl), or
• R 16 and R 17 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 -6 alkyl, Ci -6 fiuoroalkyl, OH, SH, OCi -6 alkyl, OCi-gfluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci. 6 alkyl)(Ci.
• Ci -6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3 -iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl);
• A is fluoro; and all alkyl and alkylene groups are optionally fluorosubstituted.
• the present application also includes a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:
• R 1 is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, C 1-6 alkyl, C 1-6 fluoroalkyl, OR 4 , SR 4 , NR 5 R 6 , Ci_ 6 alkyleneOR 4 , Ci- 6 alkyleneSR 4 and Ci- 6 alkyleneNR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom;
• R 4 and R 7 are independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C(0)Ci_ 6 alkyl and C(0)Ci- 6 fiuoroalkyl;
• R 5 and R 6 are independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, heterocycloalkyl, C(0)Ci- 6 alkyl and C(0)Ci- 6 fluoroalkyl, or R 5 and R 6 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 -6 alkyl, Ci -6 fluoroalkyl, OCi -6 fluoroalkyl, C(0)Ci -6 alkyl and C(0)d.
• R 8 and R 9 are independently selected from H, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C(0)Ci_ 6 alkyl and C(0)Ci- 6 fluoroalkyl, or R 8 and R 9 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- 6 alkyl, OCi- 6 alkyl, Ci- 6 fluoroalkyl and OCi- 6 fluoroalkyl;
• X 1 , X 2 , X 3 and X 4 are each independently selected from CR 10 and N;
• X 5 , X 6 and X 7 are each independently selected from CH and N;
• R 10 is selected from H, halo, CN, Ci -6 alkyl, Ci -6 fluoroalkyl, OR 11 , SR. 11 , NR 12 R 13 , R 14 , Ci -6 alkyleneR 14 , OCi -6 alkyleneR 14 , SCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 , Ci. salkyleneOR 11 , Ci-galkyleneSR 11 , OCi -6 alkyleneNR 12 R 13 , SCi -6 alkyleneNR 12 R 13 , OCi.
• R 11 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 11 is other than H, it is unsubstituted or substituted with one or more substituents selected from halo, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C 3- i 0 cycl
• R 12 and R 13 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci- 6 alkyl, C(0)Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, Ce- l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 12 and R 13 are other than H they are each independently unsubstituted or substituted with one or more substituents selected from halo, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci- 6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, hetero
• R 12 and R 13 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, OR 15 , SR 15 , NR 16 R 17 , C 1-6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 15 , Ci_ salkyleneOR 15 , Ci -6 alkyleneSR 15 and Ci -6 alkyleneNR 16 R 17 ;
• R 14 is selected from C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and when R 14 is other than H it is unsubstituted or substituted with one or more substituents independently selected from halo, OR 15 , SR 15 , NR 16 R 17 , Ci -6 alkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci- 6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci_ 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 15 ,
• R 15 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl and Ci- 6 alkyleneheterocycloalkyl, and when R 15 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, Ci_ salkyl, Ci -6 fluoroalkyl, OH, SH, OCi -6 alkyl, OCi -6 fluoroalkyl, SCi -6 alkyl, SCi.
• R 16 and R 17 are each independently selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci- 6 alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci_ 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl and when R 16 and R 17 are other than H they are each unsubstituted or substituted with one or more substituents independently selected from halo, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, OH, SH, OCi- 6 alkyl, OCi -6 fluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci -6 alkyl)(Ci.
• Ci- 6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl), or
• R 16 and R 17 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- 6 alkyl, Ci- 6 fiuoroalkyl, OH, SH, OCi- 6 alkyl, OCi- sfiuoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, NCCi-salkylXCi-salkyl), C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C(0)OH, C(0)OCi -6 alkyl, C(0)NH 2 , C(0)NHCi_ salkyl, C(0)N(Ci -6 alkyl)(Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroary
• A is halo; and all alkyl and alkylene groups are optionally fluorosubstituted.
• R 1 is a heterocycloalkyl that is unsubstituted or substituted with one, two or three substituents selected from halo, Ci- 6 alkyl, Ci_ efluoroalkyl, Ci -6 alkyleneOR 4 , NR 5 R 6 and Ci -6 alkyleneNR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom.
• R 1 is a heterocycloalkyl that is substituted with one, two or three substituents selected from halo, Ci -6 alkyl, Ci -6 alkyleneOR 4 and NR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom.
• R 1 is a heterocycloalkyl that is substituted with one or two substituents selected from Ci- 6 alkyl, Ci- 6 alkyleneOR 4 and NR 5 R 6 , provided that R 1 comprises at least one basic nitrogen atom. In some embodiments, R 1 is selected from:
• R 1 is selected from:
• R 1 is selected from:
• R 1 is selected from:
• R 1 is selected from:
• R 1 is selected from:
• R is selected from C6-ioaryl and heteroaryl
• R is selected from:
• R is selected from:
• R is selected from:
• R 2 is selected from:
• R 2 is selected from:
• R 4 is selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl and C(0)Ci -6 alkyl. In some embodiments, R 4 is selected from H, Ci -6 alkyl and C(0)Ci- 6 alkyl. In some embodiments, R 4 is selected from H, CH 3 and C(0)CH 3 . In some embodiments, R 4 is selected from H and CH 3 .
• R 5 and R 6 are independently selected from H,
• Ci- 6 alkyl and heterocycloalkyl are independently selected from H and Ci- 6 alkyl.
• R 5 and R 6 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_ 6 alkyl.
• R 5 and R 6 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.
• R 5 and R 6 together with the nitrogen atom to which they are attached form 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, mo holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, piperaz
• R 7 is selected from ⁇ , Ci- 6 alkyl, Ci- 6 fluoroalkyl and C(0)Ci- 6 alkyl. In some embodiments, R 7 is selected from ⁇ , CH 3 and C(0)CH 3 . In some embodiments, R 7 is selected from H and Ci- 6 alkyl. In some embodiments, R 7 is selected from H and CH 3 .
• one of X 1 , X 2 , X 3 and X 4 is N and the others of X 1 , X 2 , X 3 and X 4 are CR 10 .
• X 1 , X 2 , X 3 and X 4 are CR 10 .
• X 1 and X 4 are CH.
• one of X 2 and X 3 is CR 10 and R 10 is other than H.
• one of X 5 , X 6 and X 7 is N and the others of X 5 , X 6 and X 7 are CH. In some embodiments, X 5 , X 6 and X 7 are CH.
• R 10 is selected from H, halo, CN, Ci- 6 alkyl, Ci_ sfiuoroalkyl, OR 11 , NR 12 R 13 , R 14 , Ci -6 alkyleneR 14 , OCi -6 alkyleneR 14 , Ci. 6 alkyleneNR 12 R 13 , Ci -6 alkyleneOR n , OCi -6 alkyleneNR 12 R 13 , OCi -6 alkyleneOR n , C(0)OR n and C(0)NR 12 R 13 .
• R 10 is selected from H, halo, CN, OR 11 , NR 12 R 13 , R 14 , Ci -6 alkyleneR 14 , OCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 , Ci. salkyleneOR 11 , OCi -6 alkyleneNR 12 R 13 , OCi -6 alkyleneOR n , C(0)OR n and C(0)NR 12 R 13 .
• R 10 is selected from H, halo, CN, OR 11 , R 14 , OCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 , OCi -6 alkyleneOR n , C(0)OR n and C(0)NR 12 R 13 .
• R 10 is selected from OR 11 , OCi -6 alkyleneR 14 , Ci -6 alkyleneNR 12 R 13 and C(0)NR 12 R 13 .
• R 10 is selected from Ci -6 alkyleneNR 12 R 13 and C(0)NR 12 R 13 .
• R 11 is selected from H, Ci- 6 alkyl, Ci_
• R 11 is selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl and heteroaryl.
• R 11 is selected from H, Ci- 6 alkyl, Ci_ 6 fluoroalkyl and heterocycloalkyl. In some embodiments, R 11 is heterocycloalkyl. In some embodiments, R 11 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, thiomorpholin
• R 12 and R 13 are each independently selected from ⁇ , Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- l ocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci_ 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 12 and R 13 are other than ⁇ they are each independently unsubstituted or substituted with one, two or three substituents selected from halo and Ci -6 alkyl.
• R 12 and R 13 are each independently selected from ⁇ , Ci-ioalkyl, Ci_ l ofluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and when R 12 and R 13 are other than ⁇ they are each independently unsubstituted or substituted with one, two or three substituents selected from halo and Ci- 6 alkyl.
• R 12 and R 13 are each independently selected from ⁇ , Ci-ioalkyl, C3- l ocycloalkyl and heterocycloalkyl, and when R 12 and R 13 are other than ⁇ they are each independently unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl. In some embodiments, R 12 and R 13 are each independently selected from ⁇ , Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and each of R 12 and R (other than H) is unsubstituted.
• R and R are each independently selected from H, Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and when R 12 and R 13 are other than H they are each are independently substituted with halo.
• R 12 and R 13 are each independently selected from H, Ci. l oalkyl, C3-iocycloalkyl and heterocycloalkyl.
• R 12 and R 13 are each independently selected from H and C3-iocycloalkyl.
• R 12 and R 13 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 independently selected from halo, OR 15 , SR 15 , NR 16 R 17 , Ci-galkyl, C(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 , S(0)Ci -6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 - l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci_
• Ci- 6 alkyleneheterocycloalkyl Ci- 6 alkyleneR 15 , Ci- 6 alkyleneOR 15 , Ci- 6 alkyleneSR 15 and
• Ci- 6 alkyleneNR 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 two substituents independently selected from halo, OR 15 , NR 16 R 17 , Ci -6 alkyl, S0 2 Ci -6 alkyl, heterocycloalkyl, Ci.galkyleneCs- l ocycloalkyl and Ci- 6 alkyleneR 15 .
• R 12 and R 13 together with the nitrogen atom to which they are attached form 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,
• R 14 is selected from C(0)Ci -6 alkyl, C(0)Ci_
• R 14 is selected from C3-iocycloalkyl and heterocycloalkyl. In some embodiments, R is C3-iocycloalkyl or heterocycloalkyl.
• R 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, mo holinyl, thiomo holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridiny
• R 15 is selected from ⁇ , Ci- 6 alkyl, Ci_
• R 15 is selected from ⁇ , C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl and Ci_ 6 alkyleneheterocycloalkyl, and when R 15 is other than ⁇ it is unsubstituted or substituted with one, two or three substituents selected from halo, Ci- 6 alkyl and Ci_ 6 fluoroalkyl.
• R 15 is selected from ⁇ , C6-ioaryl and Ci_ 6 alkyleneC 6 -ioaryl, and when R 15 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci -6 alkyl. In some embodiments, R 15 is selected from ⁇ and C6-ioaryl, and when R 15 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl. In some embodiments, R 15 is selected from ⁇ and C6-ioaryl, and when R 15 is other than ⁇ it is unsubstituted or substituted with halo.
• R 16 and R 17 are each independently selected from
• Ci -6 alkyl S(0)Ci_ 6 alkyl, C 6- ioaryl, heteroaryl, C 3- iocycloalkyl, heterocycloalkyl, Ci -6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci_ 6 alkyleneNH 2 , Ci-
• R 16 and R 17 are each independently selected from H, Ci- 6 alkyl, Ci -6 fluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, C 6- ioaryl, Ci -6 alkyleneC 6 -ioaryl, Ci. 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl.
• R 16 and R 17 are each independently selected from H, Ci- 6 alkyl and Ci- 6 fluoroalkyl.
• R 16 and R 17 are Ci- 6 alkyl.
• the compound of Formula I is selected from:
• the compound of Formula I is selected from:
• the compound of Formula (I) is selected from:
• the compound of Formula (I) is selected from, and pharmaceutically acceptable salts and/or solvates thereof:
• the compound of Formula (I) is selected from, and pharmaceutically acceptable salts and/or solvates thereof:
• the present application also includes a compound of Formula (la) or a pharmaceutically acceptable salt and/or solvate thereof:
• R is a heterocycloalkyl that is unsubstituted or substituted with one or more substituents selected from halo, Ci -6 alkyl, Ci. 6 fluoroalkyl, OR 20 , SR 20 , NR 21 R 22 , Ci- salkyleneOR 20 , Ci -6 alkyleneSR 20 and Ci -6 alkyleneNR 21 R 22 , provided that R 18 comprises at least one basic nitrogen atom;
• R 21 and R 22 are independently selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, heterocycloalkyl, C(0)Ci- 6 alkyl and C(0)Ci- 6 fluoroalkyl, or R 21 and R 22 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 -6 alkyl, Ci -6 fluoroalkyl, OCi -6 fluoroalkyl, C(0)Ci -6 alkyl and C(0)d. 6 fluoroalkyl;
• R 24 and R 25 are independently selected from H, Ci- 6 alkyl, Ci- 6 fiuoroalkyl, C(0)Ci_ 6 alkyl and C(0)Ci- 6 fluoroalkyl, or R 24 and R 25 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- 6 alkyl, OCi- 6 alkyl, Ci- 6 fluoroalkyl and OCi- 6 fluoroalkyl;
• X 8 and X 9 are each independently selected from CR 26 and N;
• R 26 is selected from H, halo, CN, Ci -6 alkyl, Ci -6 fluoroalkyl, OR 27 , SR 27 , NR 28 R 29 , R 30 , Ci -6 alkyleneR 30 , OCi -6 alkyleneR 30 , SCi -6 alkyleneR 30 , Ci -6 alkyleneNR 28 R 29 , Ci. salkyleneOR 27 , Ci -6 alkyleneSR 27 , OCi -6 alkyleneNR 28 R 29 , SCi -6 alkyleneNR 28 R 29 , OCi.
• R 27 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 27 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, OR 31 , SR 31 , NR 32 R 33 , Ci -6 alkyl, C(0)R 31 , C(0)OR 31 , C(0)NR 32 R , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3- iocycloalky
• R 28 and R 29 are each independently selected from H, Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci- 6 alkyl, C(0)Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl, Ce- l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci -6 alkyleneheterocycloalkyl, and when R 28 and R 29 are other than H they are each independently unsubstituted or substituted with one or more substituents selected from halo, OR 31 , SR 31 , NR 32 R 33 , Ci -6 alkyl, C(0)R 31 , C(0)OR 31 , C(0)NR 32 R 33 , S(0)Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocyclo
• R 28 and R 29 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, OR 31 , SR 31 , NR 32 R 33 , Ci -6 alkyl, C(0)R 31 , C(0)OR 31 , C(0)NR 32 R 33 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 31 , Ci_ salkyleneOR 31 , Ci -6 alkyleneSR 31 and Ci -6 alkyleneNR 32 R 33 ;
• R 30 is selected from C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, heteroaryl and C 6- ioaryl, and when R 30 is other than H it is unsubstituted or substituted with one or more substituents independently selected from halo, OR 31 , SR 31 , NR 32 R 33 , Ci -6 alkyl, C(0)R 31 , C(0)OR 31 , C(0)NR 32 R 33 , S(0)Ci- 6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci_ 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 31 ,
• efluoroalkyl NH 2 , NHCi -6 alkyl, N(Ci -6 alkyl)(Ci -6 alkyl), C(0)Ci -6 alkyl, C(0)d. sfluoroalkyl, C(0)OH, C(0)OCi -6 alkyl, C(0)NH 2 , C(0)NHCi -6 alkyl, C(0)N(d.
• Ci- 6 alkyl (Ci- 6 alkyl), S0 2 Ci- 6 alkyl, S(0)Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci_ 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci -6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci -6 alkyleneNH 2 , Ci- 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl);
• R 32 and R 33 are each independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C(0)Ci- 6 alkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci_ 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl and when R 32 and R 33 are other than H they are each unsubstituted or substituted with one or more substituents independently selected from halo, Ci -6 alkyl, Ci -6 fiuoroalkyl, OH, SH, OCi -6 alkyl, OCi-gfluoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, N(Ci.
• Ci -6 alkyl (Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci -6 alkyleneSH, Ci -6 alkyleneSCi -6 alkyl, Ci -6 alkyleneNH 2 , Ci. 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl), or
• R 32 and R 33 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 -6 alkyl, Ci -6 fiuoroalkyl, OH, SH, OCi -6 alkyl, OCi.
• a 2 is F
• R 18 is a heterocycloalkyl that is unsubstituted or substituted with one, two or three substituents selected from halo, Ci- 6 alkyl, Ci_ sfiuoroalkyl, Ci -6 alkyleneOR 20 , NR 21 R 22 and Ci -6 alkyleneNR 21 R 22 , provided that R 18 comprises at least one basic nitrogen atom.
• R 18 is a heterocycloalkyl that is substituted with one, two or three substituents selected from
• R 18 is a heterocycloalkyl that is substituted with one or two substituents selected from Ci- 6 alkyl, Ci- 6 alkyleneOR 20 and
• R comprises at least one basic nitrogen atom.
• 1 8 is selected from:
• R is selected from:
• R 18 is selected from:
• R 19 is selected from C6-ioaryl and heteroaryl, and R 19 is unsubstituted or substituted with one, two or three substituents selected from halo, Ci- 6 alkyl, Ci-6-
• R is selected from
• R 19 is selected from:
• R iy is selected from:
• R 19 is selected from
• R is
• R is selected from H, Ci- 6 alkyl, Ci_
• R 20 is selected from H, Ci_ 6 alkyl and C(0)Ci -6 alkyl. [00147] In some embodiments, R and R are independently selected from H,
• R 21 and R 22 are independently selected from H and Ci- 6 alkyl. In some embodiments, R 21 and R 22 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- 6 alkyl. In some embodiments, R 21 and R 22 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.
• R 21 and R 22 together with the nitrogen atom to which they are attached form 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, te
• R 23 is selected from ⁇ , Ci- 6 alkyl, Ci- 6 fiuoroalkyl and C(0)Ci- 6 alkyl. In some embodiments, R 23 is selected from ⁇ and Ci- 6 alkyl.
• one of X 8 and X 9 is N and the other of X 8 and X 9 is CR 26 . In some embodiments, X 8 and X 9 are CR 26 .
• R 26 is selected from ⁇ , halo, CN, Ci- 6 alkyl, Ci_ sfiuoroalkyl, OR 27 , NR 28 R 29 , R 30 , Ci -6 alkyleneR 30 , OCi -6 alkyleneR 30 , Ci. 6 alkyleneNR 28 R 29 , Ci -6 alkyleneOR 27 , OCi -6 alkyleneNR 28 R 29 , OCi -6 alkyleneOR 27 , C(0)OR 27 and C(0)NR 28 R 29 .
• R 26 is selected from ⁇ , halo, CN, OR 27 , NR 28 R 29 , R 30 , Ci -6 alkyleneR 30 , OCi -6 alkyleneR 30 , Ci -6 alkyleneNR 28 R 29 , d. salkyleneOR 27 , OCi -6 alkyleneNR 28 R 29 , OCi -6 alkyleneOR 27 , C(0)OR 27 and C(0)NR 28 R 29 .
• R 26 is selected from ⁇ , halo, CN, OR 27 , OCi. salkyleneR 30 , Ci -6 alkyleneNR 28 R 29 , OCi -6 alkyleneOR 27 , C(0)OR 27 and C(0)NR 28 R 29 .
• R is selected from OR , OCi- 6 alkyleneR , Ci_ 6 alkyleneNR 28 R 29 and C(0)NR 28 R 29 .
• R 26 is selected from Ci- 6 alkyleneNR 28 R 29 and C(0)NR 28 R 29 . [00151] In some embodiments, R is selected from H, Ci- 6 alkyl, Ci_
• R 27 is selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl and heteroaryl.
• R 27 is selected from H, Ci- 6 alkyl, Ci_ 6 fluoroalkyl and heterocycloalkyl. In some embodiments, R 27 is heterocycloalkyl. In some embodiments, R 27 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, thiomorpholin
• R 28 and R 29 are each independently selected from ⁇ , Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- l ocycloalkyl, heterocycloalkyl, heteroaryl, C 6- ioaryl, Ci. 6 alkyleneC 3 .iocycloalkyl, Ci.
• R 28 and R 29 are each independently selected from ⁇ , Ci-ioalkyl, Ci_ l ofluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and when R 28 and R 29 are other than ⁇ they are each independently unsubstituted or substituted with one, two or three substituents selected from halo and Ci- 6 alkyl.
• R 28 and R 29 are each independently selected from ⁇ , Ci-ioalkyl, C3- l ocycloalkyl and heterocycloalkyl, and when R 28 and R 29 are other than ⁇ they are each independently unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl.
• R 28 and R 29 are each independently selected from ⁇ , Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and each of R 28 and
• R is unsubstituted.
• R and R are each independently selected from H, Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and when R and R 29 are other than H they are each independently substituted with halo.
• R 28 and R 29 are each independently selected from H, Ci-ioalkyl, C3- l ocycloalkyl and heterocycloalkyl.
• R 28 and R 29 are each independently selected from H and C3-iocycloalkyl.
• R 28 and R 29 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 independently selected from halo, OR 31 , SR 31 , NR 32 R 33 , Ci-galkyl, C(0)R 31 , C(0)OR 31 , C(0)NR 32 R 33 , S(0)Ci -6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 - l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci_
• Ci- 6 alkyleneheterocycloalkyl Ci- 6 alkyleneR 31 , Ci- 6 alkyleneOR 31 , Ci- 6 alkyleneSR 31 and
• Ci- 6 alkyleneNR 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 two substituents independently selected from halo, OR 31 , NR 32 R 33 , Ci -6 alkyl, S0 2 Ci -6 alkyl, heterocycloalkyl, Ci -6 alkyleneC 3 - l ocycloalkyl and Ci- 6 alkyleneR .
• R and R together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.
• R 28 and R 29 together with the nitrogen atom to which they are attached form 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,
• R 30 is selected from C(0)Ci -6 alkyl, C(0)d.
• R 30 is selected from C3-iocycloalkyl and heterocycloalkyl. In some embodiments, R is C3-iocycloalkyl.
• R 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, mo holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,
• R 31 is selected from ⁇ , Ci- 6 alkyl, Ci_
• R 31 is selected from ⁇ , C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl and Ci_ 6 alkyleneheterocycloalkyl, and when R 31 is other than ⁇ it is unsubstituted or substituted with one, two or three substituents selected from halo, Ci- 6 alkyl and Ci_ 6 fluoroalkyl. In some embodiments, R 31 is selected from ⁇ , C 6 -ioaryl and Ci.
• R 31 is selected from ⁇ and C6-ioaryl, and when R 31 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl.
• R 31 is selected from ⁇ and C6-ioaryl, and when R 31 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl.
• R 31 is selected from ⁇ and C6-ioaryl, and when R 31 is other than ⁇ it is unsubstituted or substituted with halo.
• R 32 and R 33 are each independently selected from
• R 32 and R 33 are each independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci_ 6 alkyleneC 3- iocycloalkyl and Ci -6 alkyleneheterocycloalkyl.
• R 32 and R 33 are each independently selected from H, Ci- 6 alkyl and Ci- 6 fiuoroalkyl.
• R 32 and R 33 are Ci- 6 alkyl.
• the compound of Formula 1(a) is selected from:
• the compound of Formula 1(a) is selected from:
• the compound of Formula (la) is selected from:
• the present application also includes a compound of Formula (lb) or a pharmaceutically acceptable salt and/or solvate thereof:
• X 10 , X 11 and X 13 are independently selected from CH and N;
• X 12 is CR
• R 35 is selected from ;
• R 36 is selected from CF 3 and CHF 2 ;
• R 37 is selected from H and CH 3 ;
• R 38 is selected from H, halo, CN, Ci -6 alkyl, Ci -6 fluoroalkyl, OR 39 , SR 39 , NR 40 R 41 , R 42 , Ci -6 alkyleneR 42 , OCi -6 alkyleneR 42 , SCi -6 alkyleneR 42 , Ci -6 alkyleneNR 40 R 41 , Ci. salkyleneOR 39 , Ci -6 alkyleneSR 39 , OCi -6 alkyleneNR 40 R 41 , SCi -6 alkyleneNR 40 R 41 , OCi.
• R 39 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3 -iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 39 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, OR 43 , SR 43 , NR 44 R 45 , Ci -6 alkyl, C(0)R 43 , C(0)OR 43 , C(0)NR 44 R 45 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6 -i 0 aryl, heteroaryl, C 3- iocyclo
• R 40 and R 41 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, OR 43 , SR 43 , NR 44 R 45 , C 1-6 alkyl, C(0)R 43 , C(0)OR 43 , C(0)NR 44 R 45 , S(0)Ci -6 alkyl, S0 2 Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneR 43 , Ci_ salkyleneOR 43 , Ci -6 alkyleneSR 43 and Ci -6 alkyleneNR 44 R 45 ;
• R 42 is selected from C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, heteroaryl and C6-ioaryl, and when R 42 is other than H it is unsubstituted or substituted with one or more substituents independently selected from halo, OR 43 , SR 43 , NR 44 R 45 , Ci -6 alkyl, C(0)R 43 , C(0)OR 43 , C(0)NR 44 R 45 , S(0)Ci- 6 alkyl, S02Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci -6 alkyleneC 6 -ioaryl, Ci.
• R 43 is selected from H, Ci -6 alkyl, Ci -6 fluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl and Ci- 6 alkyleneheterocycloalkyl, and when R 43 is other than H it is unsubstituted or substituted with one or more substituents selected from halo, Ci_ salkyl, Ci -6 fluoroalkyl, OH, SH, OCi -6 alkyl, OCi -6 fluoroalkyl, SCi -6 alkyl, SCi.
• Ci- 6 alkyl (Ci- 6 alkyl), S0 2 Ci- 6 alkyl, S(0)Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci_ 6 alkyleneheteroaryl, Ci -6 alkyleneheterocycloalkyl, Ci -6 alkyleneOH, Ci -6 alkyleneOCi.
• Ci -6 alkyleneSH Ci- 6 alkyleneSCi- 6 alkyl
• Ci- 6 alkyleneNH 2 Ci- 6 alkyleneNHCi- 6 alkyl
• Ci- 6 alkyleneN Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl);
• R 44 and R 45 are each independently selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C(0)Ci -6 alkyl, C 3- iocycloalkyl, heterocycloalkyl, C 6- ioaryl, Ci -6 alkyleneC 6 -ioaryl, Ci.
• Ci -6 alkyl S(0)Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 - l ocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci- 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHC
• R 44 and R 45 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- 6 alkyl, Ci- 6 fiuoroalkyl, OH, SH, OCi- 6 alkyl, OCi- sfiuoroalkyl, SCi -6 alkyl, SCi -6 fluoroalkyl, NH 2 , NHCi -6 alkyl, NCCi-salkylXCi-salkyl), C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C(0)OH, C(0)OCi -6 alkyl, C(0)NH 2 , C(0)NHCi.
• Ci- 6 alkyl C(0)N(Ci -6 alkyl)(Ci -6 alkyl), S0 2 Ci -6 alkyl, S(0)Ci -6 alkyl, C 6- i 0 aryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci- 6 alkyleneheterocycloalkyl, Ci- 6 alkyleneOH, Ci_ 6 alkyleneOCi- 6 alkyl, Ci- 6 alkyleneSH, Ci- 6 alkyleneSCi- 6 alkyl, Ci- 6 alkyleneNH 2 , Ci_ 6 alkyleneNHCi- 6 alkyl and Ci- 6 alkyleneN(Ci- 6 alkyl)(Ci- 6 alkyl); and
• X 10 , X 11 and X 13 are each CH.
• R is selected from H, Ci- 6 alkyl, Ci_
• R 39 is selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl and Ci -6 alkyleneheterocycloalkyl.
• R 39 is selected from H, Ci- 6 alkyl, Ci- 6 fluoroalkyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl and heteroaryl.
• R 39 is selected from H, Ci- 6 alkyl, Ci_ 6 fluoroalkyl and heterocycloalkyl.
• R 39 is heterocycloalkyl.
• R 39 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, mo holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyri
• R 40 and R 41 are each independently selected from ⁇ , Ci-ioalkyl, Ci-iofluoroalkyl, C(0)Ci -6 alkyl, C(0)Ci -6 fluoroalkyl, C 3- l ocycloalkyl, heterocycloalkyl, heteroaryl, C6-ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci_ 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneheteroaryl and Ci- 6 alkyleneheterocycloalkyl, and when R 40 and R 41 are other than ⁇ they are each independently unsubstituted or substituted with one, two or three substituents selected from halo and Ci- 6 alkyl.
• R 40 and R 41 are each independently selected from ⁇ , Ci.i 0 alkyl, Ci. l ofluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, heteroaryl and C 6- ioaryl, and when R 40 and R 41 are other than ⁇ they are each independently unsubstituted or substituted with one, two or three substituents selected from halo and Ci- 6 alkyl.
• R 40 and R 41 are each independently selected from ⁇ , Ci-ioalkyl, C3- l ocycloalkyl and heterocycloalkyl, and when R 40 and R 41 are other than ⁇ they are each independently unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl. In some embodiments, R 40 and R 41 are each independently selected from ⁇ , Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and each of R 40 and R is unsubstituted.
• R and R are each independently selected from H, Ci-ioalkyl, C3-iocycloalkyl and heterocycloalkyl, and when R 40 and R 41 are other than H they are each independently substituted with halo.
• R 40 and R 41 are each independently selected from H, Ci.i 0 alkyl, C 3- l ocycloalkyl and heterocycloalkyl.
• R 40 and R 41 are each independently selected from H and C3-iocycloalkyl.
• R 40 and R 41 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 independently selected from halo, OR 43 , SR 43 , NR 44 R 45 , Ci -6 alkyl, C(0)R 43 , C(0)OR 43 , C(0)NR 44 R 45 , S(0)Ci -6 alkyl, S0 2 Ci- 6 alkyl, C6-ioaryl, heteroaryl, C3-iocycloalkyl, heterocycloalkyl, Ci- 6 alkyleneC 6 - l oaryl, Ci- 6 alkyleneC 3 -iocycloalkyl, Ci- 6 alkyleneheteroaryl, Ci_
• R 40 and R 41 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 independently selected from halo, OR 43 , 45 Ci- 6 alkyl, S0 2 Ci- 6 alkyl, heterocycloalkyl, Ci- 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneR 43 .
• R 40 and R 41 together with the nitrogen atom to which they are attached form a 3-10 membered heterocycle that is unsubstituted.
• R 40 and R 41 together with the nitrogen atom to which they are attached form 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, thiophanyl, piperidin
• R 42 is selected from C(0)Ci -6 alkyl, C(0)Ci_
• R is selected from C3-iocycloalkyl and heterocycloalkyl.
• R 42 is C3-iocycloalkyl.
• R 42 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,
• R 43 is selected from ⁇ , Ci- 6 alkyl, Ci_
• R 43 is selected from ⁇ , C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, Ci- 6 alkyleneC 6 -ioaryl, Ci- 6 alkyleneC 3 -iocycloalkyl and Ci_ 6 alkyleneheterocycloalkyl, and when R 43 is other than ⁇ it is unsubstituted or substituted with one, two or three substituents selected from halo, Ci -6 alkyl and Ci. 6 fluoroalkyl.
• R 43 is selected from ⁇ , C6-ioaryl and Ci_ 6 alkyleneC 6 -ioaryl, and when R 43 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl. In some embodiments, R 43 is selected from ⁇ and C6-ioaryl, and when R 43 is other than ⁇ it is unsubstituted or substituted with one or two substituents selected from halo and Ci- 6 alkyl. In some embodiments, R 43 is selected from ⁇ and C6-ioaryl, and when R 43 is other than ⁇ it is unsubstituted or substituted with halo.
• R 44 and R 45 are each independently selected from
• R 44 and R 45 are each independently selected from H, Ci- 6 alkyl, Ci_ 6 fluoroalkyl, C 3- iocycloalkyl, heterocycloalkyl, C 6- ioaryl, Ci -6 alkyleneC 6 -ioaryl, Ci. 6 alkyleneC 3 -iocycloalkyl and Ci- 6 alkyleneheterocycloalkyl.
• R 44 and R 45 are each independently selected from H, Ci- 6 alkyl and Ci- 6 fluoroalkyl.
• R 44 and R 45 are Ci- 6 alkyl.
• the compounds of Formula lb are selected from:
• 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 any of the diseases, disorders or conditions described herein. [00172] 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• the tablets are coated by methods well known in the art.
• Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
• 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.
• SR sustained-release
• ER extended- release
• CR controlled-release
• Contin continuous-release
• 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.
• liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• useful carriers or diluents include lactose and dried com starch.
• 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.
• 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).
• 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
• preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid
• Useful diluents include lactose and high mole
• a compound of the application is administered parenterally.
• solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• 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.
• sterile solutions of the compounds of the application are usually prepared, and the pH's of the solutions are suitably adjusted and buffered.
• ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers.
• ocular delivery systems known to the art such as applicators or eye droppers.
• 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.
• diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
• 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.
• 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.
• compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
• 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.
• 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.
• 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.
• the dosage unit is suitably determined by providing a valve to deliver a metered amount.
• 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.
• 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.
• 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.
• a compound of the application is coupled with soluble polymers as targetable drug carriers.
• soluble polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• 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.
• 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.
• 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.
• 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.
• 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.
• a compound of the application is administered contemporaneously with those agents.
• "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.
• two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances.
• a combination of agents is administered to a subject in a non-contemporaneous fashion.
• 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.
• 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.
• 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 subj ect to be treated.
• One of skill in the art can determine the appropriate dosage based on the above factors.
• 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 ⁇ g/cc to about 1000 ⁇ g/cc, or about 0.1 ⁇ g/cc to about 100 ⁇ g/cc.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• a compound also includes embodiments wherein one or more compounds are referenced.
• 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.
• the binding partner for WDR5 is MLL1, or a portion thereof.
• the binding partner forWDR5 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].
• 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.
• 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.
• 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.
• the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners is a neoplastic disorder.
• 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.
• 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.
• the disease, disorder or condition mediated or treatable by inhibition of binding between WDR5 protein and its binding partners is cancer.
• 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.
• the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.
• the cancer is selected from, but not limited to:
• the cancer is selected from solid cancer and leukemias.
• the cancer is selected from leukaemia, lymphoma, non- Hodgkin's lymphoma, Burkitt lymphoma, MLL-fusion lymphoma, primary effusion leukemia and multiple myeloma.
• 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.
• the cancer is selected from leukemia, bladder cancer, brain cancer, prostate cancer and neuroblastoma.
• the cancer is selected from bladder cancer, gliomas, glioblastomas, acute myeloid leukemia (AML) and MYCN-amplified neuroblastoma
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Scheme 1 illustrates one embodiment of a route to compounds of the application in which Suzuki or related coupling is performed on commercially available 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) are prepared by first coupling with the carboxylic acid or acyl halides with aniline A followed by Suzuki or related coupling (scheme 2).
• Scheme 2 a) R 2 C(0)OH, coupling agent or R 2 C(0)X, wherein X is a halide amine; aB(O ester, Pd(Amphos)Cl 2 , K 3 PO4, dioxane/H 2 0, ⁇ wave,
• Nucleophilic aromatic substitution with, for example, various piperazines provide intermediate E.
• reduction of E under reductive conditions by various means including catalytic hydrogenation and dissolving metal reductions both in their various forms affords aniline F.

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