trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyridin-2-yl)methyl)cyclohexanecarbonitrile

ID: ALA3936303

PubChem CID: 59152208

Max Phase: Preclinical

Molecular Formula: C22H21ClFN5O

Molecular Weight: 425.89

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  N#C[C@]1(Cc2cccc(Nc3cc[nH]n3)n2)CC[C@@H](Oc2cccc(Cl)c2F)CC1

Standard InChI:  InChI=1S/C22H21ClFN5O/c23-17-4-2-5-18(21(17)24)30-16-7-10-22(14-25,11-8-16)13-15-3-1-6-19(27-15)28-20-9-12-26-29-20/h1-6,9,12,16H,7-8,10-11,13H2,(H2,26,27,28,29)/t16-,22-

Standard InChI Key:  DVRASPTYCUVMOS-CIEDQVTBSA-N

Molfile:  

     RDKit          2D

 30 33  0  0  0  0  0  0  0  0999 V2000
    2.4277  -17.8954    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.4265  -18.7227    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1414  -19.1356    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8577  -18.7223    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8549  -17.8917    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1395  -17.4826    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5678  -17.4766    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    5.2838  -17.8864    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.2843  -18.7131    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9962  -19.1229    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7115  -18.7112    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7104  -17.8852    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9939  -17.4710    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.4260  -19.1237    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.4259  -19.9487    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7115  -20.3566    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    6.7111  -21.1809    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.4260  -21.5942    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.1429  -21.1773    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.1398  -20.3544    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9964  -21.5930    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.2822  -21.1801    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.4207  -18.2912    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1370  -16.6577    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    1.7131  -17.4831    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
    5.1951  -20.3633    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.3882  -20.1914    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.9753  -20.9056    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.5271  -21.5189    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.1298  -17.8713    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  2  0
  2  3  1  0
  3  4  2  0
  4  5  1  0
  5  6  2  0
  6  1  1  0
  5  7  1  0
  8  7  1  6
  8  9  1  0
  8 13  1  0
  9 10  1  0
 10 11  1  0
 11 12  1  0
 12 13  1  0
 11 14  1  0
 14 15  1  0
 15 16  2  0
 16 17  1  0
 17 18  2  0
 18 19  1  0
 19 20  2  0
 20 15  1  0
 17 21  1  0
 21 22  1  0
 11 23  1  1
  6 24  1  0
  1 25  1  0
 22 26  1  0
 26 27  2  0
 27 28  1  0
 28 29  1  0
 29 22  2  0
 23 30  3  0
M  END

Alternative Forms

1. Parent:

   

   ALA3936303

   4-(3-chloro-2-fluorophenoxy)-1-[[6-(1H-pyrazol-5-ylamino)pyridin-2-yl]methyl]cyclohexane-1-carbonitrile

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 425.89

Molecular Weight (Monoisotopic): 425.1419

AlogP: 5.41

#Rotatable Bonds: 6

Polar Surface Area: 86.62

Molecular Species: NEUTRAL

HBA: 5

HBD: 2

#RO5 Violations: 1

HBA (Lipinski): 6

HBD (Lipinski): 2

#RO5 Violations (Lipinski): 1

CX Acidic pKa: 13.52

CX Basic pKa: 3.74

CX LogP: 5.37

CX LogD: 5.37

Aromatic Rings: 3

Heavy Atoms: 30

QED Weighted: 0.55

Np Likeness Score: -1.05

References

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2. Fancelli, Daniele D and 24 more authors.  2006-11-30  1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.  [PMID:17125279]

3. Yang, Jing J and 11 more authors.  2007-09-15  AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo.  [PMID:17495131]

4. McDermott, Ultan U and 24 more authors.  2007-12-11  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.  [PMID:18077425]

5. Weiss, Matthew M MM and 30 more authors.  2008-03-27  Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.  [PMID:18324759]

6. Shiotsu, Yukimasa Y and 16 more authors.  2009-08-20  KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.  [PMID:19541823]

7. Zarrinkar, Patrick P PP and 15 more authors.  2009-10-01  AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).  [PMID:19654408]

8. Shimomura, Toshiyasu T and 14 more authors.  2010-01  MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel.  [PMID:20053775]

9. Adams, Nicholas D ND and 31 more authors.  2010-05-27  Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.  [PMID:20420387]

10. Bavetsias, Vassilios V and 21 more authors.  2010-07-22  Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.  [PMID:20565112]

11. Payton, Marc M and 20 more authors.  2010-12-01  Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.  [PMID:20935223]

12. Medina, Jesús R JR and 24 more authors.  2011-03-24  Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.  [PMID:21341675]

13. Mollard, Alexis A and 8 more authors.  2011-12-08  Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors.  [PMID:22247788]

14. Lawrence, Harshani R and 14 more authors.  2012-09-13  Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.  [PMID:22803810]

15. Elkins, Jonathan M; Santaguida, Stefano; Musacchio, Andrea and Knapp, Stefan.  2012-09-13  Crystal structure of human aurora B in complex with INCENP and VX-680.  [PMID:22920039]

16. Glaser, Keith B KB and 22 more authors.  2012-12  Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.  [PMID:22935731]

17. Weïwer, Michel M and 12 more authors.  2012-12-13  A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells.  [PMID:23256033]

18. Li, Jie J and 6 more authors.  2013-07  A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting Aurora B kinase activity.  [PMID:23707920]

19. Shiao, Hui-Yi HY and 18 more authors.  2013-07-11  Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.  [PMID:23808327]

20. Sampson, Peter B PB and 23 more authors.  2015-01-08  The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.  [PMID:24867403]

21. Alder, Catherine M CM and 18 more authors.  2013-10-10  Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.  [PMID:24900590]

22. Jagtap, Ajit Dhananjay AD and 8 more authors.  2014-10-06  Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia.  [PMID:25089810]

23. Carry, Jean-Christophe JC and 32 more authors.  2015-01-08  SAR156497, an exquisitely selective inhibitor of aurora kinases.  [PMID:25369539]

24. An, Ying Y and 7 more authors.  2016-07-01  Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors.  [PMID:27209235]

25. Klaeger, Susan S and 47 more authors.  2017-12-01  The target landscape of clinical kinase drugs.  [PMID:29191878]

26. Barker, Michael D MD and 11 more authors.  2018-11-15  Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.  [PMID:30249354]

27. Narayan, Satya S and 7 more authors.  2019-01-01  ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells.  [PMID:30384048]

28. Fan, Chengcheng and 7 more authors.  2020-03-15  Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition.  [PMID:32058239]

29. Lakkaniga, Naga Rajiv and 5 more authors.  2020-10-01  Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression.  [PMID:32717530]

Source

Source(1):

• Patent Bioactivity Data