US20190119272A1 - Triazolopyridines and triazolopyrazines as lsd1 inhibitors - Google Patents

Triazolopyridines and triazolopyrazines as lsd1 inhibitors Download PDF

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US20190119272A1
US20190119272A1 US16/144,365 US201816144365A US2019119272A1 US 20190119272 A1 US20190119272 A1 US 20190119272A1 US 201816144365 A US201816144365 A US 201816144365A US 2019119272 A1 US2019119272 A1 US 2019119272A1
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alkyl
independently selected
haloalkyl
halo
cycloalkyl
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Liangxing Wu
Xiaozhao Wang
Wenqing Yao
Colin Zhang
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Incyte Corp
Incyte Holdings Corp
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Incyte Corp
Incyte Holdings Corp
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Priority to US16/592,371 priority patent/US10968221B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
  • Epigenetic modifications can impact genetic variation but, when dysregulated, can also contribute to the development of various diseases (Portela, A. and M. Esteller, Epigenetic modifications and human disease . Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M. van Lohuizen, Epigenetics and cancer . Genes Dev, 2004. 18(19): p. 2315-35). Recently, in depth cancer genomics studies have discovered many epigenetic regulatory genes are often mutated or their own expression is abnormal in a variety of cancers (Dawson, M. A. and T. Kouzarides, Cancer epigenetics: from mechanism to therapy . Cell, 2012. 150(1): p. 12-27; Waldmann, T. and R.
  • LSD1 lysine specific demethylase-1
  • the N-terminal SWIRM which functions in nucleosome targeting
  • the tower domain which is involved in protein-protein interaction, such as transcriptional co-repressor, co-repressor of RE1-silencing transcription factor (CoREST), and lastly the C terminal catalytic domain whose sequence and structure share homology with the flavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e., MAO-A and MAO-B)
  • FAD flavin adenine dinucleotide
  • MAO-A and MAO-B flavin adenine dinucleotide
  • LSD1 also shares a fair degree of homology with another lysine specific demethylase (LSD2) (Karytinos, A., et al., A novel mammalian flavin - dependent histone demethylase . J Biol Chem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism of action is conserved in two isoforms, the substrate specificities are thought to be distinct with relatively small overlap.
  • LSD2 lysine specific demethylase
  • LSD1 and LSD2 are dependent on the redox process of FAD and the requirement of a protonated nitrogen in the methylated lysine is thought to limit the activity of LSD1/2 to mono- and di-methylated lysines at the position of 4 or 9 of histone 3 (H3K4 or H3K9).
  • H3K4 or H3K9 histone 3
  • These mechanisms make LSD1/2 distinct from other histone demethylase families (i.e. Jumonji domain containing family) that can demethylate mono-, di-, and tri-methylated lysines through alpha-ketoglutarate dependent reactions (Kooistra, S. M. and K. Helin, Molecular mechanisms and potential functions of histone demethylases . Nat Rev Mol Cell Biol, 2012.
  • Methylated histone marks on H3K4 and H3K9 are generally coupled with transcriptional activation and repression, respectively.
  • corepressor complexes e.g., CoREST
  • LSD1 has been reported to demethylate H3K4 and repress transcription
  • LSD1 in nuclear hormone receptor complex (e.g., androgen receptor)
  • Metzger, E., et al. LSD 1 demethylates repressive histone marks to promote androgen - receptor - dependent transcription . Nature, 2005. 437(7057): p.
  • LSD1 may demethylate non-histone proteins. These include p53 (Huang, J., et al., p 53 is regulated by the lysine demethylase LSD 1. Nature, 2007. 449(7158): p.
  • E2F Kontaki, H. and I. Talianidis, Lysine methylation regulates E 2 F 1- induced cell death . Mol Cell, 2010. 39(1): p. 152-60
  • STAT3 Yamamoto, J., et al., Reversible methylation of promoter - bound STAT 3 by histone - modifying enzymes . Proc Natl Acad Sci USA, 2010. 107(50): p. 21499-504
  • Tat Sakane, N., et al., Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine - specific demethylase 1 ( LSD 1 /KDM 1). PLoS Pathog, 2011.
  • LSD1 also associates with other epigenetic regulators, such as DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysine demethylase LSD 1 ( KDM 1) is required for maintenance of global DNA methylation . Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases (HDACs) complexes (Hakimi, M. A., et al., A core - BRAF 35 complex containing histone deacetylase mediates repression of neuronal - specific genes . Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M.
  • DNMT1 DNA methyltransferase 1
  • HDACs histone deacetylases
  • LSD1 has been reported to contribute to a variety of biological processes, including cell proliferation, epithelial-mesenchymal transition (EMT), and stem cell biology (both embryonic stem cells and cancer stem cells) or self-renewal and cellular transformation of somatic cells (Chen, Y., et al., Lysine - specific histone demethylase 1 ( LSD 1): A potential molecular target for tumor therapy . Crit Rev Eukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histone demethylase LSD 1 regulates neural stem cell proliferation . Mol Cell Biol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J.
  • cancer stem cells or cancer initiating cells have some pluripotent stem cell properties that contribute to the heterogeneity of cancer cells. This feature may render cancer cells more resistant to conventional therapies, such as chemotherapy or radiotherapy, and then develop recurrence after treatment (Clevers, H., The cancer stem cell. premises, promises and challenges . Nat Med, 2011. 17(3): p.
  • LSD1 was reported to maintain an undifferentiated tumor initiating or cancer stem cell phenotype in a spectrum of cancers (Zhang, X., et al., Pluripotent Stem Cell Protein Sox 2 Confers Sensitivity to LSD 1 Inhibition in Cancer Cells . Cell Rep, 2013. 5(2): p. 445-57; Wang, J., et al., Novel histone demethylase LSD 1 inhibitors selectively target cancer cells with pluripotent stem cell properties . Cancer Res, 2011. 71(23): p. 7238-49).
  • AMLs Acute myeloid leukemias
  • LSC leukemia stem cell
  • LSD1 Overexpression of LSD1 is frequently observed in many types of cancers, including bladder cancer, NSCLC, breast carcinomas, ovary cancer, glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostate cancer, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.
  • studies found over-expression of LSD1 was significantly associated with clinically aggressive cancers, for example, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer, ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma.
  • LSD 1 Lysine - specific demethylase 1
  • LSD 1 Lysine - specific demethylase 1
  • LSD 1 lysine - specific demethylase 1
  • KDM 1 is a novel therapeutic target for the treatment of gliomas .
  • Lysine - specific demethylase 1 ( LSD 1 /KDM 1 A/AOF 2 /BHC 110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma . Hum Pathol, 2012. 43(8): p. 1300-7; Schulte, J. H., et al., Lysine - specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy . Cancer Res, 2009. 69(5): p.
  • CD86 expression is a marker of maturation of dendritic cells (DCs) which are involved in antitumor immune response.
  • DCs dendritic cells
  • CD86 functions as a co-stimulatory factor to activate T cell proliferation (Greaves, P. and J. G. Gribben, The role of B 7 family molecules in hematologic malignancy . Blood, 2013. 121(5): p. 734-44; Chen, L. and D. B. Flies, Molecular mechanisms of T cell co - stimulation and co - inhibition . Nat Rev Immunol, 2013. 13(4): p. 227-42).
  • LSD1 activity has also been associated with viral pathogenesis.
  • LSD1 activity appears to be linked with viral replications and expressions of viral genes.
  • LSD1 functions as a co-activator to induce gene expression from the viral immediate early genes of various type of herpes virus including herpes simplex virus (HSV), varicella zoster virus (VZV), and ⁇ -herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting the JMJD 2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency . Sci Transl Med, 2013. 5(167): p.
  • HSV herpes simplex virus
  • VZV varicella zoster virus
  • ⁇ -herpesvirus human cytomegalovirus Liang, Y., et al., Targeting the JMJD 2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency .
  • LSD1 histone demethylase LSD 1 blocks alpha - herpesvirus lytic replication and reactivation from latency . Nat Med, 2009. 15(11): p. 1312-7).
  • a LSD1 inhibitor showed antiviral activity by blocking viral replication and altering virus associated gene expression.
  • fetal globin gene would be potentially therapeutically beneficial for the disease of ⁇ -globinopathies, including ⁇ -thalassemia and sickle cell disease where the production of normal ⁇ -globin, a component of adult hemoglobin, is impaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal to adult hemoglobin . Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643; Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetal hemoglobin: prospects for new therapies for the beta - globin disorders . Blood, 2012. 120(15): p. 2945-53).
  • LSD1 inhibition may potentiate other clinically used therapies, such as hydroxyurea or azacitidine. These agents may act, at least in part, by increasing ⁇ -globin gene expression through different mechanisms.
  • LSD1 contributes to tumor development by altering epigenetic marks on histones and non-histone proteins. Accumulating data have validated that either genetic depletion or pharmacological intervention of LSD1 normalizes altered gene expressions, thereby inducing differentiation programs into mature cell types, decreasing cell proliferation, and promoting apoptosis in cancer cells. Therefore, LSD1 inhibitors alone or in combination with established therapeutic drugs would be effective to treat the diseases associated with LSD1 activity.
  • the present invention is directed to, inter alia, a compound of Formula I:
  • the present invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.
  • the present invention is further directed to a method of inhibiting LSD1 comprising contacting the LSD1 with a compound of Formula I.
  • the present invention is further directed to a method of treating an LSD1-mediated disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I.
  • the present invention provides, inter alia, LSD1-inhibiting compounds such as a compound of Formula I:
  • X is N or CR X ;
  • Ring A is C 6-10 aryl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R A ;
  • Ring B is C 6-10 aryl; 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; C 3-10 cycloalkyl; or 4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S; wherein said C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R B ;
  • R 1 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C( ⁇ NR e1 )R b1 , C( ⁇ NR e1 )NR c1 R d1 , NR c1 C( ⁇ NR e1 )NR c1 R d1 , NR c1 S(O)R b1 ,
  • R 1 is not CN
  • R 2 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 2 , CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C( ⁇ NR e2 )R b2 , C( ⁇ NR e2 )NR c2 R d2 , NR c2 C( ⁇ NR e2 )NR c2 R d2 , NR c2 S(O)R b2 ,
  • each R A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C( ⁇ NR e4 )R b4 , C( ⁇ NR e4 )NR c4 R d4 , NR c4 C( ⁇ NR e4 )NR c4 R d4 , NR c4 S(O)R
  • each R B is independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , C( ⁇ NR e5 )R b5 , C( ⁇ NR e5 )NR c5 R d5 , NR c5 C( ⁇ NR e5 )NR c5 R d5 , NR c5 S(
  • R X is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C( ⁇ NR e7 )R b7 , C( ⁇ NR e7 )NR c7 R d7 , NR c7 C( ⁇ NR e7 )NR c7 R d7 , NR c7 S(O)R b7
  • each Cy 1 , Cy 2 , Cy 3 , and Cy 4 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy ;
  • each R Cy is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C( ⁇ NR e6 )NR c
  • each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy 4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C( ⁇ NR e3 )R b3 , C( ⁇ NR e3 )NR
  • each R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycl
  • R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR
  • each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c
  • each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c7 C(O)OR a7 , C( ⁇ NR e7 )NR c7 R d7 , NR c7 C
  • each R a5 , R b5 , R c5 , and R d5 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR
  • R c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c7 C(O)OR a7 , C( ⁇ NR e7 )NR c7 R d7 , NR c7 C
  • each R a7 , R b7 , R c7 , and R d7 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and
  • each R e1 , R e2 , R e3 , R e4 , R e5 , R e6 , and R e7 is independently selected from H, C 1-4 alkyl, and CN.
  • X is N or CR X ;
  • Ring A is phenyl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R A ;
  • Ring B is phenyl or 5-6 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R B ;
  • R 1 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C( ⁇ NR e1 )R b1 , C( ⁇ NR e1 )NR c1 R d1 , NR c1 C( ⁇ NR e1 )NR c1 R d1 , NR c1 S(O)R b1 ,
  • R 1 is not CN
  • R 2 is H, halo, C 1-6 alkyl, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , S(O) 2 R b2 , or S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
  • each R A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 R d4 , NR c4 C(O)R b4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 R d4 , NR c4 C(O)R b4 , S(O) 2 R b4 , and S(
  • each R B is independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 haloalkyl, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR
  • R X is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , NR c7 R d7 , NR c7 C(O)R b7 , S(O) 2 R b7 , and S(O) 2 NR c7 R d7 ;
  • each Cy 1 , Cy 3 , and Cy 4 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy ;
  • each R Cy is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C 14 alkyl-, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , C( ⁇ NR e6 )NR c6
  • each R a1 is independently selected from H, C 1-6 alkyl, and Cy 4 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;
  • each R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycl
  • R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR
  • each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c
  • each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c7 C(O)OR a7 , C( ⁇ NR e7 )NR c7 R d7 , NR c7 C
  • each R a5 , R b5 , R c5 , and R d5 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR
  • R c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR c7 C(O)OR a7 , C( ⁇ NR e7 )NR c7 R d7 , NR c7 C
  • each R a7 , R b7 , R c7 , and R d7 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and
  • each R e1 , R e6 , and R e7 is independently selected from H, C 1-4 alkyl, and CN.
  • X is N or CR X ;
  • Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from R A ;
  • Ring B is phenyl optionally substituted by 1 or 2 substituents independently selected from R B ;
  • R 1 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1
  • R 2 is H
  • each R A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from CN and OR a4 ;
  • each R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, and OR a5 ;
  • R X is H
  • each Cy 1 and Cy 4 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy ;
  • each R Cy is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 C(O)NR c6 R d6 , NR c6 S(O)R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , S(O)R b
  • each R a1 is independently selected from H, C 1-6 alkyl, and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 , and wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a6 , C(O)R b6 , C(O)NR c6
  • each R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, (5-6 membered heteroaryl)-C 1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4
  • R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)NR c7 R d7 , NR c7 C(O)OR d7 , NR
  • each R a3 , R b3 , R c3 , and R d3 is independently selected from H and C 1-6 alkyl;
  • each R a4 is independently selected from H and C 1-6 alkyl
  • each R a5 is independently selected from H and C 1-6 alkyl
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H and C 1-6 alkyl;
  • each Ra7, R b7 , R c7 , and R d7 is independently selected from H and C 1-4 alkyl.
  • X is N.
  • X is CR X .
  • Ring A is phenyl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R A .
  • Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from R A .
  • Ring A is phenyl substituted by one R A .
  • Ring A is phenyl substituted by CN.
  • Ring B is phenyl or 5-6 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from R B .
  • Ring B is phenyl optionally substituted by 1 or 2 substituents independently selected from R B .
  • Ring B is phenyl substituted by one R B .
  • Ring B is phenyl substituted by methyl.
  • R 1 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, Cy 1 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,
  • R 1 is C 1-6 alkyl, Cy 1 , or OR a1 , wherein said C 1-6 alkyl is substituted with one Cy 1 .
  • R 1 is pyrrolidin-3-ylmethoxy, 2-pyrrolidin-3-ylethyl, (1-methylpyrrolidin-3-yl)ethyl, 3-[(methylamino)methyl]phenyl, 3-aminopyrrolidin-1-yl)methyl]phenyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, or (1-methylpyrrolidin-3-yl)methoxy.
  • R 2 is H.
  • each R A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 R d4 , NR c4 C(O)R b4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 R d4 NR c4 C(O)R b4 , S(O) 2 R b4 , and
  • each R A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from CN and OR a4 .
  • R A is CN
  • each R B is independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a5 , C(O)R b5 S, C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 haloalkyl, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C
  • each R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, and OR a5 .
  • R B is C 1-6 alkyl.
  • R B is methyl
  • R X is H.
  • each Cy 1 is independently selected from phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy .
  • each Cy 1 is phenyl or 4-7 membered heterocycloalkyl, each optionally substituted with 1 or 2 substituents independently selected from R Cy .
  • each Cy 1 is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from R Cy .
  • each Cy 1 is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from C 1-4 alkyl and NR c6 R d6 , wherein said C 1-4 alkyl is optionally substituted with NR c6 R d6 .
  • each R Cy is C 1-4 alkyl and NR c6 R d6 , wherein said C 1-4 alkyl is optionally substituted with NR c6 R d6 .
  • each R a1 is independently selected from H, C 1-6 alkyl, and Cy 4 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 NR c3 C(O)R b3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .
  • each R a1 is independently selected from H, C 1-6 alkyl, and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 NR c3 C(O)R b3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 , and wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a6 , C(O)R b6 , C(O)NR
  • each R a1 is C 1-4 alkyl substituted by 4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , NR c6 R d6 , NR c6 C(O)R b6 , S(O) 2 R b6 , and S(O) 2 NR c6 R d6 .
  • each R a1 is pyrrolidinylmethyl optionally substituted with one C 1-4 alkyl.
  • the compounds of the invention have Formula IIa:
  • the compounds of the invention have Formula IIb:
  • the compounds of the invention have Formula IIIa:
  • the compounds of the invention have Formula IIIb:
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a monovalent substituent, or two hydrogen atoms are replaced with a divalent substituent like a terminal oxo group. It is to be understood that substitution at a given atom is limited by valency.
  • C i-j indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 , and the like.
  • z-membered typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is z.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • C i-j alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbons.
  • the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
  • C i-j alkoxy refers to a group of formula —O-alkyl, wherein the alkyl group has i to j carbons.
  • Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).
  • the alkyl group has 1 to 3 carbon atoms.
  • C i-j alkenyl refers to an unsaturated hydrocarbon group having one or more double carbon-carbon bonds and having i to j carbons.
  • the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
  • C i-j alkynyl refers to an unsaturated hydrocarbon group having one or more triple carbon-carbon bonds and having i to j carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • C i-j alkylamino employed alone or in combination with other terms, refers to a group of formula —NH(alkyl), wherein the alkyl group has i to j carbon atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • the alkylamino group is —NH(C 1-4 alkyl) such as, for example, methylamino, ethylamino or propylamino.
  • C i-j alkylthio refers to a group of formula —S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylthio group is C 1-4 alkylthio such as, for example, methylthio or ethylthio.
  • amino employed alone or in combination with other terms, refers to a group of formula —NH 2 .
  • aryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl is C 6-10 aryl.
  • the aryl group is a naphthalene ring or phenyl ring.
  • the aryl group is phenyl.
  • aryl-C i-j alkyl refers to an alkyl group substituted by an aryl group.
  • An example of a aryl-C i-j alkyl group is benzyl.
  • carbonyl employed alone or in combination with other terms, refers to a —C(O)— group.
  • C i-j cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems.
  • cycloalkyl Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages.
  • cycloalkyl is C 3-10 cycloalkyl, C 3-7 cycloalkyl, or C 5-6 cycloalkyl.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like.
  • Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C i-j cycloalkyl-C i-j alkyl refers to an alkyl group substituted by a cycloalkyl group.
  • An example of a C i-j cycloalkyl-C i-j alkyl group is cyclopropylmethyl.
  • C i-j haloalkoxy refers to a group of formula —O-haloalkyl having i to j carbon atoms.
  • An example haloalkoxy group is OCF 3 .
  • An additional example haloalkoxy group is OCHF 2 .
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • the haloalkoxy group is C 1-4 haloalkoxy.
  • halo refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F.
  • C i-j haloalkyl refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the haloalkyl group is trifluoromethyl.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members.
  • the heteroaryl group has 1, 2, or 3 heteroatom ring members.
  • the heteroaryl group has 1 or 2 heteroatom ring members.
  • the heteroaryl group has 1 heteroatom ring member.
  • the heteroaryl group is 5- to 10-membered or 5- to 6-membered.
  • the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine, and the like.
  • a 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising wherein one or more of the ring-forming atoms are independently selected from N, O, and S.
  • the 5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members.
  • the 5-membered heteroaryl group has 1 or 2 heteroatom ring members.
  • the 5-membered heteroaryl group has 1 heteroatom ring member.
  • Example ring-forming members include CH, N, NH, O, and S.
  • Example five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4-oxadiazolyl.
  • a 6-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more of the ring-forming atoms is N. In some embodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 heteroatom ring member.
  • Example ring-forming members include CH and N.
  • Example six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.
  • heteroaryl-C i-j alkyl refers to an alkyl group substituted by a heteroaryl group.
  • An example of a heteroaryl-C i-j alkyl group is pyridylmethyl.
  • heterocycloalkyl refers to non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • the heterocycloalkyl group has 1, 2, 3, or 4 heteroatom ring members.
  • the heterocycloalkyl group has 1, 2, or 3 heteroatom ring members.
  • the heterocycloalkyl group has 1 or 2 heteroatom ring members.
  • the heterocycloalkyl group has 1 heteroatom ring member.
  • heterocycloalkyl group contains more than one heteroatom in the ring
  • the heteroatoms may be the same or different.
  • Example ring-forming members include CH, CH 2 , C(O), N, NH, O, S, S(O), and S(O) 2 .
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or 6-membered.
  • heterocycloalkyl groups examples include 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran.
  • heterocycloalkyl-C i-j alkyl refers to an alkyl group substituted by a heterocycloalkyl group.
  • An example of a heterocycloalkyl-C i-j alkyl group is pyrrolidinylmethyl.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ⁇ N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compounds of the invention can be any of the possible stereoisomers.
  • the stereochemistry of the chiral center can be (R) or (S).
  • the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S).
  • each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).
  • An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in a compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C. to about 30° C.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al.,
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4 th Ed., Wiley & Sons, Inc., New York (2006), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“ Preparative LC - MS Purification: Improved Compound Specific Method Optimization ” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated
  • Compounds of formula 9 can be synthesized as shown in Scheme 1.
  • Compound 1 can undergo Suzuki reaction with an appropriate boronic acid or ester of formula 2 in the presence of a palladium catalyst and a suitable base such as K 2 CO 3 to provide compound of formula 3.
  • Installation of ring B to give compound of formula 5 can be achieved by coupling of compound 3 with compound of formula 4 under standard Suzuki coupling conditions (M is a boronic acid or ester, with palladium catalysis), or standard Negishi coupling conditions (M is Zn-halo, in the presence of a palladium catalyst), or standard Buchwald amination conditions (M is H attached to a ring-forming N atom in ring B, in the presence of a palladium catalyst and a suitable base).
  • Suzuki coupling conditions M is a boronic acid or ester, with palladium catalysis
  • Negishi coupling conditions M is Zn-halo, in the presence of a palladium catalyst
  • standard Buchwald amination conditions M is H
  • Halogenation of compound 5 using N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide can provide a compound of formula 6 (Hal is Cl, Br or I).
  • Compound 6 can be converted to a formamidoxime derivative of formula 7 by reacting with N,N-dimethylformamide dimethyl acetal, followed by treatment with hydroxylamine.
  • the formamidoxime derivative 7 can undergo cyclization upon treating with trifluoroacetic anhydride (TFAA) to afford a triazole compound of formula 8.
  • TFAA trifluoroacetic anhydride
  • the aryl halide 8 can react with R 1 -M to give a compound of formula 9 under standard cross coupling conditions, such as Suzuki coupling conditions (M is a boronic acid or ester, with palladium catalysis), Sonogashira coupling conditions (M is a terminal alkynyl, with palladium catalysis), Negishi coupling conditions (M is ZnCl, ZnBr or ZnI, with palladium catalysis), Buchwald amination conditions (R 1 -M is an amine (M is H), with palladium catalysis) or Ullmann coupling conditions (R 1 -M is an alcohol (M is H), with palladium or copper catalysis).
  • Suzuki coupling conditions M is a boronic acid or ester, with palladium catalysis
  • Sonogashira coupling conditions M is a terminal alkynyl, with palladium catalysis
  • Negishi coupling conditions M is ZnCl, ZnBr or ZnI,
  • aryl halide 10 can react with R 1 -M under standard cross coupling conditions as described in Scheme 1 (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) to give compounds of formula 11.
  • Scheme 1 e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling
  • compounds of formula 11 can be prepared as shown in Scheme 3.
  • Aryl halide 6 can react with R 1 -M under standard cross coupling conditions as described in Scheme 1 (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) to give compounds of formula 12.
  • Condensation of amino-pyridine derivative 12 with ethoxycarbonyl isothiocyanate, followed by treatment with hydroxylamine can give the aminotriazole of formula 13. Transformation of the amino group in compound 13 to bromide can be achieved under standard Sandmeyer reaction conditions (e.g., NaNO 2 , HBr then CuBr) to give compounds of formula 14.
  • aryl bromide 14 with an R 2 substituent to give compound 11 can be performed under standard cross coupling reaction conditions (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) as described in the previous Schemes.
  • standard cross coupling reaction conditions e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling
  • Compounds of the invention are LSD1 inhibitors and, thus, are useful in treating diseases and disorders associated with activity of LSD1.
  • any of the compounds of the invention including any of the embodiments thereof, may be used.
  • the compounds of the invention are selective for LSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 with greater affinity or potency, compared to LSD2.
  • selectivity can be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold.
  • LSD1-mediated disease or “LSD1-mediated disorder” refers to any disease or condition in which LSD1 plays a role, or where the disease or condition is associated with expression or activity of LSD1.
  • the compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where LSD1 is known to play a role.
  • Diseases and conditions treatable using the compounds of the invention include generally cancers, inflammation, autoimmune diseases, viral induced pathogenesis, beta-globinopathies, and other diseases linked to LSD1 activity.
  • Cancers treatable using compounds according to the present invention include, for example, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
  • Example hematological cancers include, for example, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • APL acute promyelocytic
  • Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.
  • Example lung cancers include, for example, non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.
  • NSCLC non-small cell lung cancer
  • bronchogenic carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell
  • adenocarcinoma alveolar (bronchiolar) carcinoma
  • bronchial adenoma chondromatous hamartoma
  • mesothelioma mesothelioma
  • Example gastrointestinal cancers include, for example, cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.
  • Example genitourinary tract cancers include, for example, cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).
  • kidney adenocarcinoma, Wilm's tumor [nephroblastoma]
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma
  • prostate adenocarcinoma, sarcoma
  • testis seminoma, teratoma,
  • Example liver cancers include, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
  • hepatoma hepatocellular carcinoma
  • cholangiocarcinoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • Example bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma malignant giant cell tumor chordoma
  • osteochronfroma osteocartil
  • Example nervous system cancers include, for example, cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.
  • skull osteoma, hemangioma, granuloma, xanthoma, osteitis deformans
  • Example gynecological cancers include, for example, cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).
  • endometrial carcinoma endometrial carcinoma
  • cervix cervical carcinoma, pre-tumor cervical dysplasia
  • Example skin cancers include, for example, melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
  • the compounds of the invention can further be used to treat cancer types where LSD1 may be overexpressed including, for example, breast, prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g., papillary thyroid carcinoma).
  • cancer types where LSD1 may be overexpressed including, for example, breast, prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g., papillary thyroid carcinoma).
  • the compounds of the invention can further be used to treat genetic disorders such as Cowden syndrome and Bannayan-Zonana syndrome.
  • the compounds of the invention can further be used to treat viral diseases such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.
  • viral diseases such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.
  • the compounds of the invention can further be used to treat beta-globinopathies including, for example, beta-thalassemia and sickle cell anemia.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” a LSD1 protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a LSD1 protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the LSD1 protein.
  • the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • preventing refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the compounds of the invention can be used in combination treatments where the compound of the invention is administered in conjunction with other treatments such as the administration of one or more additional therapeutic agents.
  • the additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated.
  • the additional therapeutic agents can include, e.g., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K inhibitors for treatment of LSD1-mediated diseases, disorders or conditions.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • the compounds of the invention can be used in combination with a therapeutic agent that targets an epigenetic regulator.
  • epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
  • Histone deacetylase inhibitors include, e.g., vorinostat.
  • the compounds of the invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents.
  • the compounds of the invention can also be used in combination with medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.
  • chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxe
  • the compounds of the invention can be used in combination with ruxolitinib.
  • the compound of the invention can be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
  • a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
  • the compound of the invention can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
  • an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
  • the compound of the invention can be administered in combination with one or more additional agents selected from DehydrexTM (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R, 5R)-3,
  • the compound of the invention can be administered in combination with one or more additional agents such as Hydrea® (hydroxyurea).
  • the compound of the invention can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents.
  • suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorola
  • agents one or more of which a provided compound may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathi
  • the compounds of the invention can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • oral or parenteral e.g., by inhal
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention.
  • the topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating LSD1 in tissue samples, including human, and for identifying LSD1 ligands by inhibition binding of a labeled compound.
  • the present invention includes LSD1 assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br.
  • the compound incorporates 1, 2, or 3 deuterium atoms.
  • the present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
  • a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled can be evaluated for its ability to bind LSD1 by monitoring its concentration variation when contacting with LSD1, through tracking of the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to LSD1 (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to LSD1 directly correlates to its binding affinity.
  • the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:
  • Step 5 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 6 4- ⁇ 5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl ⁇ benzonitrile
  • Step 1 tert-butyl 3-ethynylpyrrolidine-1-carboxylate
  • Step 2 tert-butyl 3- ⁇ [6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]ethynyl ⁇ pyrrolidine-1-carboxylate
  • Step 3 4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 1 4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 2 4-[8- ⁇ 3-[(methylamino)methyl]phenyl ⁇ -5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 1 4-[5-(4-methylphenyl)-8-vinyl[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • a reaction vessel containing a mixture of 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 1, Step 5, 338 mg, 0.868 mmol)
  • 4-methyl-2,6-dioxo-8-vinyltetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide (206 mg, 1.13 mmol)
  • [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (42 mg, 0.052 mmol)
  • potassium carbonate (240 mg, 1.7 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was evacuated then filled with nitrogen.
  • Step 2 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 3 4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Step 4 tert-butyl (3R)-3-( ⁇ [3-amino-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy ⁇ methyl)pyrrolidine-1-carboxylate
  • Step 5 4- ⁇ 5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl ⁇ benzonitrile
  • LANCE LSD1/KDM1A demethylase assay 10 ⁇ L of 1 nM LSD-1 enzyme (ENZO BML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20, 25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 ⁇ L compound/DMSO dotted in black 384 well polystyrene plates.
  • IC 50 data for the example compounds is provided in Table 1 (+ refers to IC 50 ⁇ 50 nM; ++ refers to IC 50 >50 nM and ⁇ 100 nM; +++ refers to IC 50 >50 nM and ⁇ 100 nM; ++++ refers to IC 50 >500 nM and ⁇ 1000 nM).

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Abstract

The present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Description

    FIELD OF THE INVENTION
  • The present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
    • BACKGROUND OF THE INVENTION
  • Epigenetic modifications can impact genetic variation but, when dysregulated, can also contribute to the development of various diseases (Portela, A. and M. Esteller, Epigenetic modifications and human disease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M. van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p. 2315-35). Recently, in depth cancer genomics studies have discovered many epigenetic regulatory genes are often mutated or their own expression is abnormal in a variety of cancers (Dawson, M. A. and T. Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012. 150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histone modifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2): p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genome and epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigenetic regulators function as cancer drivers or are permissive for tumorigenesis or disease progression. Therefore, deregulated epigenetic regulators are attractive therapeutic targets.
  • One particular enzyme which is associated with human diseases is lysine specific demethylase-1 (LSD1), the first discovered histone demethylase (Shi, Y., et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists of three major domains: the N-terminal SWIRM which functions in nucleosome targeting, the tower domain which is involved in protein-protein interaction, such as transcriptional co-repressor, co-repressor of RE1-silencing transcription factor (CoREST), and lastly the C terminal catalytic domain whose sequence and structure share homology with the flavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e., MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p. 20070-4; Anand, R. and R. Marmorstein, Structure and mechanism of lysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p. 35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci USA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree of homology with another lysine specific demethylase (LSD2) (Karytinos, A., et al., A novel mammalian flavin-dependent histone demethylase. J Biol Chem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism of action is conserved in two isoforms, the substrate specificities are thought to be distinct with relatively small overlap. The enzymatic reactions of LSD1 and LSD2 are dependent on the redox process of FAD and the requirement of a protonated nitrogen in the methylated lysine is thought to limit the activity of LSD1/2 to mono- and di-methylated lysines at the position of 4 or 9 of histone 3 (H3K4 or H3K9). These mechanisms make LSD1/2 distinct from other histone demethylase families (i.e. Jumonji domain containing family) that can demethylate mono-, di-, and tri-methylated lysines through alpha-ketoglutarate dependent reactions (Kooistra, S. M. and K. Helin, Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5): p. 297-311; Mosammaparast, N. and Y. Shi, Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem, 2010. 79: p. 155-79).
  • Methylated histone marks on H3K4 and H3K9 are generally coupled with transcriptional activation and repression, respectively. As part of corepressor complexes (e.g., CoREST), LSD1 has been reported to demethylate H3K4 and repress transcription, whereas LSD1, in nuclear hormone receptor complex (e.g., androgen receptor), may demethylate H3K9 to activate gene expression (Metzger, E., et al., LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al., Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests the substrate specificity of LSD1 can be determined by associated factors, thereby regulating alternative gene expressions in a context dependent manner. In addition to histone proteins, LSD1 may demethylate non-histone proteins. These include p53 (Huang, J., et al., p53 is regulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p. 105-8.), E2F (Kontaki, H. and I. Talianidis, Lysine methylation regulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang, J., et al., Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p. 21499-504), Tat (Sakane, N., et al., Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p. e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S., et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res, 2011. 71(3): p. 655-60). The lists of non-histone substrates are growing with technical advances in functional proteomics studies. These suggest additional oncogenic roles of LSD1 beyond regulating chromatin remodeling. LSD1 also associates with other epigenetic regulators, such as DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases (HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., et al., Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al., CoREST is an integral component of the CoREST-human histone deacetylase complex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). These associations augment the activities of DNMT or HDACs. LSD1 inhibitors may therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed, preclinical studies have shown such potential already (Singh, M. M., et al., Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H., et al., Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One, 2013. 8(9): p. e75136).
  • LSD1 has been reported to contribute to a variety of biological processes, including cell proliferation, epithelial-mesenchymal transition (EMT), and stem cell biology (both embryonic stem cells and cancer stem cells) or self-renewal and cellular transformation of somatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histone demethylase LSD1 regulates neural stem cell proliferation. Mol Cell Biol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C. Izpisua Belmonte, LSD1 and pluripotency: a new player in the network. Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancer stem cells or cancer initiating cells have some pluripotent stem cell properties that contribute to the heterogeneity of cancer cells. This feature may render cancer cells more resistant to conventional therapies, such as chemotherapy or radiotherapy, and then develop recurrence after treatment (Clevers, H., The cancer stem cell. premises, promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C. Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013. 13(10): p. 727-38). LSD1 was reported to maintain an undifferentiated tumor initiating or cancer stem cell phenotype in a spectrum of cancers (Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 Confers Sensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p. 445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs) are an example of neoplastic cells that retain some of their less differentiated stem cell like phenotype or leukemia stem cell (LSC) potential. Analysis of AML cells including gene expression arrays and chromatin immunoprecipitation with next generation sequencing (ChIP-Seq) revealed that LSD1 may regulate a subset of genes involved in multiple oncogenic programs to maintain LSC (Harris, W. J., et al., The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al., Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggest potential therapeutic benefit of LSD1 inhibitors targeting cancers having stem cell properties, such as AMLs.
  • Overexpression of LSD1 is frequently observed in many types of cancers, including bladder cancer, NSCLC, breast carcinomas, ovary cancer, glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostate cancer, esophageal squamous cell carcinoma, and papillary thyroid carcinoma. Notably, studies found over-expression of LSD1 was significantly associated with clinically aggressive cancers, for example, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer, ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. In these studies, either knockdown of LSD1 expression or treatment with small molecular inhibitors of LSD1 resulted in decreased cancer cell proliferation and/or induction of apoptosis. See, e.g., Hayami, S., et al., Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p. 574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One, 2012. 7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20; Konovalov, S. and I. Garcia-Bassets, Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a novel therapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1): p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al., Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7; Schulte, J. H., et al., Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., The emerging role of histone lysine demethylases in prostate cancer. Mol Cancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations and changes in expression of histone demethylases in prostate cancer. Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma. Biochem Biophys Res Commun, 2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expression of RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol, 2013. 54(3): p. 499-503.
  • Recently, the induction of CD86 expression by inhibiting LSD1 activity was reported (Lynch, J. T., et al., CD86 expression as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1): p. 104-6). CD86 expression is a marker of maturation of dendritic cells (DCs) which are involved in antitumor immune response. Notably, CD86 functions as a co-stimulatory factor to activate T cell proliferation (Greaves, P. and J. G. Gribben, The role of B7 family molecules in hematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D. B. Flies, Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).
  • In addition to playing a role in cancer, LSD1 activity has also been associated with viral pathogenesis. Particularly, LSD1 activity appears to be linked with viral replications and expressions of viral genes. For example, LSD1 functions as a co-activator to induce gene expression from the viral immediate early genes of various type of herpes virus including herpes simplex virus (HSV), varicella zoster virus (VZV), and β-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med, 2013. 5(167): p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1 inhibitor showed antiviral activity by blocking viral replication and altering virus associated gene expression.
  • Recent studies have also shown that the inhibition of LSD1 by either genetic depletion or pharmacological intervention increased fetal globin gene expression in erythroid cells (Shi, L., et al., Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci USA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would be potentially therapeutically beneficial for the disease of β-globinopathies, including β-thalassemia and sickle cell disease where the production of normal β-globin, a component of adult hemoglobin, is impaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643; Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition may potentiate other clinically used therapies, such as hydroxyurea or azacitidine. These agents may act, at least in part, by increasing γ-globin gene expression through different mechanisms.
  • In summary, LSD1 contributes to tumor development by altering epigenetic marks on histones and non-histone proteins. Accumulating data have validated that either genetic depletion or pharmacological intervention of LSD1 normalizes altered gene expressions, thereby inducing differentiation programs into mature cell types, decreasing cell proliferation, and promoting apoptosis in cancer cells. Therefore, LSD1 inhibitors alone or in combination with established therapeutic drugs would be effective to treat the diseases associated with LSD1 activity.
    • SUMMARY OF THE INVENTION
  • The present invention is directed to, inter alia, a compound of Formula I:
  • Figure US20190119272A1-20190425-C00001
  • or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.
  • The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.
  • The present invention is further directed to a method of inhibiting LSD1 comprising contacting the LSD1 with a compound of Formula I.
  • The present invention is further directed to a method of treating an LSD1-mediated disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I.
    • DETAILED DESCRIPTION
  • The present invention provides, inter alia, LSD1-inhibiting compounds such as a compound of Formula I:
  • Figure US20190119272A1-20190425-C00002
  • or a pharmaceutically acceptable salt thereof, wherein:
  • X is N or CRX;
  • Ring A is C6-10 aryl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA;
  • Ring B is C6-10 aryl; 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; C3-10 cycloalkyl; or 4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S; wherein said C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RB;
  • R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
  • wherein when X is CRX, then R1 is not CN;
  • R2 is H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy2, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2 NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(═NRe2)Rb2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, or S(O)2NRc2Rd2; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(═NRe2)Rb2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRv2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
  • each RA is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(═NRe4)Rb4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(═NRe4)Rb4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
  • each RB is independently selected from Cy3, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(═NRe5)Rb5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy3, halo, C1-6 haloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(═NRe5)Rb5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5;
  • RX is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)ORa7, NRc7C(O)NRc7Rd7, C(═NRe7)Rb7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, NRc7S(O)Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, and S(O)2NRc7Rd7;
  • each Cy1, Cy2, Cy3, and Cy4 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy;
  • each RCy is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6, wherein said C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted by 1, 2, or 3 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6;
  • each Ra1 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy4; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(═NRe3)Rb3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3 S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;
  • each Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7 and S(O)2NRc7Rd7;
  • or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7 NRc7C(O)Rb7, NRc7C(O)NRc7Rd7 NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7 NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7 NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7 NRc7C(O)Rb7, NRc7C(O)NRc7Rd7 NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7 and S(O)2NRc7Rd7;
  • each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc6 and Rd6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra7, Rb7, Rc7, and Rd7 is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein said C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, and C1-4 haloalkoxy; and
  • each Re1, Re2, Re3, Re4, Re5, Re6, and Re7 is independently selected from H, C1-4 alkyl, and CN.
  • In some embodiments:
  • X is N or CRX;
  • Ring A is phenyl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA;
  • Ring B is phenyl or 5-6 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RB;
  • R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
  • wherein when X is CRX, then R1 is not CN;
  • R2 is H, halo, C1-6 alkyl, CN, ORa2, C(O)Rb2, C(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, S(O)2Rb2, or S(O)2NRc2Rd2; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa2, C(O)Rb2, C(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, S(O)2Rb2, and S(O)2NRc2Rd2;
  • each RA is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)2Rb4, and S(O)2NRc4Rd4;
  • each RB is independently selected from Cy3, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5, NRc5C(O)Rb5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy3, halo, C1-6 haloalkyl, CN, NO2, ORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5 NRc5C(O)Rb5, S(O)2Rb5, and S(O)2NRc5Rd5;
  • RX is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, NRc7Rd7, NRc7C(O)Rb7, S(O)2Rb7, and S(O)2NRc7Rd7;
  • each Cy1, Cy3, and Cy4 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy;
  • each RCy is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C14 alkyl-, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6, wherein said C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted by 1, 2, or 3 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6;
  • each Ra1 is independently selected from H, C1-6 alkyl, and Cy4; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, S(O)2Rb3, and S(O)2NRc3Rd3;
  • each Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7 NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc6 and Rd6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra7, Rb7, Rc7, and Rd7 is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein said C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, and C1-4 haloalkoxy; and
  • each Re1, Re6, and Re7 is independently selected from H, C1-4 alkyl, and CN.
  • In some embodiments:
  • X is N or CRX;
  • Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from RA;
  • Ring B is phenyl optionally substituted by 1 or 2 substituents independently selected from RB;
  • R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
  • R2 is H;
  • each RA is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, and ORa4, wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from CN and ORa4;
  • each RB is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and ORa5;
  • RX is H;
  • each Cy1 and Cy4 is independently selected from phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy;
  • each RCy is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6, wherein said C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, are each optionally substituted by 1, 2, or 3 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6;
  • each Ra1 is independently selected from H, C1-6 alkyl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, S(O)2Rb3, and S(O)2NRc3Rd3, and wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, S(O)2Rb6, and S(O)2NRc6Rd6;
  • each Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
  • each Ra3, Rb3, Rc3, and Rd3 is independently selected from H and C1-6 alkyl;
  • each Ra4 is independently selected from H and C1-6 alkyl;
  • each Ra5 is independently selected from H and C1-6 alkyl;
  • each Ra6, Rb6, Rc6, and Rd6 is independently selected from H and C1-6 alkyl; and
  • each Ra7, Rb7, Rc7, and Rd7 is independently selected from H and C1-4 alkyl.
  • In some embodiments, X is N.
  • In some embodiments, X is CRX.
  • In some embodiments, Ring A is phenyl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA.
  • In some embodiments, Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from RA.
  • In some embodiments, Ring A is phenyl substituted by one RA.
  • In some embodiments, Ring A is phenyl substituted by CN.
  • In some embodiments, Ring B is phenyl or 5-6 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein said phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RB.
  • In some embodiments, Ring B is phenyl optionally substituted by 1 or 2 substituents independently selected from RB.
  • In some embodiments, Ring B is phenyl substituted by one RB.
  • In some embodiments, Ring B is phenyl substituted by methyl.
  • In some embodiments, R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
  • In some embodiments, R1 is C1-6 alkyl, Cy1, or ORa1, wherein said C1-6 alkyl is substituted with one Cy1.
  • In some embodiments, R1 is pyrrolidin-3-ylmethoxy, 2-pyrrolidin-3-ylethyl, (1-methylpyrrolidin-3-yl)ethyl, 3-[(methylamino)methyl]phenyl, 3-aminopyrrolidin-1-yl)methyl]phenyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, or (1-methylpyrrolidin-3-yl)methoxy.
  • In some embodiments, R2 is H.
  • In some embodiments, each RA is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4 NRc4C(O)Rb4, S(O)2Rb4, and S(O)2NRc4Rd4.
  • In some embodiments, each RA is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, and ORa4, wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3, substituents independently selected from CN and ORa4.
  • In some embodiments, RA is CN.
  • In some embodiments, each RB is independently selected from Cy3, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa5, C(O)Rb5S, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5, NRc5C(O)Rb5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy3, halo, C1-6 haloalkyl, CN, NO2, ORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, NRc5Rd5, NRc5C(O)Rb5, S(O)2Rb5, and S(O)2NRc5Rd5.
  • In some embodiments, each RB is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and ORa5.
  • In some embodiments, RB is C1-6 alkyl.
  • In some embodiments, RB is methyl.
  • In some embodiments, RX is H.
  • In some embodiments, each Cy1 is independently selected from phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy.
  • In some embodiments, each Cy1 is phenyl or 4-7 membered heterocycloalkyl, each optionally substituted with 1 or 2 substituents independently selected from RCy.
  • In some embodiments, each Cy1 is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from RCy.
  • In some embodiments, each Cy1 is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl and NRc6Rd6, wherein said C1-4 alkyl is optionally substituted with NRc6Rd6.
  • In some embodiments, each RCy is C1-4 alkyl and NRc6Rd6, wherein said C1-4 alkyl is optionally substituted with NRc6Rd6.
  • In some embodiments, each Ra1 is independently selected from H, C1-6 alkyl, and Cy4; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3 NRc3C(O)Rb3S(O)2Rb3, and S(O)2NRc3Rd3.
  • In some embodiments, each Ra1 is independently selected from H, C1-6 alkyl, and 4-7 membered heterocycloalkyl; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3 NRc3C(O)Rb3, S(O)2Rb3, and S(O)2NRc3Rd3, and wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, S(O)2Rb6, and S(O)2NRc6Rd6.
  • In some embodiments, each Ra1 is C1-4 alkyl substituted by 4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, ORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, S(O)2Rb6, and S(O)2NRc6Rd6.
  • In some embodiments, each Ra1 is pyrrolidinylmethyl optionally substituted with one C1-4 alkyl.
  • In some embodiments, the compounds of the invention have Formula IIa:
  • Figure US20190119272A1-20190425-C00003
  • In some embodiments, the compounds of the invention have Formula IIb:
  • Figure US20190119272A1-20190425-C00004
  • In some embodiments, the compounds of the invention have Formula IIIa:
  • Figure US20190119272A1-20190425-C00005
  • In some embodiments, the compounds of the invention have Formula IIIb:
  • Figure US20190119272A1-20190425-C00006
  • It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
  • As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a monovalent substituent, or two hydrogen atoms are replaced with a divalent substituent like a terminal oxo group. It is to be understood that substitution at a given atom is limited by valency.
  • Throughout the definitions, the term “Ci-j” indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.
  • The term “z-membered” (where z is an integer) typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is z. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • As used herein, the term “Ci-j alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbons. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
  • As used herein, the term “Ci-j alkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has i to j carbons. Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms.
  • As used herein, “Ci-j alkenyl,” employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group having one or more double carbon-carbon bonds and having i to j carbons. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
  • As used herein, “Ci-j alkynyl,” employed alone or in combination with other terms, refers to an unsaturated hydrocarbon group having one or more triple carbon-carbon bonds and having i to j carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • As used herein, the term “Ci-j alkylamino,” employed alone or in combination with other terms, refers to a group of formula —NH(alkyl), wherein the alkyl group has i to j carbon atoms.
  • In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylamino group is —NH(C1-4 alkyl) such as, for example, methylamino, ethylamino or propylamino.
  • As used herein, the term “di-Ci-j-alkylamino,” employed alone or in combination with other terms, refers to a group of formula —N(alkyl)2, wherein each of the two alkyl groups has, independently, i to j carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the dialkylamino group is —N(C1-4 alkyl)2 such as, for example, dimethylamino or diethylamino.
  • As used herein, the term “Ci-j alkylthio,” employed alone or in combination with other terms, refers to a group of formula —S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylthio group is C1-4 alkylthio such as, for example, methylthio or ethylthio.
  • As used herein, the term “amino,” employed alone or in combination with other terms, refers to a group of formula —NH2.
  • As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C6-10 aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
  • As used herein, the term “aryl-Ci-j alkyl,” employed alone or in combination with other terms, refers to an alkyl group substituted by an aryl group. An example of a aryl-Ci-j alkyl group is benzyl.
  • As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(O)— group.
  • As used herein, the term “Ci-j cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 cycloalkyl, C3-7 cycloalkyl, or C5-6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • As used herein, the term “Ci-j cycloalkyl-Ci-j alkyl,” employed alone or in combination with other terms, refers to an alkyl group substituted by a cycloalkyl group. An example of a Ci-j cycloalkyl-Ci-j alkyl group is cyclopropylmethyl.
  • As used herein, “Ci-j haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group is C1-4 haloalkoxy.
  • As used herein, the term “halo,” employed alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F.
  • As used herein, the term “Ci-j haloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10-membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine, and the like.
  • A 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising wherein one or more of the ring-forming atoms are independently selected from N, O, and S. In some embodiments, the 5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the 5-membered heteroaryl group has 1 heteroatom ring member. Example ring-forming members include CH, N, NH, O, and S. Example five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4-oxadiazolyl.
  • A 6-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more of the ring-forming atoms is N. In some embodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the 6-membered heteroaryl group has 1 heteroatom ring member. Example ring-forming members include CH and N. Example six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.
  • As used herein, the term “heteroaryl-Ci-j alkyl,” employed alone or in combination with other terms, refers to an alkyl group substituted by a heteroaryl group. An example of a heteroaryl-Ci-j alkyl group is pyridylmethyl.
  • As used herein, the term “heterocycloalkyl,” employed alone or in combination with other terms, refers to non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 heteroatom ring member. When the heterocycloalkyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Example ring-forming members include CH, CH2, C(O), N, NH, O, S, S(O), and S(O)2. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or 6-membered. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran.
  • As used herein, the term “heterocycloalkyl-Ci-j alkyl,” employed alone or in combination with other terms, refers to an alkyl group substituted by a heterocycloalkyl group. An example of a heterocycloalkyl-Ci-j alkyl group is pyrrolidinylmethyl.
  • The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • When the compounds of the invention contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • The expressions, “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C. to about 30° C.
  • The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).
  • The following abbreviations may be used herein: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N, N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine); DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N, N, N′, N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); IPA (isopropyl alcohol); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC (reverse phase high performance liquid chromatography); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weight percent).
    • Synthesis
  • Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
  • The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, Inc., New York (2006), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.
  • Compounds of formula 9 can be synthesized as shown in Scheme 1. Compound 1 can undergo Suzuki reaction with an appropriate boronic acid or ester of formula 2 in the presence of a palladium catalyst and a suitable base such as K2CO3 to provide compound of formula 3. Installation of ring B to give compound of formula 5 can be achieved by coupling of compound 3 with compound of formula 4 under standard Suzuki coupling conditions (M is a boronic acid or ester, with palladium catalysis), or standard Negishi coupling conditions (M is Zn-halo, in the presence of a palladium catalyst), or standard Buchwald amination conditions (M is H attached to a ring-forming N atom in ring B, in the presence of a palladium catalyst and a suitable base). Halogenation of compound 5 using N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide can provide a compound of formula 6 (Hal is Cl, Br or I). Compound 6 can be converted to a formamidoxime derivative of formula 7 by reacting with N,N-dimethylformamide dimethyl acetal, followed by treatment with hydroxylamine. The formamidoxime derivative 7 can undergo cyclization upon treating with trifluoroacetic anhydride (TFAA) to afford a triazole compound of formula 8. Finally, the aryl halide 8 can react with R1-M to give a compound of formula 9 under standard cross coupling conditions, such as Suzuki coupling conditions (M is a boronic acid or ester, with palladium catalysis), Sonogashira coupling conditions (M is a terminal alkynyl, with palladium catalysis), Negishi coupling conditions (M is ZnCl, ZnBr or ZnI, with palladium catalysis), Buchwald amination conditions (R1-M is an amine (M is H), with palladium catalysis) or Ullmann coupling conditions (R1-M is an alcohol (M is H), with palladium or copper catalysis).
  • Figure US20190119272A1-20190425-C00007
  • Compounds of formula 11, wherein R2 is a non-hydrogen substituent, can be synthesized as shown in Scheme 2. Compound 6, which can be prepared as described in Scheme 1, can react with a nitrile R2—CN to deliver a triazole compound of formula 10 via a copper-catalyzed tandem addition-oxidative cyclization. This tandem reaction is described in Nagasawa et. al. in J. Am. Chem. Soc. 2009, 131, 42, 15080. Finally, the aryl halide 10 can react with R1-M under standard cross coupling conditions as described in Scheme 1 (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) to give compounds of formula 11.
  • Figure US20190119272A1-20190425-C00008
  • Alternatively, compounds of formula 11 can be prepared as shown in Scheme 3. Aryl halide 6 can react with R1-M under standard cross coupling conditions as described in Scheme 1 (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) to give compounds of formula 12. Condensation of amino-pyridine derivative 12 with ethoxycarbonyl isothiocyanate, followed by treatment with hydroxylamine can give the aminotriazole of formula 13. Transformation of the amino group in compound 13 to bromide can be achieved under standard Sandmeyer reaction conditions (e.g., NaNO2, HBr then CuBr) to give compounds of formula 14. Functionalization of aryl bromide 14 with an R2 substituent to give compound 11 can be performed under standard cross coupling reaction conditions (e.g., Suzuki coupling, Negishi coupling, Sonogashira coupling, Buchwald amination or Ullmann coupling) as described in the previous Schemes.
  • Figure US20190119272A1-20190425-C00009
    • Methods of Use
  • Compounds of the invention are LSD1 inhibitors and, thus, are useful in treating diseases and disorders associated with activity of LSD1. For the uses described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.
  • In some embodiments, the compounds of the invention are selective for LSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 with greater affinity or potency, compared to LSD2. In general, selectivity can be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold.
  • As inhibitors of LSD1, the compounds of the invention are useful in treating LSD1-mediated diseases and disorders. The term “LSD1-mediated disease” or “LSD1-mediated disorder” refers to any disease or condition in which LSD1 plays a role, or where the disease or condition is associated with expression or activity of LSD1. The compounds of the invention can therefore be used to treat or lessen the severity of diseases and conditions where LSD1 is known to play a role.
  • Diseases and conditions treatable using the compounds of the invention include generally cancers, inflammation, autoimmune diseases, viral induced pathogenesis, beta-globinopathies, and other diseases linked to LSD1 activity.
  • Cancers treatable using compounds according to the present invention include, for example, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
  • Example hematological cancers include, for example, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.
  • Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.
  • Example lung cancers include, for example, non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.
  • Example gastrointestinal cancers include, for example, cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.
  • Example genitourinary tract cancers include, for example, cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).
  • Example liver cancers include, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
  • Example bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors
  • Example nervous system cancers include, for example, cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.
  • Example gynecological cancers include, for example, cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).
  • Example skin cancers include, for example, melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
  • The compounds of the invention can further be used to treat cancer types where LSD1 may be overexpressed including, for example, breast, prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g., papillary thyroid carcinoma).
  • The compounds of the invention can further be used to treat genetic disorders such as Cowden syndrome and Bannayan-Zonana syndrome.
  • The compounds of the invention can further be used to treat viral diseases such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.
  • The compounds of the invention can further be used to treat beta-globinopathies including, for example, beta-thalassemia and sickle cell anemia.
  • As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a LSD1 protein with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a LSD1 protein, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the LSD1 protein.
  • As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • As used herein, the term “preventing” or “prevention” refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
    • Combination Therapies
  • The compounds of the invention can be used in combination treatments where the compound of the invention is administered in conjunction with other treatments such as the administration of one or more additional therapeutic agents. The additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated. The additional therapeutic agents can include, e.g., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K inhibitors for treatment of LSD1-mediated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • In some embodiments, the compounds of the invention can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, e.g., vorinostat.
  • For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The compounds of the invention can also be used in combination with medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.
  • For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with ruxolitinib.
  • For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
  • For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
  • For treating autoimmune or inflammatory conditions, the compound of the invention can be administered in combination with one or more additional agents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R, 5R)-3, 4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), or thalidomide.
  • For treating beta-thalassemia or sickle cell disease, the compound of the invention can be administered in combination with one or more additional agents such as Hydrea® (hydroxyurea).
  • In some embodiments, the compound of the invention can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.
  • Other examples of agents, one or more of which a provided compound may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular disease such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders such as gamma globulin.
    • Formulation, Dosage Forms and Administration
  • When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
  • Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • The therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
    • Labeled Compounds and Assay Methods
  • Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating LSD1 in tissue samples, including human, and for identifying LSD1 ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes LSD1 assays that contain such labeled compounds.
  • The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • It is to be understood that a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 125I, 35S and 82Br. In some embodiments, the compound incorporates 1, 2, or 3 deuterium atoms.
  • The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
  • A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind LSD1 by monitoring its concentration variation when contacting with LSD1, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to LSD1 (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to LSD1 directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of LSD1 as described below.
    • EXAMPLES
  • Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C18 5 μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.
  • Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:
  • pH=2 purifications: Waters Sunfire™ C18 5 μm particle size, 19×100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].
  • Typically, the flow rate used with the 30×100 mm column was 60 mL/minute. pH=10 purifications: Waters XBridge C18 5 μm particle size, 19×100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [See “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm column was 60 mL/minute.
    • Example 1 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile
  • Figure US20190119272A1-20190425-C00010
    • Step 1: 4-(6-amino-2-chloropyridin-3-yl)benzonitrile
  • Figure US20190119272A1-20190425-C00011
  • A reaction vessel containing a mixture of 5-bromo-6-chloropyridin-2-amine (415 mg, 2.00 mmol), (4-cyanophenyl)boronic acid (353 mg, 2.40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (80 mg, 0.1 mmol) and potassium carbonate (550 mg, 4.0 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was evacuated then refilled with nitrogen. The resulting mixture was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature then diluted with methylene chloride, washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 30% EtOAc/DCM to give the desired product as a white solid (320 mg, 71%). LC-MS calculated for C12H9ClN3 (M+H)+: m/z=230.0; found 230.0.
    • Step 2: 4-[6-amino-2-(4-methylphenyl)pyridin-3-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00012
  • A reaction vessel containing a mixture of 4-(6-amino-2-chloropyridin-3-yl)benzonitrile (320 mg, 1.39 mmol), 4-methyl-8-(4-methylphenyl)-2,6-dioxotetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide (413 mg, 1.67 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (60 mg, 0.07 mmol), and potassium carbonate (380 mg, 2.8 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was evacuated then filled with nitrogen. The resulting mixture was heated to 110° C. and stirred overnight. The mixture was cooled to room temperature then diluted with methylene chloride, washed with saturated NaHCO3 aqueous solution, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 30% EtOAc/DCM to give the desired product as a light yellow solid (335 mg, 84%). LC-MS calculated for C19H16N3(M+H)−: m/z=286.1; found 286.1.
    • Step 3: 4-[6-amino-5-bromo-2-(4-methylphenyl)pyridin-3-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00013
  • To a mixture of 4-[6-amino-2-(4-methylphenyl)pyridin-3-yl]benzonitrile (335 mg, 1.17 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a solution of N-bromosuccinimide (230 mg, 1.3 mmol) in tetrahydrofuran (4 mL). The resulting yellow solution was stirred at 0° C. for 1.5 h then diluted with methylene chloride, washed with saturated NaHCO3 aqueous solution, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 30% EtOAc/DCM to give the desired product as a yellow solid (432 mg, quant.). LC-MS calculated for C19H15BrN3 (M+H)+: m/z=364.0; found 364.0.
    • Step 4: N-[3-bromo-5-(4-cyanophenyl)-6-(4-methylphenyl)pyridin-2-yl]-N′-hydroxyimidoformamide
  • Figure US20190119272A1-20190425-C00014
  • To a mixture of 4-[6-amino-5-bromo-2-(4-methylphenyl)pyridin-3-yl]benzonitrile (275 mg, 0.755 mmol) in isopropyl alcohol (4 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.20 mL, 1.5 mmol). The mixture was heated to 95° C. and stirred for 5 h. The resulting yellow solution was cooled to 50° C. then hydroxylamine hydrochloride (160 mg, 2.3 mmol) was added. The reaction mixture was stirred at 50° C. overnight then cooled to room temperature and concentrated. The residue was purified on a silica gel column eluting with 0 to 10% MeOH/DCM to give the desired product as a yellow solid. LC-MS calculated for C20H16BrN4O (M+H)+: m/z=407.1; found 407.0.
    • Step 5: 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00015
  • To a solution of N-[3-bromo-5-(4-cyanophenyl)-6-(4-methylphenyl)pyridin-2-yl]-N′-hydroxyimidoformamide (307 mg, 0.754 mmol) in tetrahydrofuran (5 mL) at 0° C. was added trifluoroacetic anhydride (180 μL, 1.2 mmol). The resulting yellow solution was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO3 aqueous solution then extracted with methylene chloride. The combined extracts were washed with water and brine. The organic layer was dried over Na2SO4 then concentrated. The residue was purified on a silica gel column eluting with 0 to 20% EtOAc/DCM to give the desired product as a yellow solid. LC-MS calculated for C20H14BrN4 (M+H)+: m/z=389.0; found 389.1.
    • Step 6: 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile
  • A mixture of 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (176 mg, 0.452 mmol), tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (182 mg, 0.904 mmol), it-allylpalladium chloride dimer (8 mg, 0.02 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (22 mg, 0.045 mmol) and cesium carbonate (221 mg, 0.678 mmol) in toluene (6 mL) was evacuated then filled with nitrogen. The resulting mixture was heated to 110° C. and stirred overnight. The reaction mixture was cooled to room temperature then diluted with water and extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over Na2SO4 then concentrated. The residue was purified on a silica gel column eluted with 0 to 50% EtOAc/DCM to give a yellow solid, which was dissolved in methylene chloride (1.5 mL) then trifluoroacetic acid (0.5 mL) was added. The resulting yellow solution was stirred at room temperature for 30 min then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C25H24N5O (M+H)−: m/z=410.2; found 410.2.
    • Example 2 4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00016
    • Step 1: tert-butyl 3-ethynylpyrrolidine-1-carboxylate
  • Figure US20190119272A1-20190425-C00017
  • To a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (580 mg, 2.91 mmol) in methanol (15 mL) at room temperature was added potassium carbonate (1.00 g, 7.28 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (839 mg, 4.37 mmol). The resulting mixture was stirred at room temperature for 3 h then passed through a short pad of celite and concentrated. The residue was purified on a silica gel column eluting with 0 to 50% EtOAc/Hexanes to give the product as a colorless oil which solidified upon standing in fridge to give a white solid (374 mg, 66%).
    • Step 2: tert-butyl 3-{[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]ethynyl}pyrrolidine-1-carboxylate
  • Figure US20190119272A1-20190425-C00018
  • A mixture of 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 1, Step 5, 70. mg, 0.18 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (53 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol), and copper(I) iodide (6.8 mg, 0.036 mmol) in N,N-dimethylformamide (2 mL) was evacuated then filled with nitrogen. Then N,N-diisopropylethylamine (94 μL, 0.54 mmol) was added. The resulting mixture was heated to 85° C. and stirred for 4 h. The reaction mixture was cooled to room temperature then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 then concentrated. The residue was purified on a silica gel column eluting with 0 to 50% EtOAc/DCM to give the desired product (62 mg, 68%). LC-MS calculated for C31H30N5O2 (M+H)+: m/z=504.2; found 504.2.
    • Step 3: 4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • To a solution of tert-butyl 3-{[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]ethynyl}pyrrolidine-1-carboxylate (62 mg, 0.12 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added palladium (10 wt % on activated carbon, 26 mg, 0.025 mmol). The resulting mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through a short pad of celite then washed with THF. The filtrate was concentrated and the residue was dissolved in 3 mL of DCM then 1 mL of TFA was added. The resulting yellow solution was stirred at room temperature for 1 h then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C26H26N5(M+H)+: m/z=408.2; found 408.2.
    • Example 3 4-{5-(4-methylphenyl)-8-[2-(1-methylpyrrolidin-3-yl)ethyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile
  • Figure US20190119272A1-20190425-C00019
  • To a solution of 4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 2, Step 3, 14 mg, 0.034 mmol) in tetrahydrofuran (2 mL) was added formaldehyde (37 wt % in water, 13 μL, 0.17 mmol), followed by acetic acid (5.8 L, 0.10 mmol). The resulting solution was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (22 mg, 0.10 mmol) was added. The reaction mixture was stirred at room temperature overnight then filtered and purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C27H28N5(M+H)+: m/z=422.2; found 422.3.
    • Example 4 4-[8-{3-[(methylamino)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00020
    • Step 1: 4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00021
  • A mixture of 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 1, Step 5, 53 mg, 0.14 mmol), (3-formylphenyl)boronic acid (41 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (10 mg, 0.01 mmol), and potassium carbonate (38 mg, 0.27 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was evacuated then filled with nitrogen. The resulting mixture was heated to 90° C. and stirred for 6 h. The reaction mixture was cooled to room temperature then diluted with DCM, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 20% EtOAc/DCM to give the desired product as a yellow solid (45 mg, 80%). LC-MS calculated for C27H19N4O (M+H)+: m/z=415.2; found 415.2.
    • Step 2: 4-[8-{3-[(methylamino)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • To a solution of 4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (15 mg, 0.036 mmol) in tetrahydrofuran (2 mL) was added methylamine (2M in THF, 90. L, 0.18 mmol), followed by acetic acid (10. L, 0.18 mmol). The resulting mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (23 mg, 0.11 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with THF, filtered and purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C28H24N5(M+H)+: m/z=430.2; found 430.2.
    • Example 5 4-[8-{3-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00022
  • To a solution of 4-[8-(3-formylphenyl)-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 4, Step 1, 15 mg, 0.036 mmol) in tetrahydrofuran (2 mL) was added tert-butyl pyrrolidin-3-ylcarbamate (20 mg, 0.11 mmol), followed by acetic acid (10. L, 0.18 mmol). The resulting mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (23 mg, 0.11 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM then washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in methylene chloride (1 mL) then trifluoroacetic acid (1 mL) was added. The resulting yellow solution was stirred at room temperature for 1 h then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C31H29N6(M+H)+: m/z=485.2; found 485.3.
    • Example 6 4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00023
    • Step 1: 4-[5-(4-methylphenyl)-8-vinyl[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00024
  • A reaction vessel containing a mixture of 4-[8-bromo-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 1, Step 5, 338 mg, 0.868 mmol), 4-methyl-2,6-dioxo-8-vinyltetrahydro[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-4-ium-8-uide (206 mg, 1.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (42 mg, 0.052 mmol), and potassium carbonate (240 mg, 1.7 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was evacuated then filled with nitrogen. The resulting mixture was heated to 95° C. and stirred for 2 h. The mixture was cooled to room temperature then diluted with methylene chloride, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 30% EtOAc/DCM to give the desired product as a yellow solid (225 mg, 77%). LC-MS calculated for C22H17N4(M+H)+: m/z=337.1; found 337.1.
    • Step 2: 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00025
  • To a solution of 4-[5-(4-methylphenyl)-8-vinyl[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (225 mg, 0.669 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was added osmium tetraoxide (4 wt % in water, 420 μL, 0.067 mmol). The resulting mixture was stirred at room temperature for 10 min then sodium periodate (429 mg, 2.01 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water then extracted with DCM. The combined extracts were washed with water and brine then dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 0 to 30% EtOAc/DCM to give the desired product as a yellow solid (159 mg, 70%). LC-MS calculated for C21H15N4O (M+H)+: m/z=339.1; found 339.2.
    • Step 3: 4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • To a solution of 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (14 mg, 0.041 mmol) in methylene chloride (2 mL) was added tert-butyl piperazine-1-carboxylate (23 mg, 0.12 mmol), followed by acetic acid (12 μL, 0.21 mmol). The resulting mixture was stirred at room temperature overnight then sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in methylene chloride (1 mL) then trifluoroacetic acid (1 mL) was added. The resulting yellow solution was stirred at room temperature for 1 h then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C25H25N6(M+H)+: m/z=409.2; found 409.2.
    • Example 7 4-{5-(4-methylphenyl)-8-[(4-methylpiperazin-1-yl)methyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile
  • Figure US20190119272A1-20190425-C00026
  • To a solution of 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 6, Step 2, 14 mg, 0.041 mmol) in methylene chloride (2 mL) was added 1-methyl-piperazine (14 μL, 0.12 mmol), followed by acetic acid (12 μL, 0.21 mmol). The resulting mixture was stirred at room temperature overnight then sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C26H27N6(M+H)+: m/z=423.2; found 423.3.
    • Example 8 4-[8-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00027
  • To a solution of 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 6, Step 2, 57 mg, 0.17 mmol) in methylene chloride (3.0 mL) was added (3S)—N,N-dimethylpyrrolidin-3-amine (TCI, Cat#D2193: 64 μL, 0.50 mmol), followed by acetic acid (28 μL, 0.50 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (71 mg, 0.34 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C27H29N6(M+H)+: m/z=437.2; Found: 437.2. 1H NMR (500 MHz, DMSO) δ 8.53 (s, 1H), 7.86 (s, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 4.49 (s, 2H), 3.97 (br, 1H), 3.38 (br, 2H), 3.27 (br, 1H), 3.09 (br, 1H), 2.78 (s, 6H), 2.33 (s, 3H), 2.29 (br, 1H), 2.19-2.08 (m, 1H).
    • Example 9 4-[8-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00028
  • This compound was prepared using procedures analogous to those described for Example 8 with (3R)—N,N-dimethylpyrrolidin-3-amine replacing (3S)—N,N-dimethylpyrrolidin-3-amine. The compound was purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C27H29N6 (M+H)+: m/z=437.2; Found: 436.7.
    • Example 10 4-[8-{[(3S)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00029
  • To a solution of 4-[8-formyl-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile (Example 6, Step 2, 6.0 mg, 0.018 mmol) in methylene chloride (1.0 mL) was added tert-butyl methyl[(3S)-pyrrolidin-3-yl]carbamate (18 mg, 0.089 mmol), followed by acetic acid (10 μL, 0.18 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (11 mg, 0.053 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in methylene chloride (1 mL) then trifluoroacetic acid (0.5 mL) was added. The resulting yellow solution was stirred at room temperature for 2 h then concentrated. The residue was dissolved in acetonitrile then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C26H27N6(M+H)+: m/z=423.2; Found: 423.2.
    • Example 11 4-[8-{[(3R)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00030
  • This compound was prepared using procedures analogous to those described for Example 10 with tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate replacing tert-butyl methyl[(3S)-pyrrolidin-3-yl]carbamate. The compound was purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C26H27N6(M+H)+: m/z=423.2; Found: 423.1.
    • Example 12 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile
  • Figure US20190119272A1-20190425-C00031
    • Step 1: 4-(5-amino-3-chloropyrazin-2-yl)benzonitrile
  • Figure US20190119272A1-20190425-C00032
  • A mixture of 5-bromo-6-chloropyrazin-2-amine (1.04 g, 5.00 mmol), (4-cyanophenyl)boronic acid (0.882 g, 6.00 mmol), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (110 mg, 0.15 mmol), sodium carbonate (1.06 g, 10.0 mmol) in 1,4-dioxane (12.0 mL) and water (2.0 mL) was evacuated then filled with nitrogen. The resulting mixture was stirred at 90° C. for 4 h then cooled to room temperature. The mixture was diluted with methylene chloride (15 mL) and water (5 mL). The precipitates were collected by filtration and washed with methyl t-butyl ether then dried to afford the desired product (1.05 g, 91%). LC-MS calculated for C11H8ClN4 (M+H)+: m/z=231.0; found 231.1.
    • Step 2: 4-[5-amino-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00033
  • A reaction vessel containing a mixture of 4-(5-amino-3-chloropyrazin-2-yl)benzonitrile (1.15 g, 5.00 mmol), (4-methylphenyl)boronic acid (0.86 g, 6.4 mmol), sodium carbonate (1.06 g, 10.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.20 g, 0.25 mmol) in 1,4-dioxane (20.0 mL) and water (4.0 mL) was evacuated then refilled with nitrogen. The resulting mixture was stirred at 110° C. for 3 h then cooled to room temperature. The mixture was diluted with methylene chloride, washed with saturated NaHCO3 aqueous solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with DCM/diethyl-ether (1:1). The precipitate was collected by filtration to afford the desired product (0.61 g). The filtrate was concentrated and the residue was purified by flash chromatography on a silica gel column eluting with 0 to 100% EtOAc/DCM to afford another batch of the product (0.60 g). LC-MS calculated for C18H15N4(M+H)+: m/z=287.1; found 287.1.
    • Step 3: 4-[5-amino-6-bromo-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile
  • Figure US20190119272A1-20190425-C00034
  • To a solution of 4-[5-amino-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile (2.40 g, 8.38 mmol) in tetrahydrofuran (36 mL) at 0° C. was added N-bromosuccinimide (1.64 g, 9.22 mmol).
  • The resulting mixture was stirred at 0° C. for 1 h then warmed to room temperature. The mixture was diluted with methylene chloride, washed with saturated NaHCO3 aqueous solution, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0 to 60% EtOAc/DCM to give the desired product (2.8 g, 92%). LC-MS calculated for C18H14BrN4 (M+H)+: m/z=365.0; found 365.0.
    • Step 4: tert-butyl (3R)-3-({[3-amino-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate
  • Figure US20190119272A1-20190425-C00035
  • To a solution of tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.06 g, 10.2 mmol) in tetrahydrofuran (25 mL) at room temperature was added NaH (60 wt. % in mineral oil, 413 mg, 17.2 mmol). The resulting mixture was stirred at room temperature for 30 min then 4-[5-amino-6-bromo-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile (1.50 g, 4.10 mmol) was added. The reaction mixture was stirred at 85° C. for 15 h then cooled to room temperature. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated. The residue was purified on a silica gel column eluting with 10 to 40% EtOAc/DCM to give the product as a yellow solid. LC-MS calculated for C24H24N5O3 (M-tBu+2H)+: m/z=430.2; found 430.1.
    • Step 5: 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile
  • A mixture of tert-butyl (3R)-3-({[3-amino-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (137 μL, 1.03 mmol) in isopropyl alcohol (1.5 mL) was heated to 95° C. and stirred for 2 h. The reaction mixture was cooled to room temperature then concentrated. The residue was dissolved in methanol (1.5 mL) and cooled to 0° C. then pyridine (50 μL, 0.62 mmol) was added, followed by hydroxylamine-O-sulfonic acid (58 mg, 0.51 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined extracts were dried over Na2SO4 and then concentrated. The residue was purified on a silica gel column to give the desired intermediate, which was then dissolved in methylene chloride (1.5 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 h and then concentrated. The crude material was then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C24H23N6O (M+H)+: m/z=411.2; found 411.2. 1H NMR (500 MHz, DMSO) δ 8.86 (br, 2H), 8.61 (s, 1H), 7.80-7.72 (m, 2H), 7.57-7.51 (m, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 4.69-4.56 (m, 2H), 3.48-3.38 (m, 1H), 3.38-3.18 (m, 2H), 3.16-3.06 (m, 1H), 2.98-2.87 (m, 1H), 2.35 (s, 3H), 2.22-2.12 (m, 1H), 1.91-1.80 (m, 1H).
    • Example 13 4-(5-(4-methylphenyl)-8-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile
  • Figure US20190119272A1-20190425-C00036
  • To a solution of 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile (Example 12: 12:10 mg, 0.02 mmol) in methylene chloride (1.5 mL) was added formaldehyde (37 wt. % in water, 18.1 μL, 0.244 mmol), followed by acetic acid (6.9 μL, 0.12 mmol). The resulting mixture was stirred at room temperature for 3 h then sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for another 2 h then concentrated. The resulting residue was then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C25H25N6O (M+H)+: m/z=425.2; found 425.2.
    • Example A: LSD1 Histone Demethylase Biochemical Assay
  • LANCE LSD1/KDM1A demethylase assay—10 μL of 1 nM LSD-1 enzyme (ENZO BML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20, 25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μL compound/DMSO dotted in black 384 well polystyrene plates. Reactions were started by addition of 10 μL of assay buffer containing 0.4 μM Biotin-labeled Histone H3 peptide substrate: ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355) and incubated for 1 hour at 25° C. Reactions were stopped by addition of 10 μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with 1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225 nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mM Tranylcypromine-HCl (Millipore 616431). After stopping the reactions plates were incubated for 30 minutes and read on a PHERAstar FS plate reader (BMG Labtech). IC50 data for the example compounds is provided in Table 1 (+ refers to IC50≤50 nM; ++ refers to IC50>50 nM and ≤100 nM; +++ refers to IC50>50 nM and ≤100 nM; ++++ refers to IC50>500 nM and ≤1000 nM).
  • TABLE 1
    Example No. IC50 (nM)
    1 +
    2 +
    3 ++
    4 +++
    5 ++
    6 +++
    7 +++
    8 +
    9 ++
    10 +
    11 +
    12 +
    13 +++
  • Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims (35)

1-45. (canceled)
46. A method of treating a disease, wherein said disease is selected from leukemia, lung cancer, Ewing's sarcoma, prostate cancer, and myelofibrosis, comprising administering to a patient a therapeutically effective amount of a compound of Formula I:
Figure US20190119272A1-20190425-C00037
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CRX;
Ring A is C6-10 aryl or 5-10 membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA;
Ring B is C6-10 aryl; 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; C3-10 cycloalkyl; or 4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein said C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RB;
R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)Rc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(═NRe1)Rb1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
wherein when X is CRX, then R1 is not CN;
R2 is H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy2, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2 NRc2C(O)Rb2, NRc2C(O)ORa2 NRc2C(O)NRc2Rd2, C(═NRe2)Rb2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, or S(O)2NRc2Rd2; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(═NRe2)Rb2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
each RA is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(═NRe4)Rb4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(═NRe4)Rb4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
each RB is independently selected from Cy3, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5 NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(═NRe5)Rb5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy3, halo, C1-6 haloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(═NRe5)Rb5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5;
RX is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)ORa7, NRc7C(O)NRc7Rd7, C(═NRe7)Rb7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, NRc7S(O)Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, and S(O)2NRc7Rd7;
each Cy1, Cy2, Cy3, and Cy4 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy;
each RCy is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6 NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6, wherein said C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-4 alkyl-, C3-7 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted by 1, 2, or 3 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6;
each Ra1 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy4; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3 NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(═NRe3)Rb3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3;
each Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7 NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7 NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7 and S(O)2NRc7Rd7;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7 NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rc7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7 NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
or any Rc6 and Rd6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7 NRc7C(O)ORa7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7;
each Ra7, Rb7, Rc7, and Rd7 is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein said C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl, and C1-4 haloalkoxy; and
each Re1, Re2, Re3, Re4, Re5, Re6, and Re7 is independently selected from H, C1-4 alkyl, and CN.
47. The method of claim 46, wherein X is N.
48. The method of claim 46, wherein X is CRX.
49. The method of claim 46, wherein R1 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, S(O)2Rb1, or S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy1, halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
50. The method of claim 46, wherein R1 is pyrrolidin-3-ylmethoxy, 2-pyrrolidin-3-ylethyl, (1-methylpyrrolidin-3-yl)ethyl, 3-[(methylamino)methyl]phenyl, 3-aminopyrrolidin-1-yl)methyl]phenyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, or (1-methylpyrrolidin-3-yl)methoxy.
51. The method of claim 46, wherein each Cy1 is independently selected from phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy.
52. The method of claim 46, wherein each Cy1 is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl and NRc6Rd6, wherein said C1-4 alkyl is optionally substituted with NRc6Rd6.
53. The method of claim 46, wherein RCy is C1-4 alkyl and NRc6Rd6, wherein said C1-4 alkyl is optionally substituted with NRc6Rd6.
54. The method of claim 46, wherein each Ra1 is independently selected from H, C1-6 alkyl, and Cy4; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy4, halo, CN, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, S(O)2Rb3, and S(O)2NRc3Rd3.
55. The method of claim 46, wherein each Ra1 is pyrrolidinylmethyl optionally substituted by 1 C1-4 alkyl.
56. The method of claim 46, wherein the compound is a compound having Formula IIa:
Figure US20190119272A1-20190425-C00038
or a pharmaceutically acceptable salt thereof.
57. The method of claim 46, wherein the compound is a compound having Formula IIb:
Figure US20190119272A1-20190425-C00039
or a pharmaceutically acceptable salt thereof.
58. The method of claim 46, wherein the compound is a compound having Formula IIIa:
Figure US20190119272A1-20190425-C00040
or a pharmaceutically acceptable salt thereof.
59. The method of claim 46, wherein the compound is a compound having Formula
Figure US20190119272A1-20190425-C00041
or a pharmaceutically acceptable salt thereof.
60. The method of claim 46, wherein the compound is selected from:
4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;
4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-{5-(4-methylphenyl)-8-[2-(1-methylpyrrolidin-3-yl)ethyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;
4-[8-{3-[(methylamino)methyl]phenyl)}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-[8-{3-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-{5-(4-methylphenyl)-8-[(4-methylpiperazin-1-yl)methyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;
4-[8-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile;
4-[8-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile;
4-[8-{[(3S)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-[8-{[(3R)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;
4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile; and
4-(5-(4-methylphenyl)-8-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,
or a pharmaceutically acceptable salt of any of the aforementioned.
61. The method of claim 46, wherein said disease is leukemia.
62. The method of claim 61, wherein said leukemia is acute myelogenous leukemia.
63. The method of claim 61, wherein said leukemia is acute lymphoblastic leukemia.
64. The method of claim 61, wherein said leukemia is acute promyelocytic leukemia.
65. The method of claim 61, wherein said leukemia is chronic lymphocytic leukemia.
66. The method of claim 61, wherein said leukemia is chronic myelogenous leukemia.
67. The method of claim 46, wherein said lung cancer is undifferentiated small cell lung cancer.
68. The method of claim 46, wherein said lung cancer is non-small cell lung cancer.
69. The method of claim 46, wherein said lung cancer is bronchogenic carcinoma.
70. The method of claim 46, wherein said lung cancer is alveolar carcinoma.
71. The method of claim 46, wherein said lung cancer is bronchial adenoma.
72. The method of claim 46, wherein said lung cancer is chondromatous hamartoma.
73. The method of claim 46, wherein said lung cancer is mesothelioma.
74. The method of claim 46, wherein said lung cancer is squamous cell carcinoma.
75. The method of claim 46, wherein said lung cancer is undifferentiated large cell lung cancer.
76. The method of claim 46, wherein said lung cancer is adenocarcinoma.
77. The method of claim 46, wherein said disease is Ewing's sarcoma.
78. The method of claim 46, wherein said disease is prostate cancer.
79. The method of claim 46, wherein said disease is myelofibrosis.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10556908B2 (en) 2014-07-10 2020-02-11 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10676457B2 (en) 2014-02-13 2020-06-09 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10723700B2 (en) 2015-08-12 2020-07-28 Incyte Corporation Salts of an LSD1 inhibitor
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3392244A1 (en) 2014-02-13 2018-10-24 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9896436B2 (en) 2014-09-16 2018-02-20 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
MX2017003464A (en) 2014-09-16 2017-07-13 Celgene Quanticel Res Inc Histone demethylase inhibitors.
EP3307909A1 (en) 2015-06-12 2018-04-18 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
WO2017013061A1 (en) 2015-07-17 2017-01-26 Oryzon Genomics, S.A. Biomarkers associated with lsd1 inhibitors and uses thereof
EP3436445B1 (en) * 2016-03-15 2023-09-06 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
IL261721B (en) 2016-03-15 2022-07-01 Oryzon Genomics Sa Combinations of lsd1 inhibitors for use in the treatment of solid tumors
US11034991B2 (en) 2016-03-16 2021-06-15 Oryzon Genomics S.A. Methods to determine KDM1A target engagement and chemoprobes useful therefor
BR112018071585B1 (en) 2016-04-22 2024-01-02 Incyte Corporation FORMULATIONS OF AN LSD1 INHIBITOR, THEIR USES AND METHOD OF PREPARATION THEREOF
CN106432248B (en) * 2016-09-27 2018-11-27 郑州大学 The LSD1 of triazole containing pyrimido inhibitor, preparation method and application
EP3535420A1 (en) 2016-11-03 2019-09-11 Oryzon Genomics, S.A. Biomarkers for determining responsiveness to lsd1 inhibitors
CN106928235A (en) * 2017-05-03 2017-07-07 郑州大学 The LSD1 of triazole containing pyrimido inhibitor, its preparation method and application
AU2018269947B2 (en) 2017-05-15 2021-10-14 The Regents Of The University Of Michigan Pyrrolo(2,3-c)pyridines and related analogs as LSD-1 inhibitors
CN110996949A (en) 2017-08-03 2020-04-10 奥瑞泽恩基因组学股份有限公司 Methods for treating behavioral changes
AR112900A1 (en) 2017-09-13 2019-12-26 Hanmi Pharm Ind Co Ltd COMPOUND DERIVED FROM PIRAZOLE AND USE OF IT
WO2019068326A1 (en) 2017-10-05 2019-04-11 Université D'aix-Marseille Lsd1 inhibitors for the treatment and prevention of cardiomyopathies
KR20190040763A (en) 2017-10-11 2019-04-19 한미약품 주식회사 Pyrazolopyridine derivative compound and use thereof
KR20190040783A (en) 2017-10-11 2019-04-19 한미약품 주식회사 Pyrazole derivatives as Lysine-specific histone demethylase-1 inhibitors
US11685782B2 (en) 2017-10-23 2023-06-27 Children's Medical Center Corporation Methods of treating cancer using LSD1 inhibitors in combination with immunotherapy
IL303087B1 (en) 2018-02-27 2024-08-01 Incyte Corp Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors
WO2019222069A1 (en) 2018-05-15 2019-11-21 The Regents Of The University Of Michigan Imidazo[4,5-c]pyridine compounds as lsd-1 inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
CN113166153A (en) 2018-07-05 2021-07-23 因赛特公司 Fused pyrazine derivatives as A2A/A2B inhibitors
TWI829857B (en) 2019-01-29 2024-01-21 美商英塞特公司 Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors
WO2020159285A1 (en) 2019-02-01 2020-08-06 한미약품 주식회사 Imidazopyridine derivative compounds and use of same
EP3907225A4 (en) 2019-02-01 2022-09-14 Hanmi Pharm. Co., Ltd. Imidazopyridine derivative compounds and use of same
CN113613653A (en) 2019-03-20 2021-11-05 奥莱松基因组股份有限公司 Method of treating borderline personality disorder
JP7535797B2 (en) 2019-03-20 2024-08-19 オリソン ヘノミクス，ソシエダ アノニマ Methods for treating attention deficit hyperactivity disorder using KDM1A inhibitors such as the compound VAFIDEMSTAT
WO2021004610A1 (en) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarkers and methods for personalized treatment of small cell lung cancer using kdm1a inhibitors
EP3964204A1 (en) 2020-09-08 2022-03-09 Université d'Aix-Marseille Lsd1 inhibitors for use in the treatment and prevention of fibrosis of tissues
TW202304416A (en) 2021-04-08 2023-02-01 西班牙商奧萊松基因組股份有限公司 Combinations of lsd1 inhibitors for treating myeloid cancers
GB202115017D0 (en) 2021-10-20 2021-12-01 Univ London Queen Mary Sequential treatments and biomarkers to reverse resistance to kinase inhibitors
EP4419093A1 (en) 2021-10-20 2024-08-28 Queen Mary University of London Sequential treatments and biomarkers to reverse resistance to kinase inhibitors
CN115772170A (en) * 2021-12-03 2023-03-10 徐诺药业(南京)有限公司 Pyrazolo [1,5-a ] pyridine derivative and preparation method and application thereof
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer

Family Cites Families (314)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7013068A (en) 1969-09-17 1971-03-19
US4537889A (en) 1982-12-27 1985-08-27 Eli Lilly And Company Inotropic agents
US4625040A (en) 1984-09-24 1986-11-25 Pennwalt Corporation N-(phenyl) or N-(phenylcyclopropyl)-2,5-dihydro-2-oxo-4[(substituted phenyl)amino]-3-furancarboxamide derivatives
US4614810A (en) 1984-09-24 1986-09-30 Pennwalt Corporation 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acids and derivatives thereof
FR2607813B1 (en) 1986-12-05 1989-03-31 Montpellier I Universite ALKYLAMINO-8 IMIDAZO (1,2-A) PYRAZINES AND DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
JPH032778Y2 (en) 1986-12-15 1991-01-24
AU622330B2 (en) 1989-06-23 1992-04-02 Takeda Chemical Industries Ltd. Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides
JP2844351B2 (en) 1989-07-13 1999-01-06 株式会社科薬 Aqueous solution of stable polymyxin antibiotics
IL96432A0 (en) 1989-11-30 1991-08-16 Schering Ag Pesticidal compositions containing pyridine derivatives and novel pyridine derivatives
FR2662163A1 (en) 1990-05-16 1991-11-22 Lipha New 8-amino-1,2,4-triazolo[4,3-a]pyrazines, preparation processes and medicaments containing them
ATE177426T1 (en) 1992-06-17 1999-03-15 Upjohn Co PYRRIDINO-, PYRROLIDINO- AND AZEPINO- SUBSTITUTED OXIMES AS ANTIATHEROSCLEROSIC AGENTS AND ANTIHYPERCHOLESTEROLEMIC AGENTS
DE4327027A1 (en) 1993-02-15 1994-08-18 Bayer Ag Imidazoazine
FR2711993B1 (en) 1993-11-05 1995-12-01 Rhone Poulenc Rorer Sa Drugs containing 7H-imidazol [1,2-a] pyrazine-8-one derivatives, new compounds and their preparation.
US5932223A (en) 1996-09-26 1999-08-03 Merck & Co., Inc. Rotavirus vaccine formulations
CN1285834A (en) 1997-11-11 2001-02-28 小野药品工业株式会社 Fused pyrazine compound
JP2000319277A (en) 1999-05-11 2000-11-21 Ono Pharmaceut Co Ltd Condensed pyrazine compound and medicinal agent having the same as active ingredient
JP2000319278A (en) 1999-05-11 2000-11-21 Ono Pharmaceut Co Ltd Condensed pyrazine compound and medicinal agent having the same as active ingredient
JP4032566B2 (en) 1999-06-21 2008-01-16 東レ株式会社 Light emitting element
JP4041624B2 (en) 1999-07-21 2008-01-30 三井化学株式会社 Organic electroluminescence device
JP2001057292A (en) 1999-08-20 2001-02-27 Toray Ind Inc Luminescent element
AP1954A (en) 1999-09-28 2009-02-10 Panacea Biotec Ltd Controlled release compositions comprising nimesulide.
SE9903611D0 (en) 1999-10-06 1999-10-06 Astra Ab Novel compounds III
DE19948434A1 (en) 1999-10-08 2001-06-07 Gruenenthal Gmbh Substance library containing bicyclic imidazo-5-amines and / or bicyclic imidazo-3-amines
JP4409680B2 (en) 1999-10-18 2010-02-03 株式会社ヤクルト本社 Tricyclic fused imidazole derivatives
ATE300540T1 (en) 2000-04-27 2005-08-15 Yamanouchi Pharma Co Ltd IMIDAZOPYRIDINE DERIVATIVES
US6403588B1 (en) 2000-04-27 2002-06-11 Yamanouchi Pharmaceutical Co., Ltd. Imidazopyridine derivatives
CZ303572B6 (en) 2000-06-28 2012-12-12 Smithkline Beecham P. L. C. Finely divided preparation and process for preparing thereof
AR029538A1 (en) 2000-07-06 2003-07-02 Wyeth Corp PHARMACEUTICAL COMPOSITIONS OF ESTROGEN AGENTS
EP1301511A2 (en) 2000-07-14 2003-04-16 Bristol-Myers Squibb Pharma Company IMIDAZO 1,2-a]PYRAZINES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
DE10050663A1 (en) 2000-10-13 2002-04-18 Gruenenthal Gmbh Use of amino-substituted imidazo(1,2-a)pyridine, imidazo(1,2-a)pyrimidine and imidazo(1,2-a)pyrazine derivatives as NO synthase inhibitors, e.g. in treatment of migraine and neurodegenerative diseases
WO2002034748A1 (en) 2000-10-24 2002-05-02 Sankyo Company, Limited Imidazopyridine derivatives
JP2002205992A (en) 2000-11-08 2002-07-23 Takeda Chem Ind Ltd Bicyclic triazolone derivative and herbicide comprising the same
ES2251518T3 (en) 2000-11-10 2006-05-01 MERCK SHARP & DOHME LTD. IMIDAZO-TRIAZINE DERIVATIVES AS LIGANDOS FOR GABA RECEPTORS.
AU2002224927A1 (en) 2000-12-13 2002-06-24 Basf Aktiengesellschaft Use of substituted imidazoazines, novel imidazoazines, methods for the production thereof, and agents containing these compounds
EP1217000A1 (en) 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibitors of factor Xa and factor VIIa
TWI312347B (en) 2001-02-08 2009-07-21 Eisai R&D Man Co Ltd Bicyclic nitrogen-containing condensed ring compounds
WO2002072549A1 (en) 2001-03-12 2002-09-19 Millennium Pharmaceuticals, Inc. Functionalized heterocycles as modulators of chemokine receptor function and methods of use therefor
AR035543A1 (en) 2001-06-26 2004-06-16 Japan Tobacco Inc THERAPEUTIC AGENT FOR HEPATITIS C THAT INCLUDES A CONDENSED RING COMPOUND, CONDENSED RING COMPOUND, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS, BENZIMIDAZOL, THIAZOL AND BIFENYL COMPOUNDS USED AS INTERMEDIARY COMPARTMENTS OF COMPARTMENTS
IL159811A0 (en) 2001-07-13 2004-06-20 Neurogen Corp Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands
US6921762B2 (en) 2001-11-16 2005-07-26 Amgen Inc. Substituted indolizine-like compounds and methods of use
WO2003062392A2 (en) 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor
US20050113283A1 (en) 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
AU2003255845A1 (en) 2002-08-22 2004-03-11 Piramed Limited Phosphadidylinositol 3,5-biphosphate inhibitors as anti-viral agents
UA80296C2 (en) 2002-09-06 2007-09-10 Biogen Inc Imidazolopyridines and methods of making and using the same
CA2502148A1 (en) 2002-10-16 2005-02-17 Board Of Regents, The University Of Texas System Methods and compositions for increasing the efficacy of biologically-active ingredients
AU2003301226A1 (en) 2002-12-20 2004-07-22 Pharmacia Corp Acyclic pyrazole compounds for the inhibition of mitogen activated protein kinase-activated protein kinase-2
WO2004072081A1 (en) 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity
GB0303910D0 (en) 2003-02-20 2003-03-26 Merck Sharp & Dohme Therapeutic agents
US7157460B2 (en) 2003-02-20 2007-01-02 Sugen Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
US7186832B2 (en) 2003-02-20 2007-03-06 Sugen Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
MXPA05009771A (en) 2003-03-14 2005-10-26 Ono Pharmaceutical Co Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient.
DE602004025220D1 (en) 2003-04-11 2010-03-11 High Point Pharmaceuticals Llc PHARMACEUTICAL USES OF CONDENSED 1,2,4-TRIAZOLENE
WO2004089416A2 (en) 2003-04-11 2004-10-21 Novo Nordisk A/S Combination of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent
US7579355B2 (en) 2003-04-24 2009-08-25 Merck & Co., Inc. Inhibitors of Akt activity
SE0301653D0 (en) 2003-06-05 2003-06-05 Astrazeneca Ab Novel compounds
WO2005007658A2 (en) 2003-07-14 2005-01-27 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
ES2385219T3 (en) 2003-09-12 2012-07-19 Merck Serono Sa Sulfonamide derivatives for the treatment of diabetes
JP2005089352A (en) 2003-09-16 2005-04-07 Kissei Pharmaceut Co Ltd NEW IMIDAZO[1,5-a]PYRAZINE DERIVATIVE, MEDICINE COMPOSITION CONTAINING THE SAME AND THEIR USE
ATE369370T1 (en) 2003-10-10 2007-08-15 Pfizer Prod Inc SUBSTITUTED 2H-(1,2,4)TRIAZOLO(4,3-A)PYRAZINE AS GSK-3 INHIBITORS
US7419978B2 (en) 2003-10-22 2008-09-02 Bristol-Myers Squibb Company Phenyl-aniline substituted bicyclic compounds useful as kinase inhibitors
EP1677791A4 (en) 2003-10-31 2007-08-15 Takeda Pharmaceutical Nitrogen-containing fused heterocyclic compounds
EP1698335A4 (en) 2003-12-26 2007-08-01 Ono Pharmaceutical Co Preventive and/or therapeutic agent for disease in which mitochondrial benzodiazepine receptor participates
JPWO2005077948A1 (en) * 2004-02-16 2008-01-10 第一製薬株式会社 Antifungal heterocyclic compounds
US7306631B2 (en) 2004-03-30 2007-12-11 The Procter & Gamble Company Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof
ES2370729T3 (en) 2004-05-11 2011-12-22 Egalet Ltd. INFLATABLE PHARMACEUTICAL FORM INCLUDING GELLAN RUBBER.
WO2006015263A2 (en) 2004-07-29 2006-02-09 Threshold Pharmaceuticals, Inc. Lonidamine analogs
MX2007001612A (en) 2004-08-18 2007-04-10 Upjohn Co Triazolopyridine compounds useful for the treatment of inflammation.
MX2007002679A (en) 2004-09-02 2007-05-16 Smithkline Beecham Corp Chemical compounds.
US7524860B2 (en) 2004-10-07 2009-04-28 Pfizer Inc. Antibacterial agents
EP1819338A4 (en) 2004-11-22 2009-11-04 Threshold Pharmaceuticals Inc Tubulin binding anti cancer agents and prodrugs thereof
ES2330872T3 (en) 2004-12-01 2009-12-16 Merck Serono Sa DERIVATIVES OF (1,2,4) TRIAZOLO (4,3-A) PIRIDINE FOR THE TREATMENT OF HYPERPROLIFERATIVE DISEASES.
US20070293456A9 (en) 2004-12-30 2007-12-20 Anthony Hayford Method for the synthesis of 3-substituted indolizine and benzoindolizine compounds
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
EP1856110B1 (en) 2005-02-22 2011-06-22 Pfizer Inc. Oxyindole derivatives as 5ht4 receptor agonists
ITBO20050123A1 (en) 2005-03-07 2005-06-06 Alfa Wassermann Spa GASTRORESISTIC PHARMACEUTICAL FORMULATIONS CONTAINING RIFAXIMINA
TW200716594A (en) 2005-04-18 2007-05-01 Neurogen Corp Substituted heteroaryl CB1 antagonists
US7579360B2 (en) 2005-06-09 2009-08-25 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
ATE480239T1 (en) 2005-06-09 2010-09-15 Oncalis Ag ANGIOGENESIS INHIBITORS
US7572807B2 (en) 2005-06-09 2009-08-11 Bristol-Myers Squibb Company Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors
US7452892B2 (en) 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
US7632837B2 (en) 2005-06-17 2009-12-15 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
TW200726765A (en) 2005-06-17 2007-07-16 Bristol Myers Squibb Co Triazolopyridine cannabinoid receptor 1 antagonists
WO2007028051A2 (en) 2005-09-02 2007-03-08 Abbott Laboratories Novel imidazo based heterocycles
JP2009507843A (en) 2005-09-09 2009-02-26 シェーリング コーポレイション Aza-fused cyclin-dependent kinase inhibitors
TW200804386A (en) 2005-11-10 2008-01-16 Schering Corp Imidazopyrazines as protein kinase inhibitors
EP1959966B1 (en) 2005-11-28 2020-06-03 Marinus Pharmaceuticals, Inc. Ganaxolone formulations and methods for the making and use thereof
ES2376357T3 (en) 2005-12-27 2012-03-13 F. Hoffmann-La Roche Ag DERIVATIVES OF ARIL-ISOXAZOL-4-IL-IMIDAZO [1,5-A] PYRIDINE.
WO2007074491A1 (en) 2005-12-28 2007-07-05 Universita Degli Studi Di Siena HETEROTRICYCLIC AMIDE DERIVATIVES AS NEUROKININ-l (NKl) RECEPTOR LIGANDS
PE20070978A1 (en) 2006-02-14 2007-11-15 Novartis Ag HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks)
MX2008012617A (en) 2006-03-31 2008-10-10 Novartis Ag Organic compounds.
WO2007145921A1 (en) 2006-06-06 2007-12-21 Schering Corporation Imidazopyrazines as protein kinase inhibitors
US20090175852A1 (en) 2006-06-06 2009-07-09 Schering Corporation Imidazopyrazines as protein kinase inhibitors
CA2628661A1 (en) 2006-06-22 2007-12-27 Mallinckrodt Inc. Pyrazine derivatives and uses thereof in renal monitoring
US9216963B2 (en) 2006-06-22 2015-12-22 Medibeacon Inc. Pyrazine derivatives with extended conjugation and methods of using the same in optical applications
CA2655720A1 (en) 2006-06-29 2008-01-10 Schering Corporation Substituted bicyclic and tricyclic thrombin receptor antagonists
WO2008005423A1 (en) 2006-07-03 2008-01-10 Cambrex Charles City, Inc. Improved method of making sufentanil
WO2008005908A2 (en) 2006-07-07 2008-01-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US8198448B2 (en) 2006-07-14 2012-06-12 Amgen Inc. Fused heterocyclic derivatives and methods of use
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
PE20080403A1 (en) 2006-07-14 2008-04-25 Amgen Inc FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
EP2044061A2 (en) 2006-07-20 2009-04-08 Mehmet Kahraman Benzothiophene inhibitors of rho kinase
WO2008027812A2 (en) 2006-08-28 2008-03-06 Forest Laboratories Holdings Limited Imidazopyridine and imidazopyrimidine derivatives
DE102006041292A1 (en) 2006-09-01 2008-03-06 Henkel Kgaa Use of optionally substituted hexagonal heterocycle with a nitrogen in the ring for activating and improving the brightening effect of the hydrogen peroxide for keratin fibers such as fur, wool, feathers and human hair
WO2008037607A1 (en) 2006-09-25 2008-04-03 Basf Se Heterocyclic compounds containing carbonyl groups, and the use thereof for controlling phytopathogenic fungi
ES2377821T3 (en) 2006-10-11 2012-04-02 Amgen Inc. Imidazo- and triazolo-pyridine compounds and methods of use thereof.
CA2669094A1 (en) 2006-11-08 2008-05-29 Novavax,Inc. Method of preparing solid dosage forms of multi-phasic pharmaceutical compositions
WO2008056176A1 (en) 2006-11-10 2008-05-15 Scottish Biomedical Limited Pyrazolopyrimidines as phosphodiesterase inhibitors
AU2007323725B2 (en) 2006-11-22 2014-02-20 Incyte Holdings Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
WO2008065198A1 (en) 2006-12-01 2008-06-05 Galapagos N.V. Triazolopyridine compounds useful for the treatment of degenerative & inflammatory diseases
AU2007338631A1 (en) 2006-12-22 2008-07-03 Combinatorx, Incorporated Pharmaceutical compositions for treatment of parkinson's disease and related disorders
EP2118101B1 (en) 2007-03-09 2012-09-26 Probiodrug AG Imidazo [1,5-a] pyridine derivatives as inhibitors of glutaminyl cyclase
DE102007012645A1 (en) 2007-03-16 2008-09-18 Bayer Healthcare Ag Substituted imidazo and triazolopyrimidines
EP1972628A1 (en) 2007-03-21 2008-09-24 Schwarz Pharma Ag Indolizines and aza-analog derivatives thereof as CNS active compounds
ES2380395T3 (en) 2007-04-16 2012-05-11 Leo Pharma A/S Triazolopyridines as phosphodiesterase inhibitors for the treatment of dermal diseases
EP2142551B1 (en) 2007-04-17 2015-10-14 Bristol-Myers Squibb Company Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type i inhibitors
ES2395583T3 (en) 2007-05-10 2013-02-13 Ge Healthcare Limited IMIDAZOL (1,2-A) PIRIDINES and compounds related to activity against CB2 cannabinoid receptors
KR101520311B1 (en) 2007-05-21 2015-05-14 도레이 카부시키가이샤 Oral preparation comprising specific organic acid, and method for improvement in elution property and chemical stability of oral preparation
US8648069B2 (en) 2007-06-08 2014-02-11 Abbvie Inc. 5-substituted indazoles as kinase inhibitors
CN101790526A (en) 2007-06-08 2010-07-28 雅培制药有限公司 5-heteroaryl substituted indazoles as kinase inhibitors
MX2009013729A (en) 2007-06-14 2010-01-25 Schering Corp Imidazopyrazines as protein kinase inhibitors.
CL2008001839A1 (en) 2007-06-21 2009-01-16 Incyte Holdings Corp Compounds derived from 2,7-diazaspirocycles, inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1; pharmaceutical composition comprising said compounds; Useful to treat obesity, diabetes, glucose intolerance, type II diabetes, among other diseases.
US20090004281A1 (en) 2007-06-26 2009-01-01 Biovail Laboratories International S.R.L. Multiparticulate osmotic delivery system
JP2010533680A (en) 2007-07-18 2010-10-28 ノバルティス アーゲー Bicyclic heteroaryl compounds and their use as kinase inhibitors
WO2009017701A2 (en) 2007-07-31 2009-02-05 Schering Corporation Anti-mitotic agent and aurora kinase inhibitor combination as anti-cancer treatment
WO2009017954A1 (en) 2007-08-01 2009-02-05 Phenomix Corporation Inhibitors of jak2 kinase
US20090176778A1 (en) 2007-08-10 2009-07-09 Franz Ulrich Schmitz Certain nitrogen containing bicyclic chemical entities for treating viral infections
US20090047336A1 (en) 2007-08-17 2009-02-19 Hong Kong Baptist University novel formulation of dehydrated lipid vesicles for controlled release of active pharmaceutical ingredient via inhalation
FR2920091A1 (en) 2007-08-24 2009-02-27 Oreal Composition for coloring keratin fibers, preferably human hair, comprises amino pyrazolopyridine oxidation bases, couplers and polyols comprising hydrocarbon chain carrying two hydroxyl functions, where the chain is free from ether function
FR2920090A1 (en) 2007-08-24 2009-02-27 Oreal Composition for coloring keratin fibers, preferably human hair, comprises amino pyrazolopyridine oxidation bases, couplers, and surfactants comprising alkyl ether carboxylic acid and alkyl polyglucosides
KR20090022616A (en) 2007-08-31 2009-03-04 한올제약주식회사 Oral administration drug, which contains clopidogrel besylate
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
GB0719803D0 (en) 2007-10-10 2007-11-21 Cancer Rec Tech Ltd Therapeutic compounds and their use
RS53552B1 (en) 2007-10-11 2015-02-27 Astrazeneca Ab Pyrrolo[2,3-d]pyrimidin derivatives as protein kinase b inhibitors
WO2009048993A2 (en) 2007-10-12 2009-04-16 Novartis Ag Compositions comprising sphingosine 1 phosphate (s1p) receptor modulators
CA2710194C (en) 2007-12-19 2014-04-22 Amgen Inc. Inhibitors of p13 kinase
EP2231662B1 (en) 2007-12-19 2011-06-22 Genentech, Inc. 8-anilinoimidazopyridines and their use as anti-cancer and/or anti-inflammatory agents
KR100988233B1 (en) 2007-12-26 2010-10-18 한미홀딩스 주식회사 Pharmaceutical composition and formulation comprising clopidogrel 1,5-naphthalene disulfonate or hydrate thereof
JP5275371B2 (en) 2008-03-11 2013-08-28 インサイト・コーポレイション Azetidine derivatives and cyclobutane derivatives as JAK inhibitors
JP5638961B2 (en) 2008-03-13 2014-12-10 ザ ジェネラル ホスピタル コーポレイション Inhibitors of BMP signaling pathway
JP5547099B2 (en) 2008-03-14 2014-07-09 インテリカイン， エルエルシー Kinase inhibitors and methods of use
EP2444403A1 (en) 2008-04-18 2012-04-25 Shionogi Co., Ltd. Heterocyclic compound having inhibitory activity on PI3K
DE102008023801A1 (en) 2008-05-15 2009-11-19 Bayer Schering Pharma Aktiengesellschaft Substituted imidazo and triazolopyrimidines, imidazo and pyrazolopyrazines and imidazotriazines
US8349210B2 (en) 2008-06-27 2013-01-08 Transitions Optical, Inc. Mesogenic stabilizers
WO2010010187A1 (en) 2008-07-25 2010-01-28 Galapagos Nv Novel compounds useful for the treatment of degenerative and inflammatory diseases
WO2010010189A1 (en) 2008-07-25 2010-01-28 Galapagos Nv Novel compounds useful for the treatment of degenerative and inflammatory diseases
WO2010010188A1 (en) 2008-07-25 2010-01-28 Galapagos Nv Novel compounds useful for the treatment of degenerative and inflammatory diseases.
WO2010010184A1 (en) 2008-07-25 2010-01-28 Galapagos Nv [1, 2, 4] triazolo [1, 5-a] pyridines as jak inhibitors
UY32049A (en) 2008-08-14 2010-03-26 Takeda Pharmaceutical CMET INHIBITORS
TR200806298A2 (en) 2008-08-22 2010-03-22 Bi̇lgi̇ç Mahmut Pharmaceutical formulation
JP2010070503A (en) 2008-09-19 2010-04-02 Daiichi Sankyo Co Ltd Antifungal 2-amino-triazolopyridine derivative
US20120021519A1 (en) 2008-09-19 2012-01-26 Presidents And Fellows Of Harvard College Efficient induction of pluripotent stem cells using small molecule compounds
JP5731978B2 (en) 2008-09-26 2015-06-10 インテリカイン， エルエルシー Heterocyclic kinase inhibitor
WO2010043721A1 (en) 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
EP2376490B1 (en) 2008-12-04 2013-01-23 Proximagen Limited Imidazopyridine compounds
US8450321B2 (en) 2008-12-08 2013-05-28 Gilead Connecticut, Inc. 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor
WO2010084160A1 (en) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Phenylcyclopropylamine derivatives and their medical use
CA2749933A1 (en) 2009-02-04 2010-08-12 Supernus Pharmaceuticals, Inc. Formulations of desvenlafaxine
EP2393813B1 (en) 2009-02-04 2013-07-31 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 ß-hydroxysteroid dehydrogenase 1 useful for the treatment of diseases related to elevated level of cortisol
TR200900878A2 (en) 2009-02-05 2010-08-23 Bi̇lgi̇ç Mahmut Pharmaceutical formulations combined in a single dosage form
TR200900879A2 (en) 2009-02-05 2010-08-23 Bi̇lgi̇ç Mahmut Pharmaceutical compositions in which the active ingredients are combined in a single dosage form
ES2435804T3 (en) 2009-02-13 2013-12-23 Bayer Intellectual Property Gmbh Condensed pyrimidines as Akt inhibitors
KR20100101054A (en) 2009-03-07 2010-09-16 주식회사 메디젠텍 Composition for treating or preventing nuclear export of gsk3- mediated disease including compound for inhibiting nuclear export of gsk3
WO2010107404A1 (en) 2009-03-16 2010-09-23 Mahmut Bilgic Stable pharmaceutical combinations
TW201035078A (en) 2009-03-20 2010-10-01 Incyte Corp Substituted heterocyclic compounds
RU2529868C2 (en) 2009-03-31 2014-10-10 Кисcеи Фармасьютикал Ко., Лтд. Indolizine derivative and its application for medical purposes
ES2475091T3 (en) 2009-04-16 2014-07-10 Centro Nacional De Investigaciones Oncol�Gicas (Cnio) Imidazopyrazines as protein kinase inhibitors
TWI461426B (en) 2009-05-27 2014-11-21 Merck Sharp & Dohme (dihydro)imidazoiso[5,1-a]quinolines
US20120077802A1 (en) 2009-06-10 2012-03-29 Sunovion Pharmaceuticals Inc. Histamine h3 inverse agonists and antagonists and methods of use thereof
EP2445343B1 (en) 2009-06-25 2021-08-04 Alkermes Pharma Ireland Limited Prodrugs of nh-acidic compounds
SG178454A1 (en) 2009-08-17 2012-03-29 Intellikine Inc Heterocyclic compounds and uses thereof
US9708255B2 (en) 2009-08-18 2017-07-18 Robert A. Casero (bis)urea and (bis)thiourea compounds as epigenic modulators of lysine-specific demethylase 1 and methods of treating disorders
EP2473495A1 (en) 2009-09-18 2012-07-11 Almac Discovery Limited Pharmaceutical compounds
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
US8946296B2 (en) 2009-10-09 2015-02-03 Oryzon Genomics S.A. Substituted heteroaryl- and aryl-cyclopropylamine acetamides and their use
WO2011050245A1 (en) 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
US8541404B2 (en) 2009-11-09 2013-09-24 Elexopharm Gmbh Inhibitors of the human aldosterone synthase CYP11B2
US8614315B2 (en) 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
US9073927B2 (en) 2010-01-22 2015-07-07 Fundacion Centro Nacional De Investigaciones Oncologicas Carlos Iii Inhibitors of PI3 kinase
US20130085133A1 (en) 2010-02-08 2013-04-04 Sourthern Research Institute Office of Commercialization and Intellectual Prop. Anti-viral treatment and assay to screenfor anti-viral agent
WO2011106106A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae
WO2011106574A2 (en) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibitors for antiviral use
TW201200518A (en) 2010-03-10 2012-01-01 Kalypsys Inc Heterocyclic inhibitors of histamine receptors for the treatment of disease
EP2547678B1 (en) 2010-03-18 2016-03-16 Institut Pasteur Korea Anti-infective compounds
US9468642B2 (en) 2010-03-18 2016-10-18 Bayer Intellectual Property Gmbh Imidazopyrazines
MX342161B (en) 2010-04-02 2016-09-19 Euroscreen Sa Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders.
RS55348B1 (en) 2010-04-19 2017-03-31 Oryzon Gnomics S A Lysine specific demethylase-1 inhibitors and their use
BR112012027062B8 (en) 2010-04-20 2021-05-25 Fond Ieo compost, process for preparing a compost and uses thereof
MX2012012145A (en) 2010-04-28 2012-11-21 Daiichi Sankyo Co Ltd [5,6] heterocyclic compound.
US20130131057A1 (en) 2010-05-13 2013-05-23 Centro Nacional De Investigaciones Oncologicas (Cnio New bicyclic compounds as pi3-k and mtor inhibitors
CN103221404B (en) 2010-05-13 2015-12-16 安姆根有限公司 Can be used as the unsaturated nitrogen heterogeneous ring compound of PDE10 inhibitor
CN102247321A (en) 2010-05-20 2011-11-23 上海亚盛医药科技有限公司 Apogossypolone self-emulsifying drug delivery system and preparation method thereof
WO2011149438A1 (en) 2010-05-28 2011-12-01 Mahmut Bilgic Combination of antihypertensive agents
CN102295642B (en) 2010-06-25 2016-04-06 中国人民解放军军事医学科学院毒物药物研究所 2-Aryimidazole is [1,2-a] pyridine-3-acetamide, Preparation Method And The Use also
BR112012033402A2 (en) 2010-07-02 2017-01-24 Gilead Sciences Inc ion channel modulators according to fused heterocyclic compounds
CA2804845A1 (en) 2010-07-12 2012-01-19 Stuart Ince Substituted imidazo[1,2-a]pyrimidines and -pyridines
WO2012009475A1 (en) 2010-07-14 2012-01-19 Oregon Health & Science University Methods of treating cancer with inhibition of lysine-specific demethylase 1
CN101987082B (en) 2010-07-16 2013-04-03 钟术光 Solid preparation and preparation method thereof
CN101987081B (en) 2010-07-16 2012-08-08 钟术光 Controlled release preparation
EP2598480B1 (en) 2010-07-29 2019-04-24 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as lsd1 inhibitors
EP2598482B1 (en) 2010-07-29 2018-04-04 Oryzon Genomics, S.A. Arylcyclopropylamine based demethylase inhibitors of lsd1 and their medical use
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
CN102397552B (en) 2010-09-10 2016-06-08 广州自远生物科技有限公司 A kind of medicine compound preparation of quinolone containing class and its preparation method and application
US9527805B2 (en) 2010-09-10 2016-12-27 Robert A. Casero Small molecules as epigenetic modulators of lysine-specific demethylase 1 and methods of treating disorders
JP5906191B2 (en) 2010-09-29 2016-04-20 キッセイ薬品工業株式会社 (Aza) indolizine derivatives and their pharmaceutical use
US20130303545A1 (en) 2010-09-30 2013-11-14 Tamara Maes Cyclopropylamine derivatives useful as lsd1 inhibitors
JP2013540767A (en) 2010-10-07 2013-11-07 ザ ジェイ． デヴィッド グラッドストーン インスティテューツ Compositions and methods for modulating immunodeficiency virus transcription
BR112013007604B1 (en) 2010-10-18 2018-06-05 E.I. Du Pont De Nemours And Company COMPOUND, COMPOSITION, METHOD FOR CONTROLING A PARASITARY NEMATOID AND TREATED SEED
EP2444084A1 (en) 2010-10-21 2012-04-25 Centro Nacional de Investigaciones Oncológicas (CNIO) Use of PI3K inibitors for the treatment of obesity
AR083502A1 (en) 2010-10-21 2013-02-27 Biomarin Pharm Inc TOSILADA SALT OF (8S, 9R) -5-FLUORO-8- (4-FLUOROFENIL) -9- (1-METHYL-1H-1,2,4-TRIAZOL-5-IL) -8,9-DIHIDRO-2H -PIRIDO [4,3,2-DE] FTALAZIN-3 (7H) -ONA CRISTALINA
WO2012052745A1 (en) 2010-10-21 2012-04-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Combinations of pi3k inhibitors with a second anti -tumor agent
WO2012071469A2 (en) 2010-11-23 2012-05-31 Nevada Cancer Institute Histone demethylase inhibitors and uses thereof for treatment o f cancer
WO2012072713A2 (en) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae
CA2818903C (en) 2010-12-14 2021-03-23 Electrophoretics Limited 5-(1,3-benzoxazol-2-yl)-4-(pyridin-4-yl)pyrimidin-2-amine and its use as a casein kinase 1delta inhibitor
JP2013545779A (en) 2010-12-17 2013-12-26 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 6-substituted imidazopyrazines for use as MPS-1 and TKK inhibitors in the treatment of hyperproliferative disorders
UY33805A (en) 2010-12-17 2012-07-31 Boehringer Ingelheim Int ? Dihydrobenzofuranyl-piperidinyl, aza-dihydrobenzofuranylpiperidinyl and diaza-dihydrobenzofuranyl-piperidinyl derivatives, pharmaceutical compositions containing them and uses thereof?
US20140187548A1 (en) 2010-12-17 2014-07-03 Bayer Intellectual Property Gmbh 6 substituted imidazopyrazines for use as mps-1 and tkk inhibitors in the treatment of hyperproliferative disorders
JP5822944B2 (en) 2010-12-17 2015-11-25 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ Disubstituted imidazopyrazines for use as MPS-1 and TKK inhibitors in the treatment of hyperproliferative disorders
US9284317B2 (en) 2010-12-17 2016-03-15 Bayer Intellectual Property Gmbh Substituted imidazo[1,2-a]pyrazines as MPS-1 inhibitors
EP2655334B1 (en) 2010-12-22 2018-10-03 Eutropics Pharmaceuticals, Inc. Compositions and methods useful for treating diseases
TWI617559B (en) 2010-12-22 2018-03-11 江蘇恆瑞醫藥股份有限公司 2-arylimidazo[1,2-b]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives
WO2012100229A2 (en) 2011-01-21 2012-07-26 The General Hospital Corporation Compositions and methods for cardiovascular disease
WO2012107498A1 (en) 2011-02-08 2012-08-16 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative disorders
US20140163041A1 (en) 2011-02-08 2014-06-12 Oryzon Genomics S.A. Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders
JP5808826B2 (en) 2011-02-23 2015-11-10 インテリカイン， エルエルシー Heterocyclic compounds and uses thereof
BRPI1101013A2 (en) 2011-03-03 2013-06-04 Luciano Rabinowicz composition for preparation of energy drink and energy drink
US9464065B2 (en) 2011-03-24 2016-10-11 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
WO2012135113A2 (en) 2011-03-25 2012-10-04 Glaxosmithkline Llc Cyclopropylamines as lsd1 inhibitors
WO2012147890A1 (en) 2011-04-27 2012-11-01 持田製薬株式会社 Novel azole derivative
WO2012156531A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for inflammatory diseases or conditions
WO2012156537A2 (en) 2011-05-19 2012-11-22 Oryzon Genomics, S.A. Lysine demethylase inhibitors for thrombosis and cardiovascular diseases
EP2524918A1 (en) 2011-05-19 2012-11-21 Centro Nacional de Investigaciones Oncológicas (CNIO) Imidazopyrazines derivates as kinase inhibitors
RU2013156437A (en) 2011-06-07 2015-07-20 СПАЙ Груп Лтд. COMPOSITION AND METHODS FOR IMPROVING STABILITY AND EXTENDING THE PERIOD OF STORAGE OF SENSITIVE FOOD ADDITIVES AND FOOD PRODUCTS FROM THEM
AR086983A1 (en) 2011-06-20 2014-02-05 Incyte Corp DERIVATIVES OF AZETIDINIL FENIL, PIRIDIL OR PIRAZINIL CARBOXAMIDA AS JAK INHIBITORS
TW201311149A (en) 2011-06-24 2013-03-16 Ishihara Sangyo Kaisha Pesticide
EP2548877A1 (en) 2011-07-19 2013-01-23 MSD Oss B.V. 4-(5-Membered fused pyridinyl)benzamides as BTK-inhibitors
AP2014007488A0 (en) 2011-08-09 2014-03-31 Takeda Pharmaceutical Cyclopropaneamine compound
MX356486B (en) 2011-08-15 2018-05-30 Univ Utah Res Found Substituted (e)-n'-(1-phenylethylidene) benzohydrazide analogs as histone demethylase inhiitors.
US9289415B2 (en) 2011-09-01 2016-03-22 The Brigham And Women's Hospital, Inc. Treatment of cancer
JP6067019B2 (en) 2011-09-02 2017-01-25 プロメガ コーポレイションＰｒｏｍｅｇａ Ｃｏｒｐｏｒａｔｉｏｎ Compounds and methods for assessing the redox state of metabolically active cells, and methods for measuring NAD (P) / NAD (P) H
CA2886885C (en) 2011-10-10 2019-07-16 H. Lundbeck A/S Pde9i with imidazo pyrazinone backbone
CL2014000988A1 (en) 2011-10-20 2014-11-03 Oryzon Genomics Sa Compounds derived from (aryl or heteroaryl) cyclopropylamide, lsd1 inhibitors; procedure to prepare them; pharmaceutical composition that includes them; and method to treat or prevent cancer, a neurological disease, a viral infection and viral reactivation after latency.
IN2014CN03337A (en) 2011-10-20 2015-07-03 Oryzon Genomics Sa
MX356344B (en) 2011-10-20 2018-05-23 Oryzon Genomics Sa (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors.
ITMI20111971A1 (en) 2011-10-28 2013-04-29 Mesogenics Srl LSD-1 ENZYME INHIBITORS FOR THE INDUCTION OF OSTEOGENIC DIFFERENTIATION
WO2013074390A1 (en) 2011-11-14 2013-05-23 Merck Sharp & Dohme Corp. Triazolopyridinone pde10 inhibitors
WO2013085877A1 (en) 2011-12-05 2013-06-13 Brandeis University Treatment of amyloidosis by compounds that regulate retromer stabilization
US20150051202A1 (en) 2012-03-07 2015-02-19 Merck Patent Gmbh Triazolopyrazine derivatives
CN102579381B (en) 2012-03-30 2013-07-10 河南中帅医药科技发展有限公司 Guanidine hydrochloride sustained release preparation and preparation method thereof
GB201205669D0 (en) 2012-03-30 2012-05-16 Agency Science Tech & Res Bicyclic heterocyclic derivatives as mnk2 and mnk2 modulators and uses thereof
CN103373996A (en) 2012-04-20 2013-10-30 山东亨利医药科技有限责任公司 Bicyclic derivatives serving as CRTH2 receptor antagonist
JP6273274B2 (en) 2012-06-28 2018-01-31 ノバルティス アーゲー Complement pathway modulators and uses thereof
CN102772444A (en) 2012-07-06 2012-11-14 周明千 Method for processing traditional Chinese medicinal ultramicro wall-broken oral tablet slices
GB201212513D0 (en) 2012-07-13 2012-08-29 Ucb Pharma Sa Therapeutic agents
KR102092988B1 (en) 2012-09-28 2020-03-25 벤더르빌트 유니버시티 Fused heterocyclic compounds as selective bmp inhibitors
WO2014055955A1 (en) 2012-10-05 2014-04-10 Rigel Pharmaceuticals, Inc. Gdf-8 inhibitors
CN105051005B (en) 2012-10-12 2017-06-13 武田药品工业株式会社 Cyclopropylamine compound and application thereof
EP2919770A4 (en) 2012-11-14 2017-03-08 The Board of Regents of The University of Texas System Inhibition of hif-2 heterodimerization with hif1 (arnt)
WO2014084298A1 (en) 2012-11-28 2014-06-05 京都府公立大学法人 Lsd1-selective inhibitor having lysine structure
EP2925307B1 (en) 2012-11-30 2020-10-28 McCord, Darlene E. Hydroxytyrosol and oleuropein compositions for induction of dna damage, cell death and lsd1 inhibition
EP2740474A1 (en) 2012-12-05 2014-06-11 Instituto Europeo di Oncologia S.r.l. Cyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a
JP6111475B2 (en) 2012-12-19 2017-04-12 ウォックハート リミテッド Stable aqueous composition comprising human insulin or analogs or derivatives thereof
CN103054869A (en) 2013-01-18 2013-04-24 郑州大学 Application of amino dithio formic ester compound with triazolyl in preparing medicine taking LSD1 (Lysine Specificity Demethylase 1) as target
CN103933036B (en) 2013-01-23 2017-10-13 中国人民解放军军事医学科学院毒物药物研究所 2 Aryimidazoles simultaneously the acetamide derivative of [1,2 α] pyridine 3 prepare preventing and treating PTSD medicine in purposes
JP2016513112A (en) 2013-02-18 2016-05-12 ザ スクリプス リサーチ インスティテュート Vasopressin receptor modulators with therapeutic potential
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
WO2014164867A1 (en) 2013-03-11 2014-10-09 Imago Biosciences Kdm1a inhibitors for the treatment of disease
JP2016516399A (en) 2013-03-13 2016-06-09 オーストラリアン ニュークリア サイエンス アンド テクノロジー オーガニゼーション Transgenic non-human organism having non-functional TSPO gene
AU2014236348B2 (en) 2013-03-14 2018-05-10 Epizyme, Inc. Combination therapy for treating cancer
US20140343118A1 (en) 2013-03-14 2014-11-20 Duke University Methods of treatment using arylcyclopropylamine compounds
WO2014194280A2 (en) 2013-05-30 2014-12-04 The Board of Regents of the Nevada System of Higher Education on behalf of the University of Novel suicidal lsd1 inhibitors targeting sox2-expressing cancer cells
CN110015984A (en) 2013-06-19 2019-07-16 犹他大学研究基金会 Substituted (E)-N '-(1- phenylethylene) benzoyl hydrazine analog as histone demethylase inhibitor
UA117929C2 (en) 2013-06-21 2018-10-25 Міокардіа, Інк. Pyrimidinedione compounds against cardiac conditions
US9186391B2 (en) 2013-08-29 2015-11-17 Musc Foundation For Research Development Cyclic peptide inhibitors of lysine-specific demethylase 1
US9556170B2 (en) 2013-08-30 2017-01-31 University Of Utah Research Foundation Substituted-1H-benzo[d]imidazole series compounds as lysine-specific demethylase 1 (LSD1) inhibitors
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
PL3043778T3 (en) 2013-09-13 2018-04-30 Bayer Pharma Aktiengesellschaft Pharmaceutical compositions containing refametinib
KR101568724B1 (en) 2013-11-13 2015-11-12 서울대학교산학협력단 Novel compound, a preparing method thereof, and a use thereof as inhibitors of histone demethylase
MX2016007585A (en) 2013-12-11 2016-12-16 Celgene Quanticel Res Inc Inhibitors of lysine specific demethylase-1.
AU2015217073B2 (en) 2014-02-13 2019-08-22 Incyte Holdings Corporation Cyclopropylamines as LSD1 inhibitors
EP3392244A1 (en) 2014-02-13 2018-10-24 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
US9346776B2 (en) 2014-02-13 2016-05-24 Takeda Pharmaceutical Company Limited Fused heterocyclic compound
WO2015123437A1 (en) 2014-02-13 2015-08-20 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
EP3105226B1 (en) 2014-02-13 2019-09-04 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
US9428470B2 (en) 2014-02-13 2016-08-30 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN103893163B (en) 2014-03-28 2016-02-03 中国药科大学 The application of 2-([1,1 '-biphenyl]-4-base) 2-oxoethyl 4-((the chloro-4-aminomethyl phenyl of 3-) is amino)-4-oxobutanoic acid esters in preparation LSD1 inhibitor medicaments
ES2700549T3 (en) 2014-04-02 2019-02-18 Bristol Myers Squibb Co Biaryl kinase inhibitors
US10130618B2 (en) 2014-04-11 2018-11-20 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dabigatran and proton pump inhibitors
AR099994A1 (en) 2014-04-11 2016-08-31 Takeda Pharmaceuticals Co CYCLOPROPANAMINE COMPOUND AND ITS USES
EP2929884A1 (en) 2014-04-11 2015-10-14 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
CN103961340B (en) 2014-04-30 2019-06-25 南通中国科学院海洋研究所海洋科学与技术研究发展中心 A kind of LSD1 inhibitor and its application
AU2015265820C1 (en) 2014-05-30 2020-01-16 Ieo - Istituto Europeo Di Oncologia S.R.L. Cyclopropylamine compounds as histone demethylase inhibitors
CN104119280B (en) 2014-06-27 2016-03-16 郑州大学 Containing the pyrimidine derivatives of amino urea and Terminal Acetylenes structural unit, preparation method and application
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
TWI687419B (en) 2014-07-10 2020-03-11 美商英塞特公司 Imidazopyridines and imidazopyrazines as LSD1 inhibitors
GB201417828D0 (en) 2014-10-08 2014-11-19 Cereno Scient Ab New methods and compositions
CN104173313B (en) 2014-08-25 2017-05-17 杭州朱养心药业有限公司 Rivaroxaban troche pharmaceutical composition
JP6653116B2 (en) 2014-08-27 2020-02-26 日本ケミファ株式会社 Olmesartan prodrug formulations
SG11201702335VA (en) 2014-10-08 2017-04-27 Hoffmann La Roche Spirodiamine derivatives as aldosterone synthase inhibitors
EA201792205A1 (en) 2015-04-03 2018-02-28 Инсайт Корпорейшн HETEROCYCLIC COMPOUNDS AS LSD1 INHIBITORS
AU2016242973A1 (en) 2015-04-03 2017-11-23 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
WO2016156597A1 (en) 2015-04-03 2016-10-06 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
WO2017027678A1 (en) 2015-08-12 2017-02-16 Incyte Corporation Salts of an lsd1 inhibitor
CN105232488B (en) 2015-10-15 2021-05-04 上海凌凯医药科技有限公司 Solid pharmaceutical composition containing rivaroxaban
CA3009805C (en) 2015-12-29 2023-10-17 Mirati Therapeutics, Inc. Lsd1 inhibitors
JPWO2017130933A1 (en) 2016-01-25 2018-11-29 国立大学法人 熊本大学 Neurodegenerative disease therapeutic agent
BR112018071585B1 (en) 2016-04-22 2024-01-02 Incyte Corporation FORMULATIONS OF AN LSD1 INHIBITOR, THEIR USES AND METHOD OF PREPARATION THEREOF
US20200054643A1 (en) 2017-01-18 2020-02-20 Vanderbilt University Fused heterocyclic compounds as selective bmp inhibitors
EP3575301A4 (en) 2017-03-16 2020-08-05 Jiangsu Hengrui Medicine Co., Ltd. Heteroaryl[4,3-c]pyrimidine-5-amine derivative, preparation method therefor, and medical uses thereof
CN113166153A (en) 2018-07-05 2021-07-23 因赛特公司 Fused pyrazine derivatives as A2A/A2B inhibitors
WO2020047198A1 (en) 2018-08-31 2020-03-05 Incyte Corporation Salts of an lsd1 inhibitor and processes for preparing the same

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US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
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US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
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