WO2012045196A1 - Phosphoglycerate kinase inhibitors - Google Patents

Phosphoglycerate kinase inhibitors Download PDF

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Publication number
WO2012045196A1
WO2012045196A1 PCT/CN2010/001579 CN2010001579W WO2012045196A1 WO 2012045196 A1 WO2012045196 A1 WO 2012045196A1 CN 2010001579 W CN2010001579 W CN 2010001579W WO 2012045196 A1 WO2012045196 A1 WO 2012045196A1
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Prior art keywords
chloro
ethyl
quinoxalin
ethylamino
bis
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PCT/CN2010/001579
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French (fr)
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Xiangdong Xu
Jurgent Dinges
Lisa Hasvold
Kenton L. Longenecker
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Abbott Laboratories
Abbott Laboratories Trading (Shanghai) Company, Ltd.
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Priority to PCT/CN2010/001579 priority Critical patent/WO2012045196A1/en
Publication of WO2012045196A1 publication Critical patent/WO2012045196A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention pertains to compounds that inhibit phosphoglycerate kinase, compositions containing the compounds, and methods of treating diseases using the compounds.
  • Cancer cells metabolize glucose at a higher rate than their non-transformed counterparts. In addition, less differentiated, rapidly growing tumors exhibit a higher glycolytic rate than better differentiated, slower growing tumors. (Pedersen, P.L. et al. Biochim. Biophys. Acta, 1555
  • Phosphoglycerate kinase is the sixth often enzymes in the glycolytic pathway.
  • PGK equilibrates the transfer of the phosphate in position 1 of 1,3-bisphosphoglycerate (1,3-BPG) and the ⁇ -position of ATP in the presence of Mg 2+ as a cofactor (Scopes, R.K. The Enzymes, 3 rd Ed.; Boyer, P.D., Ed., Academic Press: New York, 1973; Vol. VIII. Chapter 10.).
  • PGK competes with diphosphoglycerate mutase for its substrate.
  • PGK2 is testis specific and is considered to be critical to normal motility and fertility of mammalian spermatozoa (Yoshioka, H. et al. Mol. Cell. Biol. 27 (2007) 7871.).
  • PGKl on the other hand is ubiquitously expressed and appears to be associated with a multi-drug resistant phenotype in different cancers (Duan, Z. et al. Anticancer Res. 22 (2002) 1933.).
  • Multidrug resistance is a significant barrier to the development of successful cancer treatments.
  • cancer cells which display resistance to apoptotic stimuli such as irradiation or chemotherapy often carry active oncogenes (e.g. Akt, Ras, Her2) and/or lack single tumor suppressors (e.g. TSCl/2, p53, LKB1).
  • active oncogenes e.g. Akt, Ras, Her2
  • single tumor suppressors e.g. TSCl/2, p53, LKB1
  • TSCl/2, p53, LKB1 single tumor suppressors
  • PGKl Overexpression of human PGKl in a U-20S osteogenic sarcoma cell line can induce a multidrug resistant (paclitaxel, vincristine, adriamycin and mitoxantrone) phenotype through an MDR-1 independent mechanism (Duan, Z. et al. Anticancer Res. 22 (2002) 1933.). Inhibition of PGKl therefore offers an opportunity to selectively affect multi-drug resistant cancer cells.
  • Inhibition of PGKl may have wide applicability in the treatment of various cancers.
  • overexpression of human PGKl in a U-20S osteogenic sarcoma cell line can induce a multidrug resistant phenotype through an MDR-1 independent mechanism (Duan, Z. et al.
  • PGKl overexpression in pancreatic ductal adenocarcinoma is discussed in Hwang, T.L. et al. Proteomics, 6 (2006) 2259.
  • Involvement of PGKl in the onset of prostate cancer is discussed in Wang. J. et al. Cancer Res. 67 (2007) 149.
  • Involvement of PGKl in the onset of breast cancer is discussed in Zhang, D. et al. Mol. Cell Proteomics, 4 (2005) 1686.
  • Involvement of PGKl in the onset of gastric cancer is discussed in Zieker, D. et al. Cell Physiol. Biochem. 21 (2008) 429.
  • PGK1 as a potential cytotoxic T
  • lymphocyte-directed tumor-associated antigen of HLA-A2+ colon cancer is discussed in Shichijo, S. et al. Clin. Cancer Res. 10 (2004) 5828.
  • the down-regulation of COX-2 expression and the promotion of the Thl immune response in Lewis lung carcinoma cells based on overexpression of PGK1 is discussed in Sun, K.H. et al. Int. J. Cancer, 123 (2008) 2840.
  • PGKl 's critical as a downstream target of the chemokine axis and as an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth is discussed in Taichman, R.S. et al. Cancer Res. 67 (2007) 149.
  • PGKl's role in supporting the interactions between cancer cells and their microenvironment is discussed in Taichman, R.S. et al. Cancer Res. 70 (2010) 471.
  • PGK When red blood cells pass through inadequately oxygenated tissues, PGK is inhibited and bisphosphogly cerate mutase catalyzes the conversion of 1,3-BPG to 2,3 -BPG. The increase in 2,3-BPG then decreases the hemoglobin affinity for oxygen, which enables more oxygen to be extracted from blood as it passes through those tissues.
  • inhibition of PGK is a potential means for treatment of cardiovascular and respiratory disorders (Voet, D. et al. Biochemistry, 1 st Ed.; John Wiley & Sons: New- York, 1990, Vol. 1.).
  • R 1 , R 2 , R 3 , and R are as defined herein.
  • compositions comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
  • One embodiment is directed a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Yet another embodiment pertains to a method for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Still another embodiment pertains to methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, or stomach cancer.
  • Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
  • alkyl (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 10 carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms.
  • substituents examples include ethenyl (vinyl), 2-propenyl, 3- propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms.
  • substituents include ethynyl, 2-propynyl, 3-propynyI, 2- butynyl, and 3-butynyl and the like.
  • Carbocyclyl (alone or in combination with another term(s)) means a saturated cyclic (i.e., “cycloalkyl”), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms
  • a carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a carbocyclyl may be a single ring structure, which typically contains from 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl may alternatively be polycyclic (i.e., may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls.
  • a spirocyclic carbocyclyl In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl.
  • a bridged carbocyclyl the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
  • a fused-ring carbocyclyl system two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include
  • cycloalkyl (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring atoms and more typically from 3 to 6 ring atoms.
  • single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y - refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 - C 8 -cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
  • hydrogen (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
  • hydroxy (alone or in combination with another term(s)) means -OH.
  • carboxy (alone or in combination with another term(s)) means -C(0)-OH.
  • amino (alone or in combination with another term(s)) means -N3 ⁇ 4-
  • halogen or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -CI), bromine radical (which may be depicted as -Br), or iodine radical (which may be depicted as -I).
  • a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical.
  • haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • perhalo indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
  • carbonyl (alone or in combination with another term(s)) means -C(O)-.
  • aminocarbonyl (alone or in combination with another term(s)) means -C(O)-
  • oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -0-.
  • alkylhydroxy (alone or in combination with another term(s)) means -alkyl-
  • alkylamino (alone or in combination with another term(s)) means -alkyl-NH 2 .
  • alkyloxy (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-O-CH3), ethoxy, n- propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • alkylcarbonyl (alone or in combination with another term(s)) means -C(O)- alkyl.
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means - C(0)-alkyl-NH 2 .
  • alkyloxy carbonyl (alone or in combination with another term(s)) means -
  • carbocyclylcarbonyl (alone or in combination with another term(s)) means - C(0)-carbocyclyl.
  • heterocyclylcarbonyl (alone or in combination with another term(s)) means -C(0)-heterocyclyl.
  • carbocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(0)-alkyl-carbocyclyl.
  • heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(0)-alkyl-heterocyclyl.
  • carbocyclyloxycarbonyl (alone or in combination with another term(s)) means -C(0)-0-carbocyclyl.
  • carbocyclylalkyloxycarbonyl (alone or in combination with another term(s)) means -C(0)-0-alkyl-carbocyclyl.
  • thio or "thia” (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-.
  • alkyl-thio- alkyl means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
  • thiol or "sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
  • (thiocarbonyl) (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
  • sulfonyl (alone or in combination with another term(s)) means -S(0) 2 -.
  • aminosulfonyl (alone or in combination with another term(s)) means -S(0) 2 - NH 2 .
  • heterocyclyl (alone or in combination with another tenn(s)) means a saturated ⁇ i.e., “heterocycloalkyl"), partially saturated ⁇ i.e., “heterocycloalkenyl”), or completely unsaturated ⁇ i.e., "heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom ⁇ i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrblidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothi
  • a heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
  • polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls.
  • a spirocyclic heterocyclyl one atom is common to two different rings.
  • a bridged heterocyclyl the rings share at least two common non-adjacent atoms.
  • two or more rings may be fused together, such that two rings share one common bond.
  • fused ring heterocyclyls containing two or three rings include indolizinyl, pyranopyrrolyl, 4 ⁇ - quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • fused- ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1 -benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3- benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including
  • heteroaryl (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • the Ci-C 6 - prefix on Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component.
  • the prefix "halo" on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals.
  • halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkyloxyalkyl” rather than “haloalkyloxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkyloxyhaloalkyl.”
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • modulate refers to the ability of a compound to increase or decrease the function, or activity, of a kinase.
  • Module as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase.
  • Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction.
  • Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • the present invention provides compounds of formula (I):
  • R z is halogen, hydroxy, trifluoromethoxy, cyano, amino, nitro, R , R 3 , OR 3 , or
  • NHC(0)R 5 provided that, when R 2 is halogen, R 1 is cyano or methoxy;
  • R 3 is halogen, or NHR 7 ;
  • R 4 is R 7 or NHR 7 ;
  • R 5A is heterocyclyl; wherein the heterocyclyl is optionally substituted with R 6 ;
  • R 5 is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 ;
  • R 6 is alkyl, cycloalkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR 10 ; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
  • each R 7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 ; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, ind
  • each R 9 is independently alkyl, aryl, or heterocyclyl
  • R 10 is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 1 is halogen, cyano, or methoxy
  • R 2 is halogen, hydroxy, trifluoromethoxy, cyano, amino, nitro, R 5A , R 5 , OR 5 , or
  • NHC(0)R 5 provided that, when R 2 is halogen, R 1 is cyano or methoxy;
  • R 3 is halogen, or NHR 7 ;
  • R 4 is R 7 or NHR 7 ;
  • R 5A is heterocyclyl; wherein the heterocyclyl is optionally substituted with R 6 ;
  • R 5 is alkyl or alkynyl; wherein the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 ;
  • R 6 is alkyl, cycloalkyl, aiyl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR 10 ; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
  • each R 7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 ; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, ind
  • each R 8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R 9 , and (b) the aryl and heterocyclyl are optionally substituted with C(0)OR 9 ; each R 9 is independently alkyl, aryl, or heterocyclyl; and
  • R 10 is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 1 is halogen. In another embodiment of formula (I), R 1 is cyano. In another embodiment of formula (I), R 1 is methoxy.
  • R 2 is hydroxyl. In another embodiment of formula (I),
  • R 2 is trifiuoromethoxy.
  • R 2 is cyano.
  • R 2 is amino.
  • R 2 is nitro.
  • R 2 is R 5A .
  • R 2 is R 5 .
  • R 2 is OR 5 .
  • R 2 is NHC(0)R 5 .
  • R 2 halogen, provided that R 1 is cyano or methoxy.
  • R 1 is methoxy, and R 2 is halogen. In another embodiment of formula (I), R 1 is cyano, and R 2 is halogen. In another embodiment of formula (I), R 1 is cyano, and R 2 is R 5 . In another embodiment of formula (I), R 1 is halogen, and R 2 is R 5 . In another embodiment of formula (I), R 1 is methoxy, and R 2 is methoxy. In another embodiment of formula (I), R 1 is cyano, and R 2 is halogen.
  • R 1 is halogen or methoxy
  • R 2 is halogen or R 5 , provided that, when R 2 is halogen, R 1 is methoxy.
  • R 1 is halogen or methoxy; and R 2 is R 5 .
  • R 1 is halogen or methoxy
  • R 2 is R 5
  • R 5 is alkynyl
  • R 3 is halogen. In another embodiment of formula (I), R 3 is NHR 7 .
  • R 1 is methoxy, R 2 is halogen, and R 3 is halogen. In another embodiment of formula (I), R 1 is halogen, R 2 is methoxy, and R 3 is halogen. In another embodiment of formula (I), R 1 is cyano, R 2 is halogen, and R 3 is halogen. In another embodiment of formula (I), R 1 is cyano, R 2 is R 5 , and R 3 is halogen. In another embodiment of formula (I), R 1 is halogen, R 2 is R 5 , and R 3 is halogen. In another embodiment of formula (I), R 1 is methoxy, R 2 is methoxy, and R 3 is halogen. In another embodiment of formula (I), R 1 is cyano, R is halogen, and R is halogen.
  • R 1 is methoxy, R 2 is halogen, and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is methoxy, R 2 is halogen, and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is cyano, R 2 is halogen, and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is cyano, R 2 is R 5 , and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is halogen, R 2 is R s , and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is methoxy, R 2 is methoxy, and R 3 is NHR 7 . In another embodiment of formula (I), R 1 is cyano, R 2 is halogen, and R 3 is NHR 7 .
  • R 4 is R 7 . In another embodiment of formula (I), R 4 is
  • R 1 is methoxy, R 2 is halogen, R 3 is halogen, and R 4 is R 7 .
  • R 1 is halogen, R 2 is methoxy, R 3 is halogen, and R 4 is R 7 .
  • R 1 is cyano, R 2 is halogen, R 3 is halogen* and R 4 is R .
  • R is cyano, R is R , R is halogen, and R is R .
  • R 1 is halogen, R 2 is R 5 , R 3 is halogen, and R 4 is R 7 .
  • R 1 is methoxy, R 2 is methoxy, R 3 is halogen, and R 4 is R 7 .
  • R 1 is cyano, R 2 is halogen, R 3 is halogen, and R 4 is R 7 .
  • R 1 is methoxy
  • R 2 is halogen
  • R 3 is NHR 7
  • R 4 is
  • R 7 is methoxy
  • R 2 is halogen
  • R 3 i ⁇ s NHR 7 is
  • R is cyano
  • R" is halogen
  • R is NHR
  • R is R .
  • R is cyano, R is R , R is NHR , and R is R .
  • R is halogen, R is R , R is NHR , and R is R .
  • R 1 is methoxy, R ⁇ " is methoxy, R 3 is NHR 7 , and R 4 is R 7.
  • R is cyano, R is halogen, R is NHR , and R is R .
  • R 1 is methoxy, R 2 is halogen, R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is halogen, R 2 is methoxy, R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is cyano, R 2 is halogen, R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is cyano, R 2 is R 5 , R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is halogen, R 2 is R 5 , R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is methoxy, R 2 is methoxy, R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is cyano, R 2 is halogen, R 3 is halogen, and R 4 is NHR 7 .
  • R 1 is methoxy
  • R 2 is halogen
  • R 3 is NHR 7
  • R 4 is
  • R 1 is methoxy, R 2 is halogen, R 3 is NHR 7 , and R 4 is NHR 7 .
  • R 1 is cyano, R 2 is halogen, R 3 is NHR 7 , and R 4 is NHR 7 .
  • R 1 is cyano, R 2 is R 5 , R 3 is NHR 7 , and R 4 is NHR 7 .
  • R 1 is halogen, R 2 is R 5 , R 3 is NHR 7 , and R 4 is NHR 7 .
  • R 1 is methoxy
  • R 2 is methoxy
  • R 3 is NHR 7
  • R 4 is NHR 7
  • R 1 is cyano
  • R 2 is halogen
  • R 3 is NHR 7
  • R 4 is NHR 7 .
  • R 5 is alkyl. In another embodiment of formula (I) R 5 is alkynyl. In another embodiment of formula (I) R 5 is alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 .
  • R 5 is alkynyl, wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6
  • R 6 is alkyl. In another embodiment of formula (I), R 6 is cycloalkyl. In another embodiment of formula (I), R 6 is aryl. In another embodiment of formula (I), R 6 is heterocyclyl.
  • R 6 is alkyl wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR 10 .
  • R 6 is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more hydroxy.
  • R 6 is aryl.
  • R 6 is heterocyclyl wherein the heterocyclyl is optionally substituted with one or more hydroxy.
  • R 7 is Ci_3-alkyl. In another embodiment of formula (I), R 7 is alkynyl. In another embodiment of formula (I), R 7 is aryl. In another embodiment of formula (I), R 7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
  • R 7 is C].3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) .
  • R 7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 .
  • R 7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R , and C(0)R .
  • R 8 is alkyl. In another embodiment of formula (I), R 8 is aryl. In another embodiment of formula (I), R 8 is heterocyclyl.
  • R 8 is alkyl wherein the alkyl is optionally substituted with one or more R 9 .
  • R 8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 9 is alkyl. In another embodiment of formula (I), R 9 is aryl. In another embodiment of formula (I), R 9 is heterocyclyl.
  • R 10 is alkyl
  • N-ethyl-6,7-dimetlioxy-3-(pyridin-4-yl)quinoxalin-2-amine or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula ( ⁇ ):
  • R 5 is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 ;
  • R 6 is alkyl, cycloalkyl, aryl, or heterocyclyl; herein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR 10 ; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
  • each R 7 is independently Cu-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyI; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 ; (C) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indo
  • each R 8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R 9 , and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 ;
  • each R 9 is independently alkyl, aryl, or heterocyclyl
  • R 10 is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 5 is alkyl. In another embodiment of formula ( ⁇ ) R 5 is alkynyl. In another embodiment of formula (II) R 5 is alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0)NH 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 .
  • R 5 is alkynyl, wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH 2 , C(0) H 2 , R 6 , OR 6 , C(0)R 6 , C(0)OR 6 , or OC(0)R 6 .
  • R 6 is alkyl. In another embodiment of formula (II), R 6 is cycloalkyl. In another embodiment of formula (II), R 6 is aryl. In another embodiment of formula (II), R 6 is heterocyclyl.
  • R 6 is alkyl wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR 10 .
  • R 6 is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more hydroxy.
  • R 6 is aryl.
  • R 6 is heterocyclyl wherein the heterocyclyl is optionally substituted with one or more hydroxy.
  • R 7 is Ci-3-alkyl. In another embodiment of formula (II), R 7 is alkynyl. In another embodiment of fonnula (II), R 7 is aryl. In another embodiment of formula ( ⁇ ), R 7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
  • R 7 is Cu-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)N3 ⁇ 4, and C(0)NHR 8 .
  • R 7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , and C(0)R 8
  • R 8 is alkyl. In another embodiment of formula (II), R 8 is aryl. In another embodiment of formula (II), R 8 is heterocyclyl. In one embodiment of formula (II), R is alkyl wherein the alkyl is optionally substituted with one or more R 9 . In another embodiment of formula (II), R 8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 . In another embodiment of formula (II), R s is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 9 is alkyl. In another embodiment of formula (II), R 9 is aryl. In another embodiment of formula ( ⁇ ), R 9 is heterocyclyl.
  • R 10 is alkyl
  • the present invention provides compounds of formula (III):
  • each R 7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyI, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)N3 ⁇ 4 and C(0) HR 8 ; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indo
  • each R s is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R 9 , and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 ;
  • each R 9 is independently alkyl, aryl, or heterocyclyl
  • R 10 is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 7 is Ci-3-alkyl. In another embodiment of formula (III), R 7 is alkynyl. In another embodiment of formula ( ⁇ ), R 7 is aryl. In another embodiment of formula (III), R 7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
  • R 7 is Ci-3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 .
  • R 7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , arid C(0)R 8.
  • R 8 is alkyl. In another embodiment of formula (III),
  • R is aryl. In another embodiment of formula (III), R is heterocyclyl.
  • R 8 is alkyl wherein the alkyl is optionally substituted with one or more R 9 .
  • R 8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 8 is heterocyclyl, whereiii the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 9 is alkyl. In another embodiment of formula (III), R 9 is aryl. In another embodiment of formula (III), R 9 is heterocyclyl.
  • R 10 is alkyl
  • the present invention provides compounds of formula (IV):
  • each R 7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 ; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, in
  • each R 8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R 9 , and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 ;
  • each R 9 is independently alkyl, aryl, or heterocyclyl
  • R 10 is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 7 is Ci-3-alkyl. In another embodiment of formula (IV), R 7 is Ci-3-alkyl. In another embodiment of formula (IV), R 7 is Ci-3-alkyl.
  • R 7 is alkynyl. In another embodiment of formula (IV), R 7 is aryl. In another embodiment of formula (IV), R 7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazoly, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
  • R 7 is Ci-3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R ) 2 .
  • R 7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 .
  • R 7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , and C(0)R 8 .
  • R 8 is alkyl wherein the alkyl is optionally substituted with one or more R 9 .
  • R 8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 9 is alkyl. In another embodiment of formula (IV), R 9 is aryl. In another embodiment of formula (IV), R 9 is heterocyclyl.
  • R 10 is alkyl
  • the present invention provides compounds of formula (V):
  • each R 7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 , (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 ; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, ind
  • each R 8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R 9 , and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 ;
  • each R 9 is independently alkyl, aryl, or heterocyclyl; and R is alkyl; or a pharmaceutically acceptable salt thereof.
  • R 7 is Ci-3-alkyl. In another embodiment of formula (V), R 7 is alkynyl. In another embodiment of formula (V), R 7 is aryl. In another embodiment of formula (V), R 7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
  • R 7 is Ci_3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy 1, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R 8 ) 2 .
  • R 7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R 8 , C(0)NH 2 , and C(0)NHR 8 .
  • R 7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , and C(0)R 8 .
  • R 8 is alkyl. In another embodiment of formula (V),
  • R 8 is aryl. In another embodiment of formula (V), R 8 i *s heterocyclyl.
  • R 8 is alkyl wherein the alkyl is optionally substituted with one or more R 9 .
  • R 8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R 9 , C(0)OR 9 , and C(0)R 9 .
  • R 9 is alkyl. In another embodiment of formula (V), R 9 is aryl. In another embodiment of formula (V), R 9 is heterocyclyl.
  • R 10 is alkyl
  • Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R” and “S” are as defined in Pure Appl. Chem. (1976) 45, 13-10.
  • Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diastereoisomers of the compounds thereof.
  • Compounds of this invention may also contain carbon-carbon double bonds or carbon- nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon-carbon or carbon- nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules.
  • the compounds of this invention may also exist as a mixture of "E” and "Z" isomers.
  • Compounds of this invention may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another.
  • tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like.
  • This invention also is directed, in part, to all salts of the compounds of formula (I).
  • a salt of a compound may be advantageous due to one or more of the salt's properties, such as, for example, enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or other solvents.
  • the salt preferably is pharmaceutically acceptable and/or physiologically compatible.
  • pharmaceutically acceptable is used adjectivally in this patent application to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
  • salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • these salts typically may be prepared by conventional means by reacting, for example, the appropriate acid or base with a compound of the invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from an inorganic or organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate,
  • cyclohexylaminosulfonate algenic acid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate, pectinate, 2-naphthalesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
  • Pharmaceutically acceptable base addition salts of the compounds of formula (I) include, for example, metallic salts and organic salts.
  • Preferred metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Preferred organic salts can be made from amines, such as tromethamine, diethylamine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quatemized with agents such as lower alkyl (Ci-Cg) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl (Ci-Cg) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl, die
  • substantially pure in reference to a compound/salt/isomer, means that the preparation/composition containing the , compound/salt/isomer contains more than about 85% by weight of the compound/salt/isomer, preferably more than about 90% by weight of the compound/salt/isomer, preferably more than about 95% by weight of the compound/salt/isomer, preferably more than about 97% by weight of the compound/salt/isomer, and preferably more than about 99% by weight of the
  • Protecting groups for C(0)OH moieties include, but are not limited to, acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl,.
  • Protecting groups for C(O) and C(0)H moieties include, but are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal, 1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like.
  • Protecting groups for NH moieties include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4- dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoiyl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl and the like.
  • Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, l,l-dimethyl-2- propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4- methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para- toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
  • Compounds having formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally
  • intrasternally intravenously, subcutaneously
  • rectally topically
  • transdermally vaginally
  • intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature.
  • Compounds having formula (I) may be administered with or without an excipient.
  • Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents,
  • disintegrating agents emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered orally include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to,
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered parenterally include, but are not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having formula (I) to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
  • compositions and the method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions.
  • the present invention provides methods of using a compound or composition of the invention to treat or prevent a disease or condition involving mediation, overexpression or disregulation of kinases in a mammal.
  • compounds of this invention are expected to have utility in treatment of diseases or conditions during which protein kinases such as any or all phosphoglycerate kinase members are expressed.
  • One embodiment is directed a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Yet another embodiment pertains to a method for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Still another embodiment pertains to methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, or stomach cancer.
  • Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
  • One embodiment is directed a method of treating cardiovascular disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
  • One embodiment is directed a method of treating respiratory disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to a method of treating respiratory disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
  • One embodiment is directed a method of treating parasites in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to a method of treating parasites in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
  • diseases and conditions of humans or other animals that can be treated with inhibitors of kinases include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblasts, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma,
  • cystadenocarcinoma diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma
  • lymphoid malignancies of T-cell or B-cell origin leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
  • myxosarcoma neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.
  • the methods of the present invention typically involve administering to a subject in need of therapeutic treatment an effective amount of a compound of formula (1) .
  • Therapeutically effective amounts of a compound having formula (I) depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered.
  • the amount of a compound having formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight.
  • Single dose compositions contain these amounts or a combination of submultiples thereof.
  • the present invention further provides methods of using a compound or composition of the invention in combination with one or more additional active agents.
  • alkylating agents alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics,
  • aurora kinase inhibitors for example, Bcl-xL, Bcl-w and Bfl-1 inhibitors, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVD's, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAP's) intercalating antibiotics, kinase inhibitors, mammalian target of rapamycin inhibitors, microRNA's mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (IAP's) intercalating antibiotics, kinase inhibitors
  • a BiTE antibody is a bi-specific antibody that directs T-cells to attach cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
  • Exemplary BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like.
  • SiRNA's are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications shall not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F- ribonucleotides, 2'-methoxyethyI ribonucleotides or a combination thereof.
  • the siRNA can have varying lengths (10-200 bps) and structures (hairpins, single/double strands, bulges, nicks/gaps, mismatches) and processed in the cell to provide active gene silencing.
  • a double- stranded siRNA can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs).
  • the overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3'-ends of a given strand.
  • Multivalent binding proteins are binding proteins comprising two or more antigen binding sites.
  • the multivalent binding protein is preferably engineered to have the three or more antigen binding sites and is generally not a naturally occurring antibody.
  • multispecific binding protein means a binding protein capable of binding two or more related or unrelated targets.
  • Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites.
  • Such DVDs may be monospecific, i.e., capable of binding one antigen or multispecific, i.e., capable of binding two or more antigens.
  • DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig.
  • Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites.
  • Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
  • Alkylating agents include altretarnine, AMD-473, AP-5280, apaziquone, bendamustine,
  • TREANDA biendamustine
  • treosulfan treosulfan
  • rofosfamide rofosfamide
  • Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors,
  • thrombospondin analogs thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
  • VEGFR vascular endothelial growth factor receptor tyrosine kinase
  • Antimetabolites include ALIMTA ® (metrexed disodium, LY231514, MTA),
  • Bcl-2 proteins inhibitors include AT- 101 ((-)gossypol), GENASENSE ® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro( 1 , 1 '-biphenyl)-2-yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 ⁇ (dimethylamino)- 1 - ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4- chlorophenyl)-5,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3
  • Bcr-Abl kinase inhibitors include DASATINIB ® (BMS-354825), GLEEVEC ® (imatinib) and the like.
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202,
  • COX-2 inhibitors include ABT-963, ARCOXIA ® (etoricoxib), BEXTRA ® (valdecoxib), BMS347070, CELEBREX ® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX ® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4-sulfamoylphenyl-lH-pyrrole), MK- 663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T- 614, VIOXX ® (rofecoxib) and the like.
  • EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD- 7200, ERBITUX ® (cetuximab), HR3, IgA antibodies, IRESSA ® (gefitinib), TARCEVA ® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB ® (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN ® (trastuzumab), TYKERB ® (lapatinib), OMNITARG ® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B- 1 and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
  • HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF- 1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB ® (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
  • Inhibitors of apoptosis proteins include ApoMab (a fully human affinity-matured IgGl monoclonal antibody), antibodies that target TRAIL or death receptors (e.g., pro-apoptotic receptor agonists DR4 and DR5), conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS- 1029, LBY-135, PRO-1762 and tratuzumab.
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.
  • Non-steroidal anti-inflammatory drugs include AMIGESIC ® (salsalate), DOLOBID ®
  • PDGFR inhibitors include C-451 , CP-673 , CP-868596 and the like.
  • Platinum chemotherapeutics include cisplatin, ELOXATIN (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN ® (carboplatin), satraplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, TSP-1 and the like.
  • VEGFR inhibitors include AVASTIN ® (bevacizumab), ABT-869, AEE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG- 13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR ® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT ® (sunitinib, SU- 11248), VEGF trap, ZACTIMATM
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE (bleomycin), daunorubicin, CAELYX or MYOCET
  • Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR (irinotecan hydrochloride), camptothecin,
  • CARDIOXANE ® (dexrazoxine), diflomotecan, edotecarin, ELLENCE ® or
  • PHARMORUBICIN epirubicin
  • etoposide exatecan
  • 10-hydroxy camptothecin gimatecan
  • lurtotecan mitoxantrone
  • orathecin pirarbucin
  • pixantrone rubitecan
  • sobuzoxane SN-38
  • tafluposide topotecan and the like.
  • Antibodies include AVASTIN ® (bevacizumab), CD40-specific antibodies, chTNT-l/B, denosumab, ERBITUX ® (cetuximab), HUMAX-CD4 ® (zanolimumab), IGFlR-specific antibodies, lintuzumab, PANOREX ® (edrecolomab), RENCAREX ® (WX G250), RITUXAN ® (rituximab), ticilimumab, trastuzimab and and the like.
  • Hormonal therapies include ARIMIDEX (anastrozole), AROMASIN (exemestane), arzoxifene, CASODEX ® (bicalutamide), CETROTIDE ® (cetrorelix), degarelix, deslorelin, DESOPAN ® (trilostane), dexamethasone, DROGENIL ® , (flutamide), EVISTA ® (raloxifene), AFEMATM (fadrozole), FARESTON ® (toremifene), FASLODEX ® (fulvestrant), FEMARA ®
  • Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN ® (aliretinoin), ATRAGEN ® (liposomal tretinoin), TARGRETIN ® (bexarotene), LGD-1550 and the like.
  • PARP inhibitors include ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • Proteasome inhibitors include VELCADE ® (bortezomib), MG132, NPI-0052, PR-171 and the like.
  • immunologicals include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- la, ACTIMMUNE ® (interferon gamma- lb), or interferon gamma-nl, combinations thereof and the like.
  • Other agents include ALFAFERONE ,(IFN-a), BAM-002 (oxidized glutathione), BEROMUN ® (tasonermin), BEXXAR ® (tositumomab), CAMPATH ® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin,
  • epratuzumab GRANOCYTE (Ienograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARGTM (gemtuzumab ozogamicin), EUPOGEN ® (filgrastim), OncoVAC-CL, OVAREX ®
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR
  • Purine analogs include LAN VIS (thioguanine) and PURI-NETHOL (mercaptopurine).
  • Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE ® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
  • Radiosensitizeser that enhance the efficacy of radiotherapy.
  • radiotherapy include external beam radiotherapy, teletherapy, brachtherapy and sealed, unsealed source radiotherapy and the like.
  • chemptherapeutic agents such as ABRAXANETM (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN (Ad5CMV-p53 vaccine), ALTOCOR ⁇ or MEVACOR (lovastatin), AMPLIGEN ® (poly Lpoly C12U, a synthetic RNA), APTOSYN ® (exisulind), AREDIA ® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methy 1-3,17-dione-androsta- 1,4- diene), AVAGE (tazarotene), AVE- 8062 (combreastatin derivative) BEC2 (mitumomab),
  • cachectin or cachexin canvaxin (vaccine), CEAVAC (cancer vaccine), CELEUK ® (celmoleukin), CEPLENE ® (histamine dihydrochloride), CERVARIX ® (human papillomavirus vaccine), CHOP ® (C: CYTOXAN ® (cyclophosphamide); H: ADRIAMYCIN ® (hydroxydoxorubicin); O: Vincristine (ONCOVIN ); P: prednisone), CYPATTM (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His- Ala linker to human epidermal growth factor) or TransMID-107RTM (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
  • DMXAA eniluracil
  • EVIZONTM squalamine lactate
  • DIMERICINE ® T4N5 liposome lotion
  • discodermolide DX-8951f (exatecan mesylate), enzastaurin, EPO906 (epithilone B)
  • GARDASIL quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine
  • GASTRIMMUNE ® GENASENSE ®
  • GMK ganglioside conjugate vaccine
  • GVAX ® prostate cancer vaccine
  • halofuginone histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13- PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon- , interferon- ⁇ , JUNO VANTM or MEPACTTM (mifamurtide), lonafarnib, 5,10-
  • methylenetetrahydrofolate miltefosine (hexadecylphosphocholine), NEOVASTAT (AE-941), NEUTREXIN ® (trimetrexate glucuronate), NIPENT ® (pentostatin), ONCONASE ® (a ribonuclease enzyme), ONCOPHAGE (melanoma vaccine treatment), ONCOVAX (IL-2 Vaccine), ORATHECINTM (rubitecan), OSIDEM ® (antibody-based cell drug), OVAREX ® MAb (murine monoclonal antibody), paditaxel, PANDIMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
  • PANVAC -VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB ® (catumaxomab), REVLIMID ® (lenalidomide), RSR13 (efaproxiral), SOMATULINE ® LA (lanreotide), SORIATANE ® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN ® (bexarotene), TAXOPREXIN ® (DHA-paclitaxel), TELCYTA (canfosfamide, TLK286), temilifene, TEMODAR (temozolomide), tesmilifene, thalidomide, THERATOPE (STn-KLH), thymitaq (2-amino-3,4- dihydro-6-methyl-4-
  • XYOTAXTM paclitaxel poliglumex
  • YONDELIS ® trabectedin
  • ZD-6126 paclitaxel poliglumex
  • ZI ECARD ® dexrazoxane
  • ZOMETA ® zolendronic acid
  • zorubicin and the like.
  • ADDP means
  • AD-mix- ⁇ means a mixture of (DHQD) 2 PHAL, K 3 Fe(CN)6, K 2 C0 3 , and K 2 S0 4 ;
  • 9-BBN means 9-borabicyclo(3.3.1)nonane;
  • Boc means tert-butoxycarbonyl;
  • (DHQD) 2 PHAL means hydroquinidine 1 ,4-phthalazinediyl diethyl ether;
  • DBU means l,8-diazabicyclo[5.4.0]undec-7-ene;
  • DIBAL means diisobutylaluminum hydride;
  • DIEA means diisopropylethylamine;
  • DMAP means ⁇ , ⁇ -dimethylaminopyridine;
  • DMF means
  • dmpe means l,2-bis(dimethylphosphino)ethane
  • DMSO means dimethylsulfoxide
  • dppb means l,4-bis(diphenylphosphino)-butane
  • dppe means 1,2- bis(diphenylphosphino)ethane
  • dppf means l,l'-bis(diphenylphosphino)ferrocene
  • dppm means l,l-bis(diphenylphosphino)methane
  • EDAC-HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • Fmoc means fluorenylmethoxycarbonyl
  • HATU means 0-(7- azabenzotriazol-l-yl)-N,N'N'N'-tetramethyluronium hexafluorophosphate
  • HMPA means hex
  • compounds of formula (1) wherein R 1 and R 2 are as described herein, can be reacted with oxalic acid in the presence of an aqueous acid, such as, but not limited to, hydrochloric acid, to provide compounds of formula (2).
  • the reaction is typically performed at an elevated temperature.
  • Compounds of formula (2) can be reacted with POCI3, SOCI2, or PBrs, using methods described herein or available in the literature, to provide compounds of formula (3), wherein X is Br or CI.
  • Compounds of formula (4) and (5) which are representative of compounds of this invention, can be prepared by reacting compounds of formula (3) with an amine of formula NH2R7.
  • reaction is typically performed neat or in a solvent such as, but not limited to, tetrahydrofuran or water, at elevated temperature, and optionally, in a microwave oven.
  • a solvent such as, but not limited to, tetrahydrofuran or water
  • Compounds of formula (5) can be reacted with a compound of formula R 7 B(OH)2 using Suzuki Coupling conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula (6), which are representative of compounds of this invention.
  • compounds of formula (7) can be reacted with iron in the presence of an aqueous acid such as, but not limited to, hydrochloric acid, to provide compounds of formula (8).
  • the reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, ⁇ , ⁇ -dimethylformamide.
  • Compounds of formula (8) can be coupled with R S C(0)C1 or R 5 C(0)OH using conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula (9), which are representative of compounds of this invention.
  • boron tribromide can be added to compounds of formula (10) at 0°C, followed by warming to room temperature to provide compounds of formula (11).
  • the reaction is typically performed in a solvent such as, but not limited to, dichloromethane.
  • Compounds of formula (11) can be reacted with compounds of formula R 5 Br in the presence of a base such as, but not limited to, potassium carbonate, to provide compounds of formula (12), which are representative of compounds of this invention.
  • the reaction is typically performed in a solvent such as, but not limited to, acetone at an elevated temperature, and optionally in a microwave oven.
  • compounds of formula (16) can be prepared by reacting compounds of formula (15) with hydroxylamine hydrochloride. The reaction is typically performed at elevated temperature in a solvent such as, but not limited to, ethanol. 3-(Tert- butyldiphenylsilyloxy)propanoic acid, prepared as described herein, can be reacted with compounds of formula (16), to provide compounds of formula (17).
  • a coupling agent such as 1- ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, and a catalyst such as, but not limited to, 4-dimethylaminopyridine are typically employed at ambient temperature in a solvent such as, but not limited to, dichloromethane.
  • Compounds of formula (18), which are representative of compounds of this invention, can be prepared from compounds of formula (17) by reacting the latter with tetrabutyl ammonium fluoride.
  • the reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.
  • 3-(Tert-butyldiphenylsilyloxy)propanoic acid prepared as described herein, caii be reacted with compounds of formula (19), to provide compounds of formula (20).
  • a coupling agent such as l-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, and a catalyst such as, but not limited to, 4-dimethylaminopyridine are typically employed at ambient temperature in a solvent such as, but not limited to, dichloromethane.
  • Compounds of formula (21), which are representative of compounds of this invention, can be prepared from compounds of formula (20) by reacting the latter with tetrabutyl ammonium fluoride. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to,
  • EXAMPLE 15A (8.0 g, 40.1 mmol) was added to fuming nitric acid (30 ml, 671 mmol) at 0°C and the mixture was stirred at 0°C for 60 minutes. The mixture was then poured into ice- water and stirred for 20 minutes. The precipitate was filtered, washed with more water and air- dried to afford the title compound.
  • 3 ⁇ 4 NMR 300 MHz, CDC1 3 ) 5 ppm 10.76 (s, 1 H) 8.58 (s, 1 H) 8.48 (s, 1 H) 4.01 (s, 3 H) 2.32 (s, 3 H).
  • reaction mixture was irradiated with microwaves (Biotage Initiator) at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude material was purified on silica gel (5-50% ethyl acetate in hexane) to afford the title compound.
  • reaction mixture was irradiated with microwaves (Biotage Initiator) at 120°C for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated and the crude material was purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um lOOA AXIA column (30mm x 75mm), 10-95% (0.1% trifluoroacetic acid in water) to afford the title compound.
  • microwaves Biotage Initiator
  • EXAMPLE 64A 0.1 lg, 0.356 mmol
  • EXAMPLE 64C 0.140 g, 0.428 mmol
  • l-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride 0.082 g, 0.428 mmol
  • dichloromethane 2.5 ml
  • Lithium diisopropylamide was added to a solution of CH 3 SiCHN 2 in tetrahydrofuran (5 mL) at -78°C. After stin-ing for 30 minutes, furan-3-carbaldehyde (0.42 mL, 0.48 g, 5.0 mmol) in tetrahydrofuran was added and the stirring continued for another 1 hour. The solvent was removed and distillation of the residue gave a solution of the title compound in tetrahydrofuran.
  • Aqueous ammonia (14.0 mL, 29% in water) was cooled to -78°C before the stepwise addition of methyl propiolate (4.2 g, 50.2 mmol) over 15 minutes via an addition funnel. The mixture was stirred for 2 hours at -78 ° C before being warmed to room temperature. The solvent was removed at 25°C under vacuum to obtain the title compound.
  • the NADH fluorescence assay was used to evaluate inhibition of purified PGK1 activity.
  • PGK1 is a monomer that catalyzes the interconversion of 1,3-bisphosphogylcerate and 3- phosphoglycerate.
  • PGK1 activity can be measured through a decrease in the NADH fluorescence signal at 340/460 (excitation/emission).
  • the final enzyme reactions contained 50 mM triethanolamine, pH 7.5, 1 mM ATP, 50 mM MgS0 4 , 50 mM KCl, 20 ⁇ g/ml glyceraldehyde 3-phosphate dehydrogenase, 0.2 mM NADH, 5 mM DTT, 40 mM (NH) 2 S0 4 , 2 mM 3-phosphoglycerate, and 5 nM PGK1.
  • Compounds in 20 ⁇ 5% DMSO were mixed with the PGK1 reaction mix (75 uL) in the absence of the 3-phosphoglycerate substrate and an initial fluorescent reading was taken.

Abstract

Disclosed are compounds of formula (I) or pharmaceutical acceptable salts thereof, wherein R1, R2, R3 and R4 are as defined in the description. Disclosed are also the methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as phosphoglycerate kinase.

Description

PHOSPHOGLYCERATE KINASE INHIBITORS
FIELD OF THE INVENTION
This invention pertains to compounds that inhibit phosphoglycerate kinase, compositions containing the compounds, and methods of treating diseases using the compounds.
BACKGROUND OF THE INVENTION
Cancer cells metabolize glucose at a higher rate than their non-transformed counterparts. In addition, less differentiated, rapidly growing tumors exhibit a higher glycolytic rate than better differentiated, slower growing tumors. (Pedersen, P.L. et al. Biochim. Biophys. Acta, 1555
(2002) 14.). Increased aerobic glycolysis is now believed to be a consequence of a more complex metabolic rearrangement with the goal to not only deliver the energy for the uncontrolled proliferation of cancer cells but also the necessary building blocks for the synthesis of nucleotides and fatty and amino acids (Moreno-Sanchez, R. et al. FEBS J. 274 (2007) 1393.). Elevation of glycolysis has been observed in human mesenchymal stem (hMSC) and fibroblast cells, fully transformed by various combinations of oncogenes. In addition, up-regulation of nucleotide metabolism, glucose transport, and down-regulation of the pentose phosphate pathway have also been observed in fully transformed hMSCs (Mazurek, S. et al. Oncogene, 20 (2001) 6891; Laman, H. et al. EMBO J. 24 (2005) 3104.). The increased uptake of glucose into cancer cells, compared to normal cells, has been exploited in tumor imaging (positron emission tomography (PET)), where 2-lsfluoro-2-deoxy-D-glucose (18FDG), a glucose analog, is used to detect and to localize tumors (Bos, R. et al. J. Clin. Oncol. 20 (2002) 379; Burt, B.M. et al. Neoplasia, 3 (2001) 189.). In addition, poor prognosis and increased tumor aggressiveness has been consistently correlated with increased glucose uptake through the use of quantitative PET analysis (Kunkel, M. et al. Cancer, 97 (2003) 1015; Mochiki, E. et al. Surgery, 2004, 247.). Cancer cells are more significantly affected by changes in glucose levels than normal cells. Low glucose levels are well tolerated by normal cells because of the abundance of reducing factors such as NADPH and NAC which can eliminate the pro-oxidants that are generated during glucose catabolism and thus prevent apoptosis (Spitz, D.R. et al. Ann. N. Y. Acad. Sci. 899 (2000) 349.). Phosphoglycerate kinase (PGK) is the sixth often enzymes in the glycolytic pathway. In the first ATP producing step of glycolysis, PGK equilibrates the transfer of the phosphate in position 1 of 1,3-bisphosphoglycerate (1,3-BPG) and the γ-position of ATP in the presence of Mg2+ as a cofactor (Scopes, R.K. The Enzymes, 3rd Ed.; Boyer, P.D., Ed., Academic Press: New York, 1973; Vol. VIII. Chapter 10.). In this step PGK competes with diphosphoglycerate mutase for its substrate. The end product of both competing reactions is the same, except that the PGK catalyzed reaction preserves the high energy phosphate in the form of ATP. Two isoforms of PGK have been identified. PGK2 is testis specific and is considered to be critical to normal motility and fertility of mammalian spermatozoa (Yoshioka, H. et al. Mol. Cell. Biol. 27 (2007) 7871.). PGKl on the other hand is ubiquitously expressed and appears to be associated with a multi-drug resistant phenotype in different cancers (Duan, Z. et al. Anticancer Res. 22 (2002) 1933.).
Multidrug resistance is a significant barrier to the development of successful cancer treatments. For example, cancer cells which display resistance to apoptotic stimuli such as irradiation or chemotherapy often carry active oncogenes (e.g. Akt, Ras, Her2) and/or lack single tumor suppressors (e.g. TSCl/2, p53, LKB1). However, many of those cells undergo apoptosis under low glucose conditions (Scatena, R. et al. Expert Opin. Investig. Drugs, 17 (2008) 1533.). Overexpression of human PGKl in a U-20S osteogenic sarcoma cell line can induce a multidrug resistant (paclitaxel, vincristine, adriamycin and mitoxantrone) phenotype through an MDR-1 independent mechanism (Duan, Z. et al. Anticancer Res. 22 (2002) 1933.). Inhibition of PGKl therefore offers an opportunity to selectively affect multi-drug resistant cancer cells.
Inhibition of PGKl may have wide applicability in the treatment of various cancers. For example, overexpression of human PGKl in a U-20S osteogenic sarcoma cell line can induce a multidrug resistant phenotype through an MDR-1 independent mechanism (Duan, Z. et al.
Anticancer Res. 22 (2002) 1933.). PGKl overexpression in pancreatic ductal adenocarcinoma is discussed in Hwang, T.L. et al. Proteomics, 6 (2006) 2259. Involvement of PGKl in the onset of prostate cancer is discussed in Wang. J. et al. Cancer Res. 67 (2007) 149. Involvement of PGKl in the onset of breast cancer is discussed in Zhang, D. et al. Mol. Cell Proteomics, 4 (2005) 1686. Involvement of PGKl in the onset of gastric cancer is discussed in Zieker, D. et al. Cell Physiol. Biochem. 21 (2008) 429. The human PGKl gene, and its association with familial prostate cancers, perineal hypospadias and androgen insensitivity is discussed in Riley, D.E. et al. Cancer, 92 (2001) 2603. Overexpression of PGK1 is reported to reduce the expression of uPAR in HI 57 human lung cancer cells and to inhibit their migration in Shetty, S. et al. Am. J. Physiol. Lung Cell Mol. Physiol. 289 (2005) L591. PGK1 as a potential cytotoxic T
lymphocyte-directed tumor-associated antigen of HLA-A2+ colon cancer is discussed in Shichijo, S. et al. Clin. Cancer Res. 10 (2004) 5828. The down-regulation of COX-2 expression and the promotion of the Thl immune response in Lewis lung carcinoma cells based on overexpression of PGK1 is discussed in Sun, K.H. et al. Int. J. Cancer, 123 (2008) 2840.
PGKl 's critical as a downstream target of the chemokine axis and as an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth is discussed in Taichman, R.S. et al. Cancer Res. 67 (2007) 149. PGKl's role in supporting the interactions between cancer cells and their microenvironment is discussed in Taichman, R.S. et al. Cancer Res. 70 (2010) 471.
When red blood cells pass through inadequately oxygenated tissues, PGK is inhibited and bisphosphogly cerate mutase catalyzes the conversion of 1,3-BPG to 2,3 -BPG. The increase in 2,3-BPG then decreases the hemoglobin affinity for oxygen, which enables more oxygen to be extracted from blood as it passes through those tissues. Thus inhibition of PGK is a potential means for treatment of cardiovascular and respiratory disorders (Voet, D. et al. Biochemistry, 1st Ed.; John Wiley & Sons: New- York, 1990, Vol. 1.).
In African trypanosomiasis the protozoan trypanosoma brucei, introduced through bites of the tsetse fly, flourishes in the mammalian bloodstream and evades the immune response via antigenic variation. In this stage the parasite develops a complete dependency on glycolysis for its energy supply. Eventually the parasite penetrates the blood-brain barrier and attacks the central nervous system (Despommier, D.D. et al. Parasitic Diseases, 3rd Ed.; Springer- Verlag: New York, 1995.), which leads to dementia, epileptic attacks, coma and, if left untreated, death. Current treatments have severe limitations due to toxicity and resistance (Croft, S.L.
Parasitology, 114 (1997) S3). Inhibition of PGK in trypanosoma brucei could offer an opportunity to kill the parasite with a high therapeutic window compared to normal mammalian cells.
Small molecule inhibitors of the protein kinase PGK are thus attractive candidates for therapeutic intervention in cancer, cardiovascular disease, respiratory disorders, and treatment of parasites. SUMMARY OF THE INVENTION
The present invention has numerous embodiments. One embodiment of this invention, therefore, pertains to compounds that have formula (I),
Figure imgf000005_0001
(I),
wherein R1, R2, R3, and R are as defined herein.
Also provided are pharmaceutical compositions comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
One embodiment is directed a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Yet another embodiment pertains to a method for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Still another embodiment pertains to methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, or stomach cancer.
Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy. DETAILED DESCRIPTION OF THE INVENTION
This detailed description is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.
Abbreviations and Definitions
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless stated otherwise.
Furthermore, the use of the term "including", as well as other forms, such as "includes" and
"included", is not limiting. With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent application (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent application, including the claims below. For a variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
It is meant to be understood that proper valences are maintained for all combinations herein, that monovalent moieties having more than one atom are attached through their left ends, and that divalent moieties are drawn from left to right.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term "alkyl" (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 10 carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms.
Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like. The term "alkenyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3- propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
The term "alkynyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms; in another embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2 to about 4 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyI, 2- butynyl, and 3-butynyl and the like.
The term "carbocyclyl" (alone or in combination with another term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated (i.e., "aryl") hydrocarbyl substituent containing from 3 to 14 carbon ring atoms
("ring atoms" are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
A carbocyclyl may be a single ring structure, which typically contains from 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl may alternatively be polycyclic (i.e., may contain more than one ring). Examples of polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include
naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl. The term "cycloalkyl" (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring atoms and more typically from 3 to 6 ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
The term "aryl" (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-Ce- alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3- C8-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
The term "hydrogen" (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
The term "hydroxy" (alone or in combination with another term(s)) means -OH.
The term "carboxy" (alone or in combination with another term(s)) means -C(0)-OH. The term "amino" (alone or in combination with another term(s)) means -N¾-
The term "halogen" or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -CI), bromine radical (which may be depicted as -Br), or iodine radical (which may be depicted as -I).
If a substituent is described as being "substituted", a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated). If a substituent is described as being "optionally substituted", the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
This patent application uses the terms "substituent" and "radical" interchangeably.
The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
The prefix "perhalo" indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term "perfluoro" means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term "perfluoroalkyl" means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
The term "carbonyl" (alone or in combination with another term(s)) means -C(O)-. The term "aminocarbonyl" (alone or in combination with another term(s)) means -C(O)-
NH2.
The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -0-.
The term "alkylhydroxy" (alone or in combination with another term(s)) means -alkyl-
OH.
The term "alkylamino" (alone or in combination with another term(s)) means -alkyl-NH2. The term "alkyloxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-O-CH3), ethoxy, n- propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term "alkylcarbonyl" (alone or in combination with another term(s)) means -C(O)- alkyl.
The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means - C(0)-alkyl-NH2.
The term "alkyloxy carbonyl" (alone or in combination with another term(s)) means -
C(0)-0-alkyl.
The term "carbocyclylcarbonyl" (alone or in combination with another term(s)) means - C(0)-carbocyclyl.
Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term(s)) means -C(0)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-carbocyclyl.
Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-heterocyclyl.
The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-carbocyclyl.
The term "carbocyclylalkyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-alkyl-carbocyclyl.
The term "thio" or "thia" (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio- alkyl" means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
The term "(thiocarbonyl)" (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
The term "sulfonyl" (alone or in combination with another term(s)) means -S(0)2-.
The term "aminosulfonyl" (alone or in combination with another term(s)) means -S(0)2- NH2.
The term "sulfinyl" or "sulfoxido" (alone or in combination with another term(s)) means -
S(0 .
The term "heterocyclyl" (alone or in combination with another tenn(s)) means a saturated {i.e., "heterocycloalkyl"), partially saturated {i.e., "heterocycloalkenyl"), or completely unsaturated {i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom {i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrblidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3 -diazinyl), or pyrazinyl (1,4- diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1 ,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3- oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3 -oxadiazinyl, 1 ,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
A heterocyclyl may alternatively be polycyclic (i.e., may contain more than one ring). Examples of polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls. In a spirocyclic heterocyclyl, one atom is common to two different rings. In a bridged heterocyclyl, the rings share at least two common non-adjacent atoms. In a fused-ring heterocyclyl, two or more rings may be fused together, such that two rings share one common bond. Examples of fused ring heterocyclyls containing two or three rings include indolizinyl, pyranopyrrolyl, 4Ή- quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused- ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1 -benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3- benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including
1.3.2- benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1 -benzoxazinyl, or 3,1,4-benzoxazinyI), and benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1,4-benzisoxazinyl).
The term "heteroaryl" (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
1.2.3- , 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6- membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, the Ci-C6- prefix on Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix "halo" on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkyloxyalkyl" rather than "haloalkyloxyalkyl." And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkyloxyhaloalkyl."
The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of a kinase. "Modulation", as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction. Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
The tenn "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human. Compounds
In one aspect, the present invention provides compounds of formula (I):
Figure imgf000014_0001
(I) wherein
halogen, cyano, or methoxy;
Rz is halogen, hydroxy, trifluoromethoxy, cyano, amino, nitro, R , R3, OR3, or
NHC(0)R5; provided that, when R2 is halogen, R1 is cyano or methoxy;
R3 is halogen, or NHR7;
R4 is R7 or NHR7;
R5A is heterocyclyl; wherein the heterocyclyl is optionally substituted with R6;
R5 is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6;
R6 is alkyl, cycloalkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
each R7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8; each R is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9;
each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl; or a pharmaceutically acceptable salt thereof.
In another embodiment of formula (I),
R1 is halogen, cyano, or methoxy;
R2 is halogen, hydroxy, trifluoromethoxy, cyano, amino, nitro, R5A, R5, OR5, or
NHC(0)R5; provided that, when R2 is halogen, R1 is cyano or methoxy;
R3 is halogen, or NHR7;
R4 is R7 or NHR7;
R5A is heterocyclyl; wherein the heterocyclyl is optionally substituted with R6;
R5 is alkyl or alkynyl; wherein the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6;
R6 is alkyl, cycloalkyl, aiyl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
each R7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8;
each R8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with C(0)OR9; each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (I), R1 is halogen. In another embodiment of formula (I), R1 is cyano. In another embodiment of formula (I), R1 is methoxy.
In one embodiment of formula (I), R2 is hydroxyl. In another embodiment of formula (I),
R2 is trifiuoromethoxy. In another embodiment of formula (I), R2 is cyano. In another embodiment of formula (I), R2 is amino. In another embodiment of formula (I), R2 is nitro. In another embodiment of formula (I), R2 is R5A. In another embodiment of formula (I), R2 is R5. In another embodiment of formula (I), R2 is OR5. In another embodiment of formula (I), R2 is NHC(0)R5. In another embodiment of formula (I), R2 halogen, provided that R1 is cyano or methoxy.
In one embodiment of formula (I), R1 is methoxy, and R2 is halogen. In another embodiment of formula (I), R1 is cyano, and R2 is halogen. In another embodiment of formula (I), R1 is cyano, and R2 is R5. In another embodiment of formula (I), R1 is halogen, and R2 is R5. In another embodiment of formula (I), R1 is methoxy, and R2 is methoxy. In another embodiment of formula (I), R1 is cyano, and R2 is halogen.
In one embodiment of formula (I), R1 is halogen or methoxy; and R2 is halogen or R5, provided that, when R2 is halogen, R1 is methoxy.
In one embodiment of formula (I), R1 is halogen or methoxy; and R2 is R5.
In one embodiment of formula (I), R1 is halogen or methoxy; R2 is R5; and R5 is alkynyl.
In one embodiment of formula (I), R3 is halogen. In another embodiment of formula (I), R3 is NHR7.
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, and R3 is halogen. In another embodiment of formula (I), R1 is halogen, R2 is methoxy, and R3 is halogen. In another embodiment of formula (I), R1 is cyano, R2 is halogen, and R3 is halogen. In another embodiment of formula (I), R1 is cyano, R2 is R5, and R3 is halogen. In another embodiment of formula (I), R1 is halogen, R2 is R5, and R3 is halogen. In another embodiment of formula (I), R1 is methoxy, R2 is methoxy, and R3 is halogen. In another embodiment of formula (I), R1 is cyano, R is halogen, and R is halogen.
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, and R3 is NHR7. In another embodiment of formula (I), R1 is methoxy, R2 is halogen, and R3 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, and R3 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is R5, and R3 is NHR7. In another embodiment of formula (I), R1 is halogen, R2 is Rs, and R3 is NHR7. In another embodiment of formula (I), R1 is methoxy, R2 is methoxy, and R3 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, and R3 is NHR7.
In one embodiment of formula (I), R4 is R7. In another embodiment of formula (I), R4 is
NHR7.
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, R3 is halogen, and R4 is R7. In another embodiment of formula (I), R1 is halogen, R2 is methoxy, R3 is halogen, and R4 is R7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is halogen* and R4 is R . In another embodiment of formula (I), R is cyano, R is R , R is halogen, and R is R . In another embodiment of formula (I), R1 is halogen, R2 is R5, R3 is halogen, and R4 is R7. In another embodiment of formula (I), R1 is methoxy, R2 is methoxy, R3 is halogen, and R4 is R7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is halogen, and R4 is R7.
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, R3 is NHR7, and R4 is
R 7.. In another embodiment of formula (I), R 1 is methoxy, R 2 is halogen, R 3 i ·s NHR 7 , and R 4 is
R . In another embodiment of formula (I), R is cyano, R" is halogen, R is NHR , and R is R .
In another embodiment of formula (I), R is cyano, R is R , R is NHR , and R is R . In another embodiment of formula (I), R is halogen, R is R , R is NHR , and R is R . In another embodiment of formula (I), R 1 is methoxy, R ^" is methoxy, R 3 is NHR 7 , and R 4 is R 7. In another embodiment of formula (I), R is cyano, R is halogen, R is NHR , and R is R .
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is halogen, R2 is methoxy, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is R5, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is halogen, R2 is R5, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is methoxy, R2 is methoxy, R3 is halogen, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is halogen, and R4 is NHR7.
In one embodiment of formula (I), R1 is methoxy, R2 is halogen, R3 is NHR7, and R4 is
NHR7. In another embodiment of formula (I), R1 is methoxy, R2 is halogen, R3 is NHR7, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is NHR7, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is R5, R3 is NHR7, and R4 is NHR7. In another embodiment of formula (I), R1 is halogen, R2 is R5, R3 is NHR7, and R4 is NHR7. In another embodiment of formula (I), R1 is methoxy, R2 is methoxy, R3 is NHR7, and R4 is NHR7. In another embodiment of formula (I), R1 is cyano, R2 is halogen, R3 is NHR7, and R4 is NHR7.
In one embodiment of formula (I), R5 is alkyl. In another embodiment of formula (I) R5 is alkynyl. In another embodiment of formula (I) R5 is alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6. In another embodiment of formula (I) R5 is alkynyl, wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6
In one embodiment of formula (I), R6 is alkyl. In another embodiment of formula (I), R6 is cycloalkyl. In another embodiment of formula (I), R6 is aryl. In another embodiment of formula (I), R6 is heterocyclyl.
In one embodiment of formula (I), R6 is alkyl wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10. In another embodiment of formula (I), R6 is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more hydroxy. In another embodiment of formula (I), R6 is aryl. In another embodiment of formula (I), R6 is heterocyclyl wherein the heterocyclyl is optionally substituted with one or more hydroxy.
In one embodiment of formula (I), R7 is Ci_3-alkyl. In another embodiment of formula (I), R7 is alkynyl. In another embodiment of formula (I), R7 is aryl. In another embodiment of formula (I), R7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
In one embodiment of formula (I), R7 is C].3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8) . In another embodiment of formula (I), R7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (I), R7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8. In another embodiment of formula (I), R7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R , and C(0)R .
In one embodiment of formula (I), R 8 is alkyl. In another embodiment of formula (I), R 8 is aryl. In another embodiment of formula (I), R8 is heterocyclyl.
In one embodiment of formula (I), R8 is alkyl wherein the alkyl is optionally substituted with one or more R9. In another embodiment of formula (I), R8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9. In another embodiment of formula (I), R8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9.
In one embodiment of formula (I), R9 is alkyl. In another embodiment of formula (I), R9 is aryl. In another embodiment of formula (I), R9 is heterocyclyl.
In one embodiment of formula (I), R10 is alkyl.
Specific embodiments contemplated as part of the invention include, but are not limited to, compounds of formula (I), for example:
3-chloro-N-ethyl-6,7-dimethoxyquinoxalin-2-amine;
N,N'-diethyl-6,7-dimethoxyquinoxaline-2,3-diamine;
3-bromo-N-ethyl-6,7-dimethoxyquinoxalin-2-amine;
3-chloro-6,7-dimethoxy-N-methylquinoxalin-2-amine;
N-ethyl-6,7-dimethoxy-N'-methylquinoxaline-2,3-diamine;
3-bromo-6,7-dimethoxy-N-[2-(4-methylpiperazin-l-yl)ethyl]quinoxalin-2-amine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-3-ylmethyl)quinoxaline-2,3 -diamine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-4-ylmethyl)quinoxaline-2,3 -diamine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-2-ylmethyl)quinoxaline-2,3-diamine;
N-ethyl-6,7-dimethoxy-N'-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3-diamine;
l-(3-{[3-(ethylamino)-6,7-dimethoxyquinoxalin-2-yl]amino}propyl)pyrrolidin-2-one; N-ethyl-6,7-dimethoxy-N'-[2-(pyridin-4-yl)ethyl]quinoxaline-2,3-diamme;
N-ethyl-6,7-dimethoxy~N'-[2-(pyridin-2-yl)ethyl]quinoxaline-2,3-diamine;
6,7-dimet oxy-3-(pyridin-4-yl)-N-(pyridin-3-yImethyl)quinoxalin-2-amine;
6-chloro-N,N'-diethyl-7-methoxyquinoxaline-2,3-diamine;
3,6-dichloro-N-ethyl-7-methoxyquinoxalin-2-amine;
6- chloro-N2-ethyl-7-methoxy-N3-(pyridin-3-ylmet yl)quinoxaline-2,3-diamine;
7- chloro-2,3-bis(et ylammo)quinoxalm-6-ol;
6-chloro-N,N'-diethyl-7-(prop-2-yn-l-yloxy)quinoxaline-2,3-diamine;
6- chloro-N,N'-diethyl-7-niti quinoxaline-2,3-diamine;
7- chloro-N2,N3-diethylquinoxaline-2,3,6-triamine;
N-[7-chloro-2,3-bis(et ylamino)quinoxalixi-6-yl]acetamide;
7-chloro-2,3-bis(ethylamino)quinoxaline-6-carbonitrile;
7-chloro-2-(ethylamino)-3-[(pyridin-3-ylmethyl)amino]quinoxaline-6-carbonitrile;
7-chloro-2-(ethylamino)-3 - { [2-(4-methylpiperazin- 1 -y l)ethyl]amino } quinoxaline-6- carbonitrile;
6-chloro-N,N'-diethyl-7-(trifluoromethoxy)quinoxaline-2,3-diamine;
6-chloro-N2-ethyl-7-methoxy-N3-[2-(4-methyIpiperazin-l-yl)ethyl]quinoxaline-2,3- diamine;
6-chloro-N2-ethyl-7-methoxy-N3-[3-(4-methylpiperazm-l-yl)propyl]quinoxaline-2,3- diamine;
6-chloro-N2-ethyl-7-methoxy-N3-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3 -diamine; 6-chloro-N3-[5-(diethylamino)pentan-2-yl]-N2-ethyl-7-methoxyquinoxaline-2,3-diamine;
4- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-l-ol;
6-chloro-N,N'-diethyl-7-ethynylquinoxaline-2,3-diamine;
5- [7-chIoro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn-2-ol;
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn-l-ol;
6- chloro-7-(cyclopropylethynyl)-N,N'-diethylquinoxaline-2,3 -diamine;
2- {4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn- 1 -yl} - 1 H-isoindole- 1 ,3(2H)- dione;
6-(4-aminobut-l-yn-l-yl)-7-chloro-N,N'-diethylquinoxaline-2,3-diamine;
6-chloro-3-(3-chlorophenyl)-N-etliyl-7-methoxyquinoxalin-2-amine; 6-chloro-3-(4-chlorophenyl)-N-ethyl-7-tnetlioxyquinoxalin-2-amine;
3-(l,3-benzodioxol-5-yI)-6-chloro-N-ethyl-7-methoxyquinoxalin-2 -amine;
6-chloro-N-ethyl-7-methoxy-3-(2-thienyl)quinoxalin-2-aniine;
3-(l-benzofuran-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
1 - { 5 - [7-chloro-3 -(ethy lamino)-6-methoxyquinoxalin-2-yl]-2-thienyl} ethanone;
3-(l-benzothiophen-3-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3 -( 1 -benzothiophen-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]benzamide;
6-chloro-N-ethyl-3-(lH-indol-4-yl)-7-methoxyquinoxalin-2-amine;
6-chloro-N-ethyl-3-(isoquinolin-4-yl)-7-methoxyquinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(quinolin-5-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(quinolin-3-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(lH-pyrazol-4-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(l-methyl-lH-pyrazol-4-yl)quinoxalin-2-amine;
6-chIoro-N-ethyl-7-methoxy-3-(l-methyl-lH-indol-5-yl)quinoxalin-2-amine;
6-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-4H-chromen-4-one;
tert-butyl 4-{5-[7-chloro-3-(ethylamino)-6-raethoxyquinoxalin-2-yl]pyridin-2- yl}piperazine-l-carboxylate;
3-(biphenyl-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-N-(2-furylmethyl)benzamide;
N-benzyl-3-[7-chloro-3-(ethylaniino)-6-methoxyquinoxalin-2-yl]benzamide;
3- (l-benzyl-lH-pyrazol-4-yl)-6-chloiO-N-ethyl-7-methoxyquinoxalin-2-amine;
5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-oxopentanoic acid;
4- [7-chloro-3-(ethylamino)-2- { [3-(4-methylpiperazin- l-yl)propyl]amino} quinoxalin-6- yl]but-3-yn-l-oI;
4-(7-chloro-2,3-bis { [2-(4-methylpiperazin- 1 -yl)ethyl]amino} quinoxalin-6-yl)but-3 -yn- 1 - ol;
4-[7-chloro-3-(ethylamino)-2-{[2-(4-methylpiperazin-l-yl)ethyl]amino}quinoxalin-6- yl]but-3-yn-l-ol;
2-{3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-l,2,4-oxadiazol-5-yl}ethanol;
N-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-3-hydroxypropanamide; 4- [2,7-dichloro3 -(ethylamino)quinoxalin-6-y l]but-3 -yn- 1 -ol;
4,4'-[7-chloro-3-(ethylamino)quinoxaline-2,6-diyl]bisbut-3-yn-l-ol;
7-chloro-2- { [2-(4-methylpiperazin- 1 -yl)ethyl]amino} -3-(pyridin-2-yl)quinoxaline-6- carbonitrile;
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-2-ol;
4- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-2-methylbut-3-yn-2-ol;
l-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-3-methylpent-l-yn-3-ol;
6-chloro-N,N'-diethyl-7-(3-methoxypiOp-l-yn-l-yl)quinoxaline-2,3-diamine;
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-yn-l-ol;
3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn- 1 -yl propionate;
6-chloro-N,N'-diethyl-7-(hex- 1 -yn- 1 -yl)quinoxaline-2,3-diamine;
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-ynenitrile;
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-ynenitrile;
3-{[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]ethynyl} phenol;
3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-ol;
1- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-l-yn-3-ol;
2- ({3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-yl}oxy)ethanol;
6- chloro-N,N'-diethyl-7-(3-furylethynyl)quinoxaline-2,3-diamine;
methyl 3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynoate;
3- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynamide;
6-(but-l-yn-l-yl)-7-chloro-N,N'-diethylquinoxaline-2,3-diamine;
1 - {3 -[7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]prop-2-yn- 1 -yl} urea;
6-chloro-N-ethyl-7-methoxy-3-(l-naphthyl)quinoxalin-2-amine;
methyl 5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-oxopentanoate;
6,7-dimethoxy-3-(pyridin-4-yl)-N-[3-(pyrrolidin-l-yl)propyl]quinoxalin-2-amine; 2-{l-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]azetidin-3-yl}ethanol;
N-ethyl-6,7-dimetlioxy-3-(pyridin-4-yl)quinoxalin-2-amine; or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides compounds of formula (Π):
Figure imgf000023_0001
wherein
R5 is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6;
R6 is alkyl, cycloalkyl, aryl, or heterocyclyl; herein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
each R7 is independently Cu-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyI; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (C) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl; and chromen-4-ony] are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8;
each R8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9;
each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (II), R5 is alkyl. In another embodiment of formula (Π) R5 is alkynyl. In another embodiment of formula (II) R5 is alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6. In another embodiment of formula (Π) R5 is alkynyl, wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0) H2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6.
In one embodiment of formula (II), R6 is alkyl. In another embodiment of formula (II), R6 is cycloalkyl. In another embodiment of formula (II), R6 is aryl. In another embodiment of formula (II), R6 is heterocyclyl.
In one embodiment of formula (II), R6 is alkyl wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10. In another embodiment of formula (II), R6 is cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more hydroxy. In another embodiment of formula (II), R6 is aryl. In another embodiment of formula (II), R6 is heterocyclyl wherein the heterocyclyl is optionally substituted with one or more hydroxy.
In one embodiment of formula (II), R7 is Ci-3-alkyl. In another embodiment of formula (II), R7 is alkynyl. In another embodiment of fonnula (II), R7 is aryl. In another embodiment of formula (Π), R7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
In one embodiment of formula (Π), R7 is Cu-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (II), R7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (II), R7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)N¾, and C(0)NHR8. hi another embodiment of formula (II), R7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8.
In one embodiment of formula (II), R8 is alkyl. In another embodiment of formula (II), R8 is aryl. In another embodiment of formula (II), R8 is heterocyclyl. In one embodiment of formula (II), R is alkyl wherein the alkyl is optionally substituted with one or more R9. In another embodiment of formula (II), R8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9. In another embodiment of formula (II), Rs is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9.
In one embodiment of formula (II), R9 is alkyl. In another embodiment of formula (II), R9 is aryl. In another embodiment of formula (Π), R9 is heterocyclyl.
In one embodiment of formula (II), R10 is alkyl.
In another aspect, the present invention provides compounds of formula (III):
Figure imgf000025_0001
(III)
wherein
each R7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyI, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)N¾ and C(0) HR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyI are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8;
each Rs is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9;
each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (ΠΙ), R7 is Ci-3-alkyl. In another embodiment of formula (III), R7 is alkynyl. In another embodiment of formula (ΠΙ), R7 is aryl. In another embodiment of formula (III), R7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
In one embodiment of formula (III), R7 is Ci-3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (III), R7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (III), R7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8. In another embodiment of formula (III), R7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , arid C(0)R 8.
In one embodiment of formula (III), R8 is alkyl. In another embodiment of formula (III),
Q Q
R is aryl. In another embodiment of formula (III), R is heterocyclyl.
In one embodiment of formula (III), R8 is alkyl wherein the alkyl is optionally substituted with one or more R9. In another embodiment of formula (ΠΙ), R8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9. In another embodiment of formula (III), R8 is heterocyclyl, whereiii the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9.
In one embodiment of formula (III), R9 is alkyl. In another embodiment of formula (III), R9 is aryl. In another embodiment of formula (III), R9 is heterocyclyl.
In one embodiment of formula (ΠΙ), R10 is alkyl.
In another aspect, the present invention provides compounds of formula (IV):
Figure imgf000026_0001
wherein each R7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R 8 , and C(0)R 8 ;
each R8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9;
each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (IV), R7 is Ci-3-alkyl. In another embodiment of formula
(IV), R7 is alkynyl. In another embodiment of formula (IV), R7 is aryl. In another embodiment of formula (IV), R7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazoly, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
In one embodiment of formula (IV), R7 is Ci-3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (IV), R7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R )2. In another embodiment of formula (IV), R7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8. In another embodiment of formula (IV), R7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8. In one embodiment of formula (IV), R is alkyl. In another embodiment of formula (IV), R8 is aryl. In another embodiment of formula (IV), R8 is heterocyclyl.
In one embodiment of formula (IV), R8 is alkyl wherein the alkyl is optionally substituted with one or more R9. In another embodiment of formula (IV), R8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9. In another embodiment of formula (IV), R8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9.
In one embodiment of formula (IV), R9 is alkyl. In another embodiment of formula (IV), R9 is aryl. In another embodiment of formula (IV), R9 is heterocyclyl.
In one embodiment of formula (IV), R10 is alkyl.
In another aspect, the present invention provides compounds of formula (V):
Figure imgf000028_0001
(V)
wherein
each R7 is independently Ci-3-alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8;
each R8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9;
each R9 is independently alkyl, aryl, or heterocyclyl; and R is alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (V), R7 is Ci-3-alkyl. In another embodiment of formula (V), R7 is alkynyl. In another embodiment of formula (V), R7 is aryl. In another embodiment of formula (V), R7 is aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl.
In one embodiment of formula (V), R7 is Ci_3-alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy 1, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (V), R7 is alkynyl wherein the alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, heterocyclyl, heterocyclylalkyl, and N(R8)2. In another embodiment of formula (V), R7 is aryl, wherein the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8. In another embodiment of formula (V), R7 is quinolinyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-only, wherein the quinolinyl, 4-pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8.
In one embodiment of formula (V), R8 is alkyl. In another embodiment of formula (V),
R 8 is aryl. In another embodiment of formula (V), R 8 i *s heterocyclyl.
In one embodiment of formula (V), R8 is alkyl wherein the alkyl is optionally substituted with one or more R9. In another embodiment of formula (V), R8 is aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9. In another embodiment of formula (V), R8 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9.
In one embodiment of formula (V), R9 is alkyl. In another embodiment of formula (V), R9 is aryl. In another embodiment of formula (V), R9 is heterocyclyl.
In one embodiment of formula (V), R10 is alkyl.
Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diastereoisomers of the compounds thereof.
Compounds of this invention may also contain carbon-carbon double bonds or carbon- nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon- nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may also exist as a mixture of "E" and "Z" isomers.
Compounds of this invention may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like.
This invention also is directed, in part, to all salts of the compounds of formula (I). A salt of a compound may be advantageous due to one or more of the salt's properties, such as, for example, enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or other solvents. Where a salt is intended to be administered to a patient (as opposed to, for example, being in use in an in vitro context), the salt preferably is pharmaceutically acceptable and/or physiologically compatible. The term "pharmaceutically acceptable" is used adjectivally in this patent application to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means by reacting, for example, the appropriate acid or base with a compound of the invention.
Pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from an inorganic or organic acid. Examples of often suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of often suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate,
cyclohexylaminosulfonate, algenic acid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate, pectinate, 2-naphthalesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
Pharmaceutically acceptable base addition salts of the compounds of formula (I) include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from amines, such as tromethamine, diethylamine, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quatemized with agents such as lower alkyl (Ci-Cg) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
Compounds of formula (I) (and salts thereof) with any level of purity (including pure and substantially pure) are within the scope of Applicants' invention. The term "substantially pure" in reference to a compound/salt/isomer, means that the preparation/composition containing the , compound/salt/isomer contains more than about 85% by weight of the compound/salt/isomer, preferably more than about 90% by weight of the compound/salt/isomer, preferably more than about 95% by weight of the compound/salt/isomer, preferably more than about 97% by weight of the compound/salt/isomer, and preferably more than about 99% by weight of the
compound/salt/isomer.
Preparation of Compounds Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
Protecting groups for C(0)OH moieties include, but are not limited to, acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl,.
diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl and the like.
Protecting groups for C(O) and C(0)H moieties include, but are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal, 1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like. Protecting groups for NH moieties include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4- dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoiyl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl and the like.
Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, l,l-dimethyl-2- propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4- methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para- toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl, triphenylmethyl, 2- (triphenylphosphonio)ethoxycarbonyl and the like.
Compositions
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient. Compounds having formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally
intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature.
Compounds having formula (I) may be administered with or without an excipient.
Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents,
disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
Excipients for preparation of compositions comprising a compound having formula (I) to be administered orally include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fiimarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered osmotically include, but are not limited to,
chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered parenterally include, but are not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like. Excipients for preparation of compositions comprising a compound having formula (I) to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
The pharmaceutical composition and the method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions.
Methods of Use
In another aspect, the present invention provides methods of using a compound or composition of the invention to treat or prevent a disease or condition involving mediation, overexpression or disregulation of kinases in a mammal. In particular, compounds of this invention are expected to have utility in treatment of diseases or conditions during which protein kinases such as any or all phosphoglycerate kinase members are expressed.
One embodiment is directed a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Yet another embodiment pertains to a method for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Still another embodiment pertains to methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, or stomach cancer.
Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
One embodiment is directed a method of treating cardiovascular disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof. Another embodiment pertains to a method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
One embodiment is directed a method of treating respiratory disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Another embodiment pertains to a method of treating respiratory disease in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
One embodiment is directed a method of treating parasites in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof.
Another embodiment pertains to a method of treating parasites in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
In one group of embodiments, diseases and conditions of humans or other animals that can be treated with inhibitors of kinases, include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblasts, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma
(Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.
The methods of the present invention typically involve administering to a subject in need of therapeutic treatment an effective amount of a compound of formula (1) . Therapeutically effective amounts of a compound having formula (I) depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered. The amount of a compound having formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.
Combination Therapy
The present invention further provides methods of using a compound or composition of the invention in combination with one or more additional active agents.
Compounds having formula (I) are expected to be useful when used with:
alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics,
antiproliferatives, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVD's, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAP's) intercalating antibiotics, kinase inhibitors, mammalian target of rapamycin inhibitors, microRNA's mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, phosphoglycerate kinase inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNA's), topoisomerase inhibitors, combinations thereof and the like.
A BiTE antibody is a bi-specific antibody that directs T-cells to attach cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell. Exemplary BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like.
SiRNA's are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications shall not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F- ribonucleotides, 2'-methoxyethyI ribonucleotides or a combination thereof. The siRNA can have varying lengths (10-200 bps) and structures (hairpins, single/double strands, bulges, nicks/gaps, mismatches) and processed in the cell to provide active gene silencing. In certain embodiments, a double- stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3'-ends of a given strand.
Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. The multivalent binding protein is preferably engineered to have the three or more antigen binding sites and is generally not a naturally occurring antibody. The term
"multispecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific, i.e., capable of binding one antigen or multispecific, i.e., capable of binding two or more antigens. DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
Alkylating agents include altretarnine, AMD-473, AP-5280, apaziquone, bendamustine,
® brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE
(laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa,
TREANDA (bendamustine), treosulfan, rofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors,
thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Antimetabolites include ALIMTA® (metrexed disodium, LY231514, MTA),
5-azacitidine, XELODA (capecitabine), carmofur, LEUSTAT (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR
®
(gemcitabine), hydroxyurea, ALKERAN (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenOlic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-l, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Bcl-2 proteins inhibitors include AT- 101 ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro( 1 , 1 '-biphenyl)-2-yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3~(dimethylamino)- 1 - ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4- chlorophenyl)-5,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 - (morpholin-4-yl)- 1 -((pheny lsulfany l)methyl)propy l)amino)-3 -
((trifluoromethyI)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like. Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202,
R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celecoxib), COX- 189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4-sulfamoylphenyl-lH-pyrrole), MK- 663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T- 614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD- 7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B- 1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF- 1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
Inhibitors of apoptosis proteins include ApoMab (a fully human affinity-matured IgGl monoclonal antibody), antibodies that target TRAIL or death receptors (e.g., pro-apoptotic receptor agonists DR4 and DR5), conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS- 1029, LBY-135, PRO-1762 and tratuzumab. MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID®
(diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE (piroxicam), ibuprofen cream, ALEVE (naproxen) and NAPROSYN (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like. PDGFR inhibitors include C-451 , CP-673 , CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN ® (carboplatin), satraplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Thrombospondin analogs include ABT-510, ABT-567, TSP-1 and the like.
VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG- 13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU- 11248), VEGF trap, ZACTIMA™
(vandetanib, ZD-6474) and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE (bleomycin), daunorubicin, CAELYX or MYOCET
®
(liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,
®
stimalamer, streptozocin, VALSTAR (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR (irinotecan hydrochloride), camptothecin,
CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or
®
PHARMORUBICIN (epirubicin), etoposide, exatecan, 10-hydroxy camptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-l/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGFlR-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and and the like.
® ®
Hormonal therapies include ARIMIDEX (anastrozole), AROMASIN (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), AFEMA™ (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®
® ®
(letrozole), formestane, glucocorticoids, HECTOROL (doxercalciferol), RENAGEL
® ®
(sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE (megesterol), MIFEPREX (mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS™
® ®
(abarelix), prednisone, PROPECIA (finasteride), rilostane, SUPREFACT (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL (trilostane or modrastane), ZOLADEX (fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.
PARP inhibitors include ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-
201, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- la, ACTIMMUNE® (interferon gamma- lb), or interferon gamma-nl, combinations thereof and the like. Other agents include ALFAFERONE ,(IFN-a), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin,
epratuzumab, GRANOCYTE (Ienograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), EUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®
(oregovomab), pemtumomab (Y-muH FGl), PROVENGE (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZI ® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF- 10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZAD ΑΧΓΝ®
(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR
(gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.
Purine analogs include LAN VIS (thioguanine) and PURI-NETHOL (mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
Compounds of this invention can also be used as radiosensitizeser that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachtherapy and sealed, unsealed source radiotherapy and the like.
Additionally, compounds having formula (I) may be combined with other
chemptherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN (Ad5CMV-p53 vaccine), ALTOCOR^ or MEVACOR (lovastatin), AMPLIGEN® (poly Lpoly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methy 1-3,17-dione-androsta- 1,4- diene), AVAGE (tazarotene), AVE- 8062 (combreastatin derivative) BEC2 (mitumomab),
®
cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine (ONCOVIN ); P: prednisone), CYPAT™ (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His- Ala linker to human epidermal growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EPO906 (epithilone B),
®
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methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE (melanoma vaccine treatment), ONCOVAX (IL-2 Vaccine), ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paditaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
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Schemes and Examples
The following abbreviations have the meanings indicated. ADDP means
l,l'-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of (DHQD)2PHAL, K3Fe(CN)6, K2C03, and K2S04; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1 ,4-phthalazinediyl diethyl ether; DBU means l,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means Ν,Ν-dimethylaminopyridine; DMF means
Ν,Ν-dimethylformamide; dmpe means l,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means l,4-bis(diphenylphosphino)-butane; dppe means 1,2- bis(diphenylphosphino)ethane; dppf means l,l'-bis(diphenylphosphino)ferrocene; dppm means l,l-bis(diphenylphosphino)methane; EDAC-HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU means 0-(7- azabenzotriazol-l-yl)-N,N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; MP means N-methylpyrrolidine; PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention.
Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
Schemes
Scheme 1
Figure imgf000045_0001
As shown in Scheme 1, compounds of formula (1), wherein R1 and R2 are as described herein, can be reacted with oxalic acid in the presence of an aqueous acid, such as, but not limited to, hydrochloric acid, to provide compounds of formula (2). The reaction is typically performed at an elevated temperature. Compounds of formula (2) can be reacted with POCI3, SOCI2, or PBrs, using methods described herein or available in the literature, to provide compounds of formula (3), wherein X is Br or CI. Compounds of formula (4) and (5), which are representative of compounds of this invention, can be prepared by reacting compounds of formula (3) with an amine of formula NH2R7. The reaction is typically performed neat or in a solvent such as, but not limited to, tetrahydrofuran or water, at elevated temperature, and optionally, in a microwave oven. Compounds of formula (5) can be reacted with a compound of formula R7B(OH)2 using Suzuki Coupling conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula (6), which are representative of compounds of this invention.
Scheme 2
Figure imgf000046_0001
As shown in Scheme 2, compounds of formula (7) can be reacted with iron in the presence of an aqueous acid such as, but not limited to, hydrochloric acid, to provide compounds of formula (8). The reaction is typically performed at an elevated temperature in a solvent such as, but not limited to, Ν,Ν-dimethylformamide. Compounds of formula (8) can be coupled with RSC(0)C1 or R5C(0)OH using conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula (9), which are representative of compounds of this invention.
Figure imgf000046_0002
As shown in Scheme 3, boron tribromide can be added to compounds of formula (10) at 0°C, followed by warming to room temperature to provide compounds of formula (11). The reaction is typically performed in a solvent such as, but not limited to, dichloromethane.
Compounds of formula (11) can be reacted with compounds of formula R5Br in the presence of a base such as, but not limited to, potassium carbonate, to provide compounds of formula (12), which are representative of compounds of this invention. The reaction is typically performed in a solvent such as, but not limited to, acetone at an elevated temperature, and optionally in a microwave oven.
Scheme 4
Figure imgf000046_0003
As shown in Scheme 4, compounds of formula (13) can be reacted with compounds of formula (13 A) wherein R50 is as described herein for substituents on R5, using Sonogashira coupling conditions described herein, known to those skilled in the art, and readily available in the literature, to provide compounds of formula (14), which are representative of compounds of this invention.
Scheme 5
Figure imgf000047_0001
As shown in Scheme 5, compounds of formula (16) can be prepared by reacting compounds of formula (15) with hydroxylamine hydrochloride. The reaction is typically performed at elevated temperature in a solvent such as, but not limited to, ethanol. 3-(Tert- butyldiphenylsilyloxy)propanoic acid, prepared as described herein, can be reacted with compounds of formula (16), to provide compounds of formula (17). A coupling agent such as 1- ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, and a catalyst such as, but not limited to, 4-dimethylaminopyridine are typically employed at ambient temperature in a solvent such as, but not limited to, dichloromethane. Compounds of formula (18), which are representative of compounds of this invention, can be prepared from compounds of formula (17) by reacting the latter with tetrabutyl ammonium fluoride. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.
Scheme 6
Figure imgf000048_0001
3-(Tert-butyldiphenylsilyloxy)propanoic acid, prepared as described herein, caii be reacted with compounds of formula (19), to provide compounds of formula (20). A coupling agent such as l-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, and a catalyst such as, but not limited to, 4-dimethylaminopyridine are typically employed at ambient temperature in a solvent such as, but not limited to, dichloromethane. Compounds of formula (21), which are representative of compounds of this invention, can be prepared from compounds of formula (20) by reacting the latter with tetrabutyl ammonium fluoride. The reaction is typically performed at ambient temperature in a solvent such as, but not limited to,
tetany drofuran.
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The exemplified compounds were named using ACD/ChemSketch Version 5.06 (05 June 2001, Advanced Chemistry Development Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13 May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).
EXAMPLES EXAMPLE 1
3-chloro-N-ethyl-6,7-dimethoxyquinoxalin-2-amine
A mixture of 2,3-dichloro-6,7-dimethoxyquinoxaline (800 mg, 3.09 mmol) and ethanamine (3.10 ml of 2.0M solution in THF, 6.20 mmol) was irradiated with microwaves (Biotage Initiator) at 100°C for 20 minutes. The solvent was removed and the residue was purified on silica gel (10~30% ethyl acetate in hexane) to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-de) δ ppm 7.62 (d, J= 8.82 Hz, 1 H) 7.42 (t, J= 5.33 Hz, 1 H) 6.96 - 7.07 (m, 2 H) 3.87 (s, 3 H) 3.40 - 3.58 (m, 2 H) 1.21 (t, J= 6.99 Hz, 3 H). MS ESI(+) m/z 267.8 (M+H)+.
EXAMPLE 2
N,N'-diethyl-6,7-dimethoxyquinoxaline-2,3-diamine
The title compound was isolated as a by-product of EXAMPLE 1. Ή NMR (300 MHz, DMSO-d6) δ ppm 6.88 (s, 2 H) 6.50 (t, J =4.23 Hz, 2 H) 3.79 (s, 6 H) 3.37 - 3.55 (m, 4 H) 1.23 (t, J= 7.17 Hz, 6 H). MS ESI(+) m/z 276.9 (M+H)+.
EXAMPLE 3
3-bromo-N-ethyl-6,7-dimethoxyquinoxalin-2 -amine
EXAMPLE 3A
6,7-dimethoxyquinoxaline-2,3(lH,4H)-dione
A mixture of 4,5-dimethoxybenzene-l,2-diamine (9 g, 53.5 mmol) and oxalic acid (9.64 g, 107 mmol) in 3 N aqueous HCl (100 mL) was heated at reflux for 4 hours. The mixture was cooled and filtered, the solid was washed with copious amount of water, and dried under vacuum at 50°C overnight to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-de) δ 11.73 (s, 2 H) 6.72 (s, 2 H) 3.34 (s, 6 H). MS ESI(+) m/z 222.9 (M+H)+.
EXAMPLE 3B
2,3-dibromo-6,7-dimethoxyquinoxaline
In a 100 mL round-bottomed flask was placed EXAMPLE 3A (3.25 g, 14.63 mmol) and phosphorus pentabromide (12.59 g, 29.3 mmol) and this mixture was heated at 155°C for 1.5 hours. The mixture was then treated with ice- water and the solid was collected by filtration, and air-dried to afford the title compound. Ή NMR (300 MHz, CDC13) δ ppm 7.29 (s, 2 H) 4.04 (s, 6 H). MS-MS ESI(+) m/z 220.0 (M+H)+.
EXAMPLE 3C
3-bromo-N-ethyl-6,7-dimethoxyquinoxalin-2-amine The title compound was prepared as described in EXAMPLE 1 except substituting 2,3- dichloro-6,7-dimethoxyquinoxaline with EXAMPLE 3B. Ή NMR (300 MHz, dimethylsulfoxide-de) δ ppm 7.19 (s, 1 H) 7.04 (s, 1 H) 6.88 (t, J= 5.52 Hz, 1 H) 3.90 (s, 3 H) 3.84 (s, 3 H) 3.39 - 3.53 (m, 2 H) 1.20 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 311.8 (M+H)+.
EXAMPLE 4
3-chloro-6,7-dimethoxy-N-methylquinoxalin-2-amine A mixture of 2,3-dichloro-6,7-dimethoxyquinoxaline (200 mg, 0.772 mmol) and sodium bis(trimethylsilyl)amide (1.158 ml, 1.158 mmol) in l,3-dimethyl-2-imidazolidinone (1 ml) was irradiated with microwaves (Biotage Initiator) at 185°C for 30 minutes. The mixture was cooled and acidified with saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate and organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified on silica gel (10-30% ethyl acetate in hexane) to afford the title compound. Ή ΝΜΡν (300 MHz, dimethylsulfoxide-d6) δ ppm 7.12 - 7.20 (m, 2 H) 7.08 (s, 1 H) 3.90 (s, 3 H) 3.85 (s, 3 H) 2.93 (d, J= 4.78 Hz, 3 H). MS ESI(+) m/z 253.9 (M+H)+.
EXAMPLE 5
N-ethyl-6,7-dimethoxy-N'-methylquinoxaline-2,3 -diamine A mixture of EXAMPLE 4 (57mg, 0.225 mmol) and ethanamine (2.0 ml, 24.72 mmol)
(70% wt in water) was irradiated with microwaves (Biotage Initiator) at 140°C for 30 minutes. The excess ethylamine was evaporated and the precipitate was filtered, washed with water and air-dried to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-de) δ ppm 6.92 (s, 1 H) 6.90 (s, 1 H) 6.63 (d, J= 4.04 Hz, 1 H) 6.40 (t, J= 4.60 Hz, 1 H) 3.79 (s, 6 H) 3.36 - 3.51 (m, 2 H) 2.92 (d, J= 4.41 Hz, 3 H) 1.23 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 262.9 (M+H)+.
EXAMPLE 6
3-bromo-6,7-dimethoxy-N-[2-(4-methylpiperazin-l-yl)ethyl]qumoxalin-2-amine The title compound was prepared as described in EXAMPLE 3C except substituting ethanamine with 2-(4-methylpiperazin-l-yl)ethanamine. !H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 7.22 (s, 1 H) 7.04 (s, 1 H) 6.93 (s, 1 H) 3.90 (s, 3 H) 3.85 (s, 3 H) 3.50 - 3.81 (m, 10 H) 2.98 (s, 2 H) 2.77 (s, 3 H). MS ESI(+) m/z 409.9 (M+H)+.
EXAMPLE 7
N-ethyl-6,7-dimethoxy-N'-(pyridin-3-ylmethyl)quinoxaline-2,3-diamine A mixture of EXAMPLE 3C (0.11 g, 0.352 mmol) and pyridin-3-ylmethanamine (1.5 ml, 14.83 mmol) was irridiated with microwave (Biotage Initiator) at 140°C for 40 minutes. Excess reagent was removed under high vacuum and the residue was purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um lOOA AXIA column (30mm x 75mm), 10-95% (0.1% trifluoroacetic acid in water) in acetonitrile) to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 9.75 (s, 1 H) 7.39 (d, J= 8.82 Hz, 1 H) 7.29 (s, 1 H) 7.03 (d, J= 2.21 Hz, 1 H) 6.90 (dd, J= 8.82, 2.57 Hz, 1 H) 3.83 (s, 8 H) 3.80 (s, 3 H) 3.47 - 3.61 (m, 2 H) 3.34 - 3.46 (m, 4 H) 1.28 (t, J= 7.35 Hz, 3 H). MS ESI(+) m/z 332.0 (M+H)+.
EXAMPLE 8
N-ethyl-6,7-dimethoxy-N'-(pyridin-4-ylmethyl)quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with pyridin-4-ylmethanamine. *H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 8.79 (d, J= 6.25 Hz, 2 H) 7.91 (d, J= 6.25 Hz, 2 H) 7.78 (s, 1 H) 7.06 (s, 1 H) 6.80 (s, 1 H) 4.92 (d, J= 4.41 Hz, 2 H) 3.81 (s, 3 H) 3.75 (s, 3 H) 3.53 (q, J= 7.23 Hz, 2 H) 1.31 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 339.9 (M+H)+.
EXAMPLE 9
N-ethyl-6,7-dimethoxy-N'-(pyridin-2-ylmethyl)quinoxaline-2,3 -diamine
The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with pyridin-2-ylmethanamine. !H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 8.67 (d, J= 4.78 Hz, 1 H) 8.07 (t, J= 7.54 Hz, 1 H) 7.93 (s, 1 H) 7.69 (d, J= 7.35 Hz, 1 H) 7.49 - 7.60 (m, 1 H) 7.11 (s, 1 H) 6.91 (s, 1 H) 4.89 (s, 2 H) 3.82 (s, 3 H) 3.78 (s, 3 H) 3.54 (q, J= 6.74 Hz, 2 H) 1.31 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 340.0 (M+H)+.
EXAMPLE 10
N-ethyl-6,7-dimethoxy-N'-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with 3-(pyrrolidin-l-yl)propan-l-amine. ^ MR (300 MHz, DMSO- d6) δ ppm 9.61 (s, 1 H) 7.32 (s, 1 H) 7.08 (s, 1 H) 6.98 (s, 1 H) 3.81 (s, 6 H) 3.42 - 3.63 (m, 6 H) 3.24 (s, 2 H) 3.24 (s, 2 H) 1.81 - 2.10 (m, 6 H) 1.29 (t, J= 7.35 Hz, 3 H). MS ESI(+) m/z 360.1 (Μ+Η)+·
EXAMPLE 11
l-(3-{[3-(ethylamino)-6,7-dimethoxyquinoxalin-2-yl]amino}propyl)pyrrolidiii-2-one The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with l-(3-aminopropyl)pyrrolidin-2-one. !H NMR (300 MHz, DMSO- d6) δ ppm 7.58 (s, 2 H) 7.13 (s, 1 H) 7.07 (s, 1 H) 3.91 (t, 2 H) 3.83 (s, 6 H) 3.24 - 3.59 (m, 6 H) 2.22 (t, J= 8.09 Hz, 2 H) 1.79 - 2.03 (m, 4 H) 1.30 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 374.0 (M+H)+.
EXAMPLE 12
N-ethyl-6,7-dimethoxy-N'-[2-(pyridin-4-yl)ethyl]quinoxaline-2,3 -diamine The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with 2-(pyridin-4-yl)ethanamine. *H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 8.78 (d, J= 6.25 Hz, 2 H) 7.89 (d, J= 6.25 Hz, 2 H) 7.31 (s, 1 H) 7.06 (s, 1 H) 6.96 (s, 1 H) 3.71 - 3.94 (m, 8 H) 3.49 (q, J= 6.86 Hz, 2 H) 3.22 (t, J= 6.80 Hz, 2 H) 1.26 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 354.0 (M+H)+.
EXAMPLE 13
N-ethyl-6,7-dimetlT.oxy-N'-[2-(pyridin-2-yl)ethyl]quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting pyridin-3-ylmethanamine with 2-(pyridin-2-yl)ethanamine. *H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 8.72 (d, J= 4.41 Hz, 1 H) 8.22 (t, J= 7.17 Hz, 1 H) 7.78 (d, J= 8.09 Hz, 1 H) 7.59 - 7.71 (m, 1 H) 7.09 (s, 1 H) 6.93 (s, 1 H) 6.88 (s, 1 H) 3.90 (t, J= 6.43 Hz, 2 H) 3.82 (s, 3 H) 3.82 (s, 3 H) 3.49 (q, J= 7.23 Hz, 2 H) 3.29 (t, J= 6.62 Hz, 2 H) 1.27 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 354.0 (M+H)+.
EXAMPLE 14
6,7-dimethoxy-3-(pyridin-4-yl)-N-(pyridin-3-ylmethyl)quinoxalin-2-amine
EXAMPLE 14A
2-chloro-6,7-dimethoxy-3-(pyridin-4-yl)quinoxaline A degassed mixture of 2, 3-dichloro-6,7-dimethoxyquinoxaline (200 mg, 0.772 mmol), pyridin-4-ylboronic acid (132 mg, 0.965 mmol, commercial), and sodium carbonate (1.930 ml, 3.86 mmol) in a mixture of ethanol (2 mL) and toluene (4 mL) was added
tetrakis(triphenylphosphine)palladium(0) and the reaction mixture was irradiated with microwaves (Biotage Initiator) at 110°C for 40 minutes. The mixture was cooled and left at room temperature for 3 days. The precipitate in the organic phase was collected by filtration to afford the title compound. 'H NMR (300 MHz, dimethylsuIfoxide-d6) δ ppm 8.76 (d, J= 5.88 Hz, 1 H) 7.80 (d, J= 5.88 Hz, 1 H) 7.09 - 7.65 (m, 4 H) 3.79 - 4.19 (m, 6 H). MS ESI(+) m/z 301.9 (M+H)+.
EXAMPLE 14B
6,7-dimethoxy-3-(pyridm-4-yl)-N-(pyridm-3-ylmethyl)quinoxalin-2-amine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 14A. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.91 (s, 1 H) 8.86 (d, J= 5.88 Hz, 2 H) 8.68 (d, J= 5.15 Hz, 1 H) 8.38 (d, J= 8.09 Hz, 1 H) 7.98 (d, J = 6.25 Hz, 2 H) 7.80 (dd, J= 7.91, 5.33 Hz, 1 H) 7.40 (t, J= 5.70 Hz, 1 H) 7.27 (s, 1 H) 7.03 (s, 1 H) 4.72 (d, J= 5.52 Hz, 2 H) 3.90 (s, 3 H) 3.86 (s, 3 H). MS ESI(+) m/z 374.0 (M+H)+.
EXAMPLE 15
6-chloro-N,N'-diethyl-7-memoxyquinoxaline-2,3-diamine
EXAMPLE 15A
N-(3-Chloro-4-methoxyphenyl)acetamide
To a mixture of ammonium acetate (11.78 g, 153 mmol) in acetic acid (50 ml) was added 3-chloro-4-methoxyaniline (8.92 g, 50.9 mmol) and the reaction mixture was heated at 100°C overnight. The mixture was neutralized with saturated sodium bicarbonate solution and the precipitate was collected by filtration, and air-dried to afford the title compound. *H NMR (300 MHz, CDC13) δ ppm 7.53 (d, J = 2.57 Hz, 1 H) 7.36 (dd, J = 8.82, 2.57 Hz, 2 H) 6.86 (d, J = 8.82 Hz, 1 H) 3.87 (s, 3 H) 2.15 (s, 3 H). MS ESI(+) m/z 199.9 (M+H)+.
EXAMPLE 15B
N-(5-chloro-4-methoxy-2-nitrophenyl)acetamide
EXAMPLE 15A (8.0 g, 40.1 mmol) was added to fuming nitric acid (30 ml, 671 mmol) at 0°C and the mixture was stirred at 0°C for 60 minutes. The mixture was then poured into ice- water and stirred for 20 minutes. The precipitate was filtered, washed with more water and air- dried to afford the title compound. ¾ NMR (300 MHz, CDC13) 5 ppm 10.76 (s, 1 H) 8.58 (s, 1 H) 8.48 (s, 1 H) 4.01 (s, 3 H) 2.32 (s, 3 H). MS ESI(+) m/z 244.7 (M+H)+.
EXAMPLE 15C
5-chloro-4-methoxy-2-nitroaniline
A suspension of EXAMPLE 15B (9.8 g, 40.1 mmol) in 6N HC1 (100 ml, 600 mmol) was heated at reflux for 4 hours. The suspension was cooled and the precipitate was collected by filtration to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-de) δ ppm 7.53 (s, 1 H) 7.32 (s, 2 H) 7.20 (s, 1 H) 3.82 (s, 3 H).
EXAMPLE 15D
4-chloro-5-methoxybenzene-l, 2-diamine dihydrochloride A mixture of iron (12.40 g, 222 mmol), ammonium chloride (0.660 g, 12.34 mmol), and acetic acid (3.11 ml, 54.3 mmol) in water (70 ml) (100 mL) was stirred mechanically at 50°C for 30 minutes. Then a solution of EXAMPLE 15C (5.0 g, 24.68 mmol) in N,N-dimetliylformamide (20 ml) was added and the mixture was stirred for another 4 hours. The suspension was basified with ammonium hydroxide to pH 9 and filtered through diatomaceous earth. The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude material was dissolved in 100 mL of ethyl acetate and treated with 2N HC1 ether solution. The salt was collected by filtration and dried to afford the title compound. HNMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.22 (s, 1 H) 6.63 (s, 1 H) 5.45 (s, 4 H) 3.77 (s, 3 H). MS ESI(+) m/z 173.0 (M+H)+.
EXAMPLE 15E
6-chloro-7-methoxyquinoxaline-2,3 ( 1 H,4H)-dione
The title compound was prepared as described for EXAMPLE 3 A except substituting 4,5-dimethoxybenzene-l, 2-diamine with EXAMPLE 15D. *H NMR (300 MHz,
dimethylsulfoxide-de) δ ppm 8.97 (d, J = 5.51 Hz, 1 H) 8.79 (d, J = 7.72 Hz, 1 H) 8.48 - 8.66 (m, 1 H) 8.23 (s, 1 H) 7.96 - 8.12 (m, 1 H) 7.61 (s, 1 H). MS ESI(+) m/z 226.8 (M+H)+.
EXAMPLE 15F
2,3,6-trichloro-7-methoxyquinoxaline
To a suspension of EXAMPLE 15E (3.8 g, 16.77 mmol) in thionyl chloride (50 ml, 685 mmol) was added N,N-dimethylformamide (0.2 ml, 2.58 mmol) and the reaction mixture was refluxed for 1 hour. Excess thionyl chloride was removed and the residue was treated with water, and stirred for 0.5 hour. The solid was filtered, washed with more water and air-dried to afford crude product. The crude product was purified by column chromatography (0~25% ethyl acetate in hexane) to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.27 (s, 1 H) 7.68 (s, 1 H) 4.06 (s, 3 H). MS ESI(+) m/z 374.8 (M+TFA-H)+. EXAMPLE 15G
6-chloro-N,N'-diethyl-7-methoxyquinoxaline-2,3-diamine A mixture of EXAMPLE 15F (2.9 g, 11.01 mmol) and ethanamine (50 ml, 100 mmol) was stirred at 120°C for 16 hours in a sealed tube. The solvent was removed and the residue was purified on silica gel (10-50% ethyl acetate in hexane) to afford the title compound. H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.38 (s, 1 H) 7.02 (s, 1 H) 6.88 - 6.94 (m, 1 H) 6.73 (t, J = 4.88 Hz, 1 H) 3.87 (s, 3 H) 3.36 - 3.60 (m, 4 H) 1.17 - 1.40 (m, 6 H). MS ESI(+) m/z 280.9 (M+H)+.
EXAMPLE 16
3 ,6-dichloro-N-ethyl-7-methoxyquinoxalin-2-amine
The title compound was prepared as described for EXAMPLE 15G except two equivalents of ethanamine were used. H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.81 (s, 1 H) 7.56 (t, J = 5.70 Hz, 1 H) 7.18 (s, 1 H) 3.98 (s, 3 H) 3.42 - 3.61 (m, 2 H) 1.21 (t, J = 6.99 Hz, 3 H). MS ESI(+) m/z 271.8 (M+H)+.
EXAMPLE 17
6-chloro-N2-ethyl-7-methoxy-N3-(pyridin-3-ylmethyl)quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 16. >H NMR (300 MHz, dimethylsulfoxide- d6) δ ppm 8.93 (d, J = 1.47 Hz, 1 H) 8.72 (d, J = 4.04 Hz, 1 H) 8.40 (d, J = 7.72 Hz, 1 H) 7.86 (dd, J = 8.09, 5.52 Hz, 1 H) 7.70 (s, 1 H) 7.43 (s, 1 H) 7.19 (s, 1 H) 7.08 (s, 1 H) 4.76 (d, J = 4.04 Hz, 2 H) 3.87 (s, 3 H) 3.50 (d, J = 8.09 Hz, 2 H) 1.26 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 343.9 (M+H)+.
EXAMPLE 18
7-chloro-2,3-bis(ethylamino)quinoxalin-6-ol
To a solution of EXAMPLE 15 (0.2 g, 0.712 mmol) in dichloromethane (10 ml) was added boron tribromide (2.85 ml, 2.85 mmol) at 0°C. The mixture was then warmed up to room temperature and stirred overnight. The reaction mixture was stirred with saturated sodium bicarbonate for 24 hours. The aqueous layer was then extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 urn ΙΟθΑ AXIA column (30mm x 75mm), 10-95% (0.1% trifluoroacetic acid in water) in acetonitrile) to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-de) δ ppm 10.27 (s, 1 H) 7.60 (s, 1 H) 7.47 (s, 1 H) 7.09 (s, 1 H) 3.35 - 3.63 (m, 4 H) 1.20 - 1.35 (m, 6 H). MS ESI(+) m/z 266.8 (M+H)+.
EXAMPLE 19
6-chloro-N,N'-diethyl-7-(prop-2-yn-l-yloxy)quinoxaline-2,3-diamine To a mixture of EXAMPLE 18 (90 mg, 0.270 mmol) and 3-bromoprop-l-yne (0.075 ml, 0.675 mmol) in acetone (2.5 ml) was added potassium carbonate (448 mg, 3.24 mmol) and the mixture was irradiated with microwaves (Biotage Initiator) at 80°C for 40 minutes. The suspension was filtered and the filtrate was concentrated. The crude material was purified on silica gel (0-50% ethyl acetate in hexane) to afford the title compound. !H NMR (300 MHz, CDCls) δ ppm 7.68 (s, 1 H) 7.25 (s, 1 H) 4.84 (d, J = 2.21 Hz, 2 H) 4.45 (s, 1 H) 4.30 (s, 1 H) 3.36 - 3.80 (m, 4 H) 2.55 (t, J = 2.39 Hz, 1 H) 1.21 - 1.47 (m, 6 H). MS ESI(+) m/z 304.9 (M+H)+.
EXAMPLE 20
6-chloro-N,N'-diethyl-7-nitroquinoxaline-2,3-diamine
EXAMPLE 20A
6-chloro-7-nitroquinoxaline-2,3(lH,4H)-dione
The title compound was synthesized as described in EXAMPLE 3A except substituting 4,5-dimethoxybenzene-l,2-diamine with 4-chloro-5-nitrobenzene-l,2-diamine. ^ MR (300 MHz, dimethylsulfoxide-de) δ ppm 12.31 (s, 1 H) 12.19 (s, 1 H) 7.81 (s, 1 H) 7.26 (s, 1 H). MS ESI(+) m/z 266.8 (M+H)+.
EXAMPLE 20B
2,3,6-trichloro-7-nitroquinoxaline
To a suspension of EXAMPLE 20A (4.0 g, 16.56 mmol)in phosphorus oxychloride (40 ml, 429 mmol) was added N,N-dimethylformamide (0.5 ml, 6.46 mmol) and the reaction mixture was refluxed for 4 hours. After the removal of the excess reagent, the residue was diluted with ice water and stirred for 10 minutes. The precipitate was collected by filtration and dried in vacuum oven overnight to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.92 (s, 1 H) 8.62 (s, 1 H). MS ESI(+) m/z 266.8 (M+H)+.
EXAMPLE 20C
6-chloro-N2,N3 -diethyl-7-nitroquinoxaline-2,3 -diamine The title compound was synthesized by using the procedures described in EXAMPLE 15G except substituting EXAMPLE 15F with EXAMPLE 20B. lH NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.00 (s, 1 H) 7.63 (t, J=4.60 Hz, 1 H) 7.53 (s, 1 H) 7.38 (t, J=4.60 Hz, 1 H) 3.44 - 3.64 (m, 4 H) 1.26 (t, J=6.99 Hz, 6 H). MS ESI(+) m/z 295.9 (M+H)+.
EXAMPLE 21
7-chloro-N ,N -diethylquinoxaline-2,3,6-triamine
The title compound was synthesized by using the procedures described in EXAMPLE 15D except substituting EXAMPLE 15C with EXAMPLE 20. lH NMR (300 MHz,
dimethylsulfoxide-d6) δ ppm 7.22 (s, 1 H) 6.79 (s, 1 H) 6.74 (t, J = 4.78 Hz, 1 H) 6.50 (t, J = 4.78 Hz, 1 H) 5.02 (s, 2 H) 3.35 - 3.52 (m, 4 H) 1.18 - 1.30 (m, 6 H). MS ESI(+) m/z 265.8 (M+H)+.
EXAMPLE 22
N-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]acetamide To a suspension of EXAMPLE 21 (50 mg, 0.188 mmol) and triethylamine (1 ml, 7.17 mmol) in dichloromethane (2 ml) was added acetic anhydride (0.027 ml, 0.282 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was then treated with an excess of methanol and concentrated. The residue was stirred with water and the precipitate was filtered and air-dried to afford the title compound. 'H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 9.36 (s, 1 H) 7.68 (s, 1 H) 7.41 (s, 1 H) 6.98 (d, J = 2.94 Hz, 2 H) 3.40 - 3.56 (m, 4 H) 2.09 (s, 3 H) 1.24 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 307.8 (M+H)+.
EXAMPLE 23
7-chloro-2,3-bis(ethylamino)quinoxaline-6-carbonitrile
EXAMPLE 23A
2-chloro-4-fluoro-5-nitrobenzonitrile
To a solution of 2-chloro-4-fluorobenzonitrile (10.1 g, 64.9 mmol) in concentrated sulfuric acid (20 mL) was added fuming nitric acid (5.80 ml, 130 mmol) at room temperature slowly and the mixture was stirred for 60 minutes. The solution was then poured into ice-water and stirred for 20 minutes. The precipitate was filtered, washed with more water and air-dried to afford the crude material, which was purified by sublimation to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.97 (d, J = 8.09 Hz, 1 H) 8.30 (d, J = 11.03 Hz, 1 H). EXAMPLE 23B
4-Amino-2-chloro-5-nitrobenzonitrile
To a solution of EXAMPLE 23A (10.0 g, 50 mmol) in ethanol (100 mL) was added ammonium hydroxide solution (28% in water, 50 mL) and suspension was stirred at room temperature for 4 hours. The precipitate was filtered and air-dried to afford the title compound. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.58 (s, 1 H) 8.21 (s, 2 H) 7.22 (s, 1 H).
EXAMPLE 23 C
4,5-diamino-2-chlorobenzonitrile
The title compound was prepared as described in EXAMPLE 15D except substituting EXAMPLE 15C with EXAMPLE 23B. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 6.78 (s, 1 H) 6.62 (s, 1 H) 5.80 (s, 2 H) 5.00 (s, 2 H). MS ESI(+) m/z 167.8 (M+H)+.
EXAMPLE 23D
7-chloro-2,3-dioxo- 1 ,2,3 ,4-tetrahydroquinoxaline-6-carbonitrile The title compound was prepared as described in EXAMPLE 3A except substituting 4,5- dimethoxybenzene-l,2-diamine with EXAMPLE 23C. MS ESI(+) m/z 262.8 (M+CH3CN+H)+.
EXAMPLE 23E
7-chloro-2,3-bis(ethylamino)quinoxaline-6-carbonitrile
The title compound was prepared as described in EXAMPLE 15F except substituting EXAMPLE 15E with EXAMPLE 23D. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.95 (s, 1 H) 8.56 (s, 1 H).
EXAMPLE 23F
7-chloro-2,3-bis(ethylamino)quinoxaline-6-carbonitrile The title compound was prepared as described in EXAMPLE 15G except substituting EXAMPLE 15F with EXAMPLE 23 E. !H NMR (300 MHz, dimethylsulfoxide- d6) δ ppm 7.83 (s, 1 H) 7.61 (t, J = 4.78 Hz, 1 H) 7.53 (s, 1 H) 7.33 (t, J = 4.60 Hz, 1 H) 3.41 - 3.71 (m, 4 H) 1.25 (t, J = 7.35 Hz, 6 H). MS ESI(+) m/z 275.8 (M+H)+.
EXAMPLE 24
7-chloro-2-(ethylamino)-3-[(pyridin-3-ylmethyl)amino]quinoxaline-6-carbonitrile
EXAMPLE 24A
3,7-dichloro-2-(ethylamino)quinoxaline-6-carbonitrile The title compound was prepared as described in EXAMPLE 1 except substituting 4,5- dimethoxybenzene-l,2-diamine with EXAMPLE 23E. lK NMR (300 MHz, dimethylsulfoxide- d6) δ ppm 8.43 (s, 1 H) 8.28 (t, J = 5.70 Hz, 1 H) 7.85 (s, 1 H) 3.44 - 3.67 (m, 2 H) 1.13 - 1.30 (m, 3 H). MS ESI(-) m/z 378.9 (M+TFA-H)".
EXAMPLE 24B
7-chloro-2-(ethylamino)-3-[(pyridin-3-ylmethyl)amino]quinoxaline-6-carbonitrile The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 24A. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.67 (d, J = 1.47 Hz, 1 H) 8.49 (dd, J = 4.78, 1.47 Hz, 1 H) 7.89 (s, 1 H) 7.79 - 7.88 (m, 2 H) 7.59 (t, J = 4.60 Hz, 1 H) 7.56 (s, 1 H) 7.38 (dd, J = 8.09, 4.78 Hz, 1 H) 4.70 (d, J = 5.15 Hz, 2 H) 3.46 - 3.61 (m, 2 H) 1.24 (t, J = 7.35 Hz, 3 H). MS ESI(+) m/z 338.9 (M+H)+.
EXAMPLE 25
7-chloro-2-(ethylamino)-3- { [2-(4-methylpiperazin- l-yl)ethyl]amino} quinoxaline-6-carbonitrile The title compound was prepared using the procedure as described for EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 24 A and pyridin-3-ylmethanamine with 2- (4-methylpiperazin-l-yl)ethanamine. lH NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.88 (s, 1 H) 8.70 (d, J = 4.04 Hz, 1 H) 8.31 (d, J = 8.09 Hz, 1 H) 7.68 - 7.90 (m, 2 H) 7.10 (s, 1 H) 6.96 (s, 1 H) 4.80 (d, J = 3.31 Hz, 2 H) 3.81 (s, 3 H) 3.80 (s, 3 H) 3.51 (q, J = 7.11 Hz, 2 H) 1.29 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 374.9 (M+H)+.
EXAMPLE 26
6-chloro-N,N'-diethyl-7-(trifluoromethoxy)quinoxaline-2,3-diamine
EXAMPLE 26A
6-chloro-7-(trifluoromethoxy)quinoxaline-2,3(lH,4H)-dione The title compound was prepared as described in EXAMPLE 3A except substituting 4,5- dimethoxybenzene-l,2-diamine with 3-chloro-4-(trifluoromethoxy)aniline. 1H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 12.29 (s, 1 H) 12.17 (s, 1 H) 7.46 (s, 1 H) 7.27 (s, 1 H).
EXAMPLE 26B
2,3,6-trichloro-7-(trifluoromethoxy)quinoxaline
The title compound was prepared as described in EXAMPLE 20B except substituting EXAMPLE 20A with EXAMPLE 26A. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.58 (s, 1 H) 8.38 (s, 1 H). 6-chloro-N,N'-diethyl-7-(trifluoromethoxy)quinoxaline-2,3-diamine
EXAMPLE 26C
The title compound was synthesized by using the procedures described in EXAMPLE 15G except substituting EXAMPLE 15F with EXAMPLE 26B. (300 MHz, dimethylsulfoxide- d6) δ ppm 7.57 (s, 1 H) 7.43 (d, J = 1.47 Hz, 1 H) 7.21 - 7.39 (m, 2 H) 3.29 - 3.66 (m, 4 H) 1.25 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 334.9 (M+H)+.
EXAMPLE 27
6-chloro-N2-ethyl-7-methoxy-N3-[2-(4-methylpiperazin-l-yl)ethyl]quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 16 and pyridin-3-ylmethanamine with 2^(4-methylpiperazin-l- yl)ethanamine. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.67 (d, J = 1.47 Hz, 1 H) 8.49 (dd, J = 4.78, 1.47 Hz, 1 H) 7.89 (s, 1 H) 7.78 - 7.88 (m, 2 H) 7.59 (t, J = 4.60 Hz, 1 H) 7.56 (s, 1 H) 7.38 (dd, J = 8.09, 4.78 Hz, 1 H) 4.70 (d, j = 5.15 Hz, 2 H) 3.44 - 3.58 (m, 2 H) 1.24 (t, J = 7.35 Hz, 3 H). MS ESI(+) m/z 379.0 (M+H)+.
EXAMPLE 28
6-chloro-N2-ethyl-7-methoxy-N3-[3-(4-methylpiperazin-l-yl)propyl]quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 16 and pyridm-3-ylmethanamine with 3-(4-methylpiperazin-l- yl)propan-l-amine. 'H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.43 (s, 1 H) 7.14 - 7.28 (m, 2 H) 7.09 (s, 1 H) 3.88 (s, 3 H) 3.50 (m, 8 H) 3.21 - 3.43 (m, 4 H) 3.13 (m, 2 H) 2.84 (s, 3 H) 1.86 - 2.10 (m, 2 H) 1.26 (t, J = 7.35 Hz, 3 H). MS ESI(+) m/z 393.1 (M+H)+.
EXAMPLE 29
6-chloro-N2-ethyl-7-methoxy-N3-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 16 and pyridin-3-ylmethanamine with 3-(pyrrolidin-l- yl)propan-l -amine. MS ESI(+) m/z 364.0 (M+H)+.
EXAMPLE 30
6-chloro-N3-[5-(diethylamino)pentan-2-yl]-N2-ethyl-7-methoxyquinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 16 and pyridin-3-yhnethanamine with N1 ,Ν'-diethylpentane- 1,4-diamine. MS ESI(+) m/z 394.1 (M+H)+. EXAMPLE 31
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-l-ol
EXAMPLE 31A
5-chloro-4-iodo-2-nitroaniline
To a mixture of 5-chloro-2-nitroaniline (8.63 g, 50 mmol) and sodium acetate (4.31 g,
52.5 mmol) in acetic acid (45 mL) was added a solution of iodine monochloride (8.52 g, 52.5 mmol) in acetic acid (25 mL) slowly. After the addition, the suspension was stirred at 90°C for 3 hours. The mixture was cooled and poured into ice-water. The precipitate was collected by filtration and air-dried to afford the title compound. ]H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.36 (s, 1 H) 7.60 (s, 2 H) 7.27 (s, 1 H). MS ESI(-) m/z 296.1 (M-H)".
EXAMPLE 3 IB
6-chloro-7-iodoquinoxaline-2,3 ( 1 H,4H)-dione
The title compound was prepared as described in EXAMPLE 3A except substituting 4,5- dimethoxybenzene-l,2-diamine with EXAMPLE 36 A. ¾ NMR (300 MHz, dimethylsulfoxide- d6) 5 ppm 11.81 - 12.13 (m, 2 H) 7.56 (s, 1 H) 7.12 (s, 1 H).
EXAMPLE 31C
2,3,6-trichloro-7-iodoquinoxaline
The title compound was prepared as described in EXAMPLE 20B except substituting EXAMPLE 20A with EXAMPLE 3 IB. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.75 (s, 1 H) 8.37 (s, 1 H).
EXAMPLE 3 ID
6-chloro-N,N'-diethyl-7-iodoquinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 15G except substituting EXAMPLE 15F with EXAMPLE 31C. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.90 (s, 1 H) 7.55 (s, 1 H) 7.41 (s, 2 H) 3.33 - 3.66 (m, 4 H) 1.25 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 376.8 (M+H)+.
EXAMPLE 3 IE
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-l-ol A solution of EXAMPLE 31D (0.055 g, 0.117 mmol), but-3-yn-l-ol (0.01 g, 0.14 mmol), and triethylamine (0.024 g, 0.234 mmol) in acetonitrile (1 ml) was degassed and then bis(triphenylphosphine)palladium (II) chloride (0.006 g, 5.84 mmol) and copper(I) iodide (1.11 rag, 5.84 mmol) were added under nitrogen. The reaction mixture was irradiated with microwaves (Biotage Initiator) at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude material was purified on silica gel (5-50% ethyl acetate in hexane) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.44 (s, 1 H) 7.39 (s, 1 H) 7.17 (t, J = 4.78 Hz, 1 H) 7.05 (t, J = 4.78 Hz, 1 H) 4.90 (t, J = 5.70 Hz, 1 H) 3.56 - 3.68 (m, 2 H) 3.40 - 3.54 (m, 4 H) 2.60 (t, J = 6.80 Hz, 2 H) 1.24 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 319.0 (M+H)+.
EXAMPLE 32
6-chloro-N,N'-diethyl-7-ethynylquinoxaline-2,3-diamine A solution of EXAMPLE 31D (0.05 g, 0.106 mmol), N,N-diisopropylethylamine (0.030 ml, 0.212 mmol), and tert-butyl(ethynyl)dimethylsilane (0.018 g, 0.127 mmol) in acetonitrile (2 ml) was degassed and then bis(triphenylphosphine)palladium(II) chloride (3.73 mg, 5.31 μηιοΓ) and copper(I) iodide (1.011 mg, 5.31 μπιοΓ) were added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was dissolved in tetrahydrofuran and treated with tetrabutylammonium fluoride (0.53 mL, 0.53 mmol). After stirring at room temperature overnight, the mixture was concentrated and the residue was stirred with water. The precipitate was filtered and purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um ΙΟθΑ AXIA column (30mm x 75mm), 10- 95% (0.1% trifluoroacetic acid in water) in acetonitrile) to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.55 (s, 1 H) 7.45 (s, 1 H) 7.42 (s, 1 H) 7.33 (s, 1 H) 4.40 (s, 1 H) 3.41 - 3.57 (m, 4 H) 1.25 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 274.8 (M+H)+.
EXAMPLE 33
5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn-2-ol The title compound was prepared as described for EXAMPLE 3 IE except substituting but-3-yn-l-ol with pent-4-yn-2-ol. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.44 (s, 1 H) 7.39 (s, 1 H) 7.17 (t, J = 4.78 Hz, 1 H) 7.05 (t, J = 4.78 Hz, 1 H) 4.85 (d, J = 4.41 Hz, 1 H) 3.81 - 3.94 (m, 1 H) 3.41 - 3.58 (m, 4 H) 2.38 - 2.70 (m, 2 H) 1.20 - 1.30 (m, 9 H). MS ESI(+) m/z 333.0 (M+H)+.
EXAMPLE 34
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn- 1 -ol The title compound was prepared as described for EXAMPLE 3 IE except substituting but-3-yn-l-ol with pent-4-yn-l-ol. *H MR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.42 (s, 1 H) 7.39 (s, 1 H) 7.16 (t, J = 4.78 Hz, 1 H) 7.05 (t, J = 4.60 Hz, 1 H) 4.52 (s, 1 H) 3.56 (t, J = 6.25 Hz, 2 H) 3.39 - 3.53 (m, 4 H) 2.46 - 2.59 (m, 2 H) 1.65 - 1.79 (m, 2 H) 1.24 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 332.9 (M+H)+.
EXAMPLE 35
6-chIoro-7-(cyclopropylethynyl)-N,N'-diethylquinoxaline-2,3-diamine The title compound was prepared as described for EXAMPLE 3 IE except substituting but-3-yn-l-ol with ethynylcyclopropane. 1H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 7.39 (s, 1 H) 7.37 (s, 1 H) 7.16 (t, J = 4.96 Hz, 1 H) 7.04 (t, J = 4.78 Hz, 1 H) 3.41 - 3.54 (m, 4 H) 1.51 - 1.64 (m, 1 H) 1.19 - 1.28 (m, 6 H) 0.87 - 0.96 (m, 2 H) 0.71 - 0.80 (m, 2 H).. MS ESI(+) m/z 314.9 (M+H)+.
EXAMPLE 36
2- {4-[7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]but-3 -yn- 1 -y 1} - 1 H-isoindole- 1 ,3 (2H)-dione The title compound was prepared as described for EXAMPLE 3 IE except substituting but-3-yn-l-ol with 2-(but-3-ynyl)isoindoline-l,3-dione. ¾ NMR (300 MHz, dimethylsulfoxide- d6) δ ppm 7.77 - 8.00 (m, 4 H) 7.31 (s, 1 H) 7.29 (s, 1 H) 7.17 (t, J = 4.78 Hz, 1 H) 7.05 (t, J - 4.78 Hz, 1 H) 3.85 (t, J = 6.80 Hz, 2 H) 3.40 - 3.54 (m, 4 H) 2.84 - 2.95 (m, 2 H) 1.18 - 1.28 (m, 6 H). MS ESI(+) m/∑ 448.1 (M+H)+.
EXAMPLE 37
6-(4-aminobut- 1 -yn- 1 -yl)-7-chloro-N,N'-diethylquinoxaline-2,3 -diamine To a solution of EXAMPLE 36 (50 mg, 0.112 mmol) in dichlororaethane (5 ml) was added hydrazine (0.55 ml, 11.22 mmol) and the mixture was heated at reflux for 4 hours until solid precipitated out. The mixture was concentrated and the residue was triturated with dichlororaethane, and filtered. The filtrate was concentrated and the crude material was treated with mixture of ethyl acetate and hexane to precipitate out the title compound. 5H NMR (300 MHz, dimethylsulfoxide-de) 5 ppm 7.45 (s, 1 H) 7.40 (s, 1 H) 7.17 (t, J = 4.60 Hz, 1 H) 7.05 (t, J = 4.78 Hz, 1 H) 3.40 - 3.56 (m, 4 H) 2.76 (t, J = 6.62 Hz, 2 H) 2.44 - 2.59 (m, 2 H) 1.67 (s, 2 H) 1.24 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 318.0 (M+H)+.
EXAMPLE 38
6-chloro-3-(3-chlorophenyl)-N-ethyl-7-methoxyqninoxalin-2-amine EXAMPLE 38 A
2,3-dibromo-6-chloro-7-methoxyquinoxaline
The title compound was prepared as described in EXAMPLE 3B except substituting EXAMPLE 3A with EXAMPLE 15E. Ή NM (300 MHz, dimethylsulfoxide-dg) δ ppm 8.26 (s, 1 H) 7.68 (s, 1 H) 4.06 (s, 3 H). MS ESI(+) m/z 367.0 (M+ NH^.
EXAMPLE 38B
3-bromo-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine A mixture of EXAMPLE 38A (1800 mg, 5.11 mmol) and ethanamine (5.11 ml, 10.22 mmol) was heated at 100°C for 6 hours in a sealed tube. The solvent was removed and the residue was purified on silica gel (10-50% ethyl acetate in hexane) to afford the title compound, which was used in the next step without further purification. !H NMR (300 MHz,
dimethylsulfoxide-d6) δ ppm 7.84 (s, 1 H) 7.35 (t, J = 5.52 Hz, 1 H) 7.17 (s, 1 H) 3.98 (s, 3 H) 3.42 - 3.56 (m, 2 H) 1.21 (t, J = 6.99 Hz, 3 H). MS ESI(+) m/z 317.8 (M+H)+.
EXAMPLE 38C
6-chloro-3-(3-chlorophenyl)-N-ethyl-7-methoxyquinoxalin-2-amine
To a suspension of EXAMPLE 38B (0.02 g, 0.06 mmol) and 3-chlorophenylboronic acid (0.0 1 g, 0.07 mmol) in a mixture of ethanol/dimethoxyethane (1:1) was added PS-P(Ph)3 (0.05 eq) and potassium carbonate (0.0096 g, 0.07 mmol). The reaction mixture was irradiated with microwaves (Biotage Initiator) at 120°C for 15 minutes. After filtration, the residue was concentrated and purified by reverse phase HPLC (Waters LC4000 purification system,
Phenomenex Luna C8(2) 5 um 100A AXIA column (30mm x 75mm), 10-95% (0.1%
trifluoroacetic acid in water) in acetonitrile) to afford the title compound. !H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 7.85 (s, 1 H) 7.55 - 7.72 (m, 5 H) 7.18 (s, 1 H) 3.99 (s, 3 H) 3.46 (q, J= 7.22 Hz, 2 H) 1.17 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 347.9 (M+H)+.
EXAMPLE 39
6-chloro-3-(4-chlorophenyl)-N-ethyl-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 4-chlorophenylboronic acid. }H NMR (500 MHz,
dimethylsulfoxide-d6) δ ppm 7.85 (s, 1 H) 7.67 - 7.74 (m, 2 H) 7.58 - 7.64 (m, 2 H) 7.18 (s, 1 H) 3.99 (s, 3 H) 3.45 (q, J= 7.22 Hz, 2 H) 1.17 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 347.9 (M+H)+.
EXAMPLE 40 3-(l,3-benzodioxol-5-yl)-6-chloro-N-emyl-7-methoxyquinoxalin-2-amine
The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with benzo[d][l,3]dioxol-5-ylboronic acid. !H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 7.81 (s, 1 H) 7.17 - 7.24 (m, 2 H) 7.16 (s, 1 H) 7.07 (d, J= 8.54 Hz, 1 H) 6.11 (s, 2 H) 3.97 (s, 3 H) 3.45 (q, J= 7.12 Hz, 2 H) 1.17 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 357.9 (M+H)+.
EXAMPLE 41
6-chloro-N-ethyl-7-methoxy-3-(2-thienyl)quinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with thiophen-2-ylboronic acid. lH NMR (500 MHz,
dimethylsulfoxide-de) δ ppm 7.83 (s, 1 H) 7.75 - 7.83 (m, 1 H) 7.26 (dd, J= 5.19, 3.66 Hz, 1 H) 7.15 - 7.20 (m, 2 H) 3.97 (s, 3 H) 3.42 - 3.60 (m, 2 H) 1.13 - 1.28 (m, 3 H). MS ESI(+) m/z 319.9 (M+H)+.
EXAMPLE 42
3-(l-benzofuran-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine
The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with benzofuran-2-ylboronic acid. ¾ NMR (500 MHz,
dimethylsulfoxide-de) δ ppm 7.64 - 7.85 (m, 2 H) 7.24 - 7.53 (m, 3 H) 7.18 (s, 1 H) 4.00 (s, 3 H) 3.61 (q, J= 7.02 Hz, 2 H) 1.29 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 353.9 (M+H)+.
EXAMPLE 43
1 - { 5- [7-chloro-3 -(ethylamino)-6-methoxyquinoxalin-2-yl]-2-thienyl} ethanone The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 5-acetylthiophen-2-ylboronic acid. }H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 7.98 (d, J= 3.97 Hz, 1 H) 7.84 - 7.89 (m, 1 H) 7.83 (s, 1 H) 7.17 (s, 1 H) 3.97 (s, 3 H) 3.50 (q, J= 7.12 Hz, 2 H) 2.60 (s, 3 H) 1.18 - 1.23 (m, 3 H). MS ESI(+) m/z 361.9 (M+H)+.
EXAMPLE 44
3-(l-benzothiophen-3-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with benzo[b]thiophen-3-ylboronic acid. Ή NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 8.18 (s, 1 H) 8.11 (d, J= 7.63 Hz, 1 H) 7.86 (s, 1 H) 7.81 (d, J= 7.32 Hz, 1 H) 7.39 - 7.53 (m, 2 H) 7.22 (s, 1 H) 4.01 (s, 3 H) 3.46 (q, J= 7.02 Hz, 2 H) 1.17 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 370.0 (M+H)+.
EXAMPLE 45
3-(l-benzothiophen-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with benzo[b]thiophen-2-ylboronic acid. 'H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 8.17 (s, 1 H) 7.94 - 8.06 (m, 2 H) 7.86 (s, 1 H) 7.38 - 7.54 (m, 2 H) 7.21 (t, J= 5.49 Hz, 1 H) 7.19 (s, 1 H) 4.00 (s, 3 H) 3.49 - 3.61 (m, 2 H) 1.28 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 370.0 (M+H)+.
EXAMPLE 46
3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]benzamide The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 3-carbamoylphenylboronic acid. lH NMR (500 MHz, dimethylsulfoxide-d6) 5 ppm 8.13 - 8.18 (m, 1 H) 8.01 (d, J= 7.93 Hz, 1 H) 7.87 (s, 1 H) 7.83 (d, J= 7.93 Hz, 1 H) 7.65 (t, J= 7.78 Hz, 1 H) 7.20 (s, 1 H) 3.99 (s, 3 H) 3.47 (q, J= 7.02 Hz, 2 H) 1.18 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 357.0 (M+H)+.
EXAMPLE 47
6-chloro-N-ethyl-3 -( 1 H-indol-4-yl)-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with lH-indol-4-ylboronic acid. MS ESI(+) m/z 353.0 (M+H)+.
EXAMPLE 48
6-chloro-N-ethyl-3-(isoquinolin-4-yl)-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with isoquinolin-4-ylboronic acid. Ή NMR (500 MHz,
dimethylsulfoxide-dg) δ ppm 9.73 (s, 1 H) 8.72 (s, 1 H) 8.48 (d, J= 7.93 Hz, 1 H) 7.90 - 8.01 (m, 2 H) 7.89 (s, 1 H) 7.67 (d, J= 8.24 Hz, 1 H) 7.27 (s, 1 H) 4.03 (s, 3 H) 3.39 (q, J= 7.02 Hz, 2 H) 1.09 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 365.0 (M+H)+.
EXAMPLE 49
6-chloro-N-ethyl-7-methoxy-3-(quinolm-5-yl)quinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with quinolin-5-ylboronic acid. MS ESI(+) m/z 365.0 (M+H)+. EXAMPLE 50
6-chloro-N-ethyl-7-methoxy-3-(quinolin-3-yl)quinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with quinolin-3-ylboronic acid. !H NMR (500 MHz,
dimethylsulfoxide-de) δ ppra 9.23 (d, J= 2.14 Hz, 1 H) 8.88 (d, J= 2.14 Hz, 1 H) 8.19 (dd, J =13.88, 8.39 Hz, 2 H) 7.94 - 8.04 (m, 1 H) 7.92 (s, 1 H) 7.80 (t, J= 7.48 Hz, 1 H) 7.23 (s, 1 H) 4.01 (s, 3 H) 3.48 (q, J= 7.22 Hz, 2 H) 1.20 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 365.0 (M+H)+.
EXAMPLE 51
6-chloro-N-ethyl-7-methoxy-3-(lH-pyrazol-4-yl)quinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole. lK NMR (500 MHz, dimethylsulfoxide-de) δ ppm 8.20 (s, 2 H) 7.82 (s, 1 H) 7.17 (s, 1 H) 3.97 (s, 3 H) 3.51 (q, J= 7.12 Hz, 2 H) 1.23 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 303.9 (M+H)+.
EXAMPLE 52
6-chloro-N-ethyl-7-methoxy-3 -(1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-2-amine
The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole. 'H MR (500 MHz, dimethylsulfoxide-d6) δ ppm 8.29 (s, 1 H) 7.98 (s, 1 H) 7.81 (s, 1 H) 7.18 (s, 1 H) 3.97 (s, 3 H) 3.95 (s, 3 H) 3.52 (q, J= 7.12 Hz, 2 H) 1.24 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 317.9 (M+H)+.
EXAMPLE 53
6-chloro-N-ethyl-7-methoxy-3-(l-methyl-lH-indol-5-yl)quinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 1 -methyl-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- indole. *H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.90 (s, 1 H) 7.89 (s, 1 H) 7.62 (d, J= 8.54 Hz, 1 H) 7.47 (dd, J= 8.54, 1.53 Hz, 1 H) 7.44 (s, 2 H) 7.27 (s, 1 H) 3.97 (s, 3 H) 3.86 (s, 3 H) 3.49 (q, J= 7.12 Hz, 2 H) 1.19 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 367.0 (M+H)+.
EXAMPLE 54
6-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-4H-chromen-4-one The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-chromen-4- one. *H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 8.29 - 8.41 (m, 2 H) 8.13 - 8.24 (m, 1 H) 7.94 (dd, J= 8.54, 2.44 Hz, 1 H) 7.88 (s, 1 H) 6.31 - 6.57 (m, 2 H) 3.99 (s, 3 H) 3.43 - 3.59 (m, 2 H) 1.18 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 382.0 (M+H)+.
EXAMPLE 55
tert-butyl 4-{5-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]pyridiii-2-yl}piperazine-l- carboxylate
The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with te -butyl 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperazine-l-carboxylate. lH NMR (500 MHz, dimethylsulfoxide-de) δ ppm 8.42 (d, J= 2.44 Hz, 1 H) 7.94 - 8.10 (m, 1 H) 7.85 (s, 1 H) 7.19 (s, 1 H) 7.18 (d, J= 9.46 Hz, 1 H) 3.98 (s, 3 H) 3.62 - 3.72 (m, 4 H) 3.51 (d, J= 4.58 Hz, 4 H) 3.46 (q, J= 7.32 Hz, 2 H) 1.44 (s, 9 H) 1.20 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 499.2 (M+H)+.
EXAMPLE 56
3-(biphenyl-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with biphenyl-2-ylboronic acid. *H NMR (500 MHz,
dimethylsulfoxide-de) δ ppm 7.82 (s, 1 H) 7.62 - 7.70 (m, 1 H) 7.56 - 7.63 (m, 1 H) 7.43 - 7.56 (m, 2 H) 7.19 - 7.29 (m, 2 H) 7.12 - 7.19 (m, 3 H) 7.10 (s, 1 H) 3.96 (s, 3 H) 3.50 (q, J= 7.22 Hz,
2 H) 1.21 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 390.0 (M+H)+.
EXAMPLE 57
3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-N-(2-furylmethyl)benzamide The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 3-((furan-2-ylmethyl)carbamoyl)phenylboronic acid. *H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 8.14 (s, 1 H) 8.01 (d, J= 8.24 Hz, 1 H) 7.87 (s, 1 H) 7.84 (d, J= 7.93 Hz, 1 H) 7.66 (t, J= 7.78 Hz, 1 H) 7.57 (s, 1 H) 7.20 (s, 1 H) 6.39 - 6.52 (m, 1 H) 6.32 (d, J= 3.66 Hz, 1 H) 4.50 (s, 2 H) 3.99 (s, 3 H) 3.47 (q, J= 7.02 Hz, 2 H) 1.01 - 1.40 (m,
3 H). MS ESI(+) m/z 437.0 (M+H)+.
EXAMPLE 58
N-benzyl-3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]benzamide
The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with 3-(benzylcarbamoyl)phenylboronic acid. !H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 8.22 (s, 1 H) 8.17 (s, 1 H) 8.03 (d, J= 7.93 Hz, 1 H) 7.92 (d, J= 7.32 Hz, 1 H) 7.87 (s, 1 H) 7.84 (d, J= 7.93 Hz, 1 H) 7.67 (t, J= 7.78 Hz, 1 H) 7.63 (t, J= 7.78 Hz, 1 H) 7.33 - 7.37 (m, 3 H) 7.23 - 7.29 (m, 1 H) 7.20 (s, 1 H) 4.47 - 4.56 (m, 2 H) 3.99 (s, 3 H) 3.47 (q, J= 7.22 Hz, 2 H) 1.17 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 447.1 (M+H)+.
EXAMPLE 59
3-(l-benzyl-lH-pyrazol-4-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine The title compound was prepared as described for EXAMPLE 38C except substituting 3- chlorophenylboronic acid with l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)-lH- pyrazole. !HNMR (500 MHz, dimethylsulfoxide-d6) δ ppm 8.47 (s, 1 H) 8.05 (s, 1 H) 7.79 (s, 1 H) 7.23 - 7.45 (m, 5 H) 7.15 (s, 1 H) 5.43 (s, 2 H) 3.97 (s, 3 H) 3.51 (q, J= 7.12 Hz, 2 H) 1.23 (t, J= 7.02 Hz, 3 H). MS ESI(+) m/z 394.0 (M+H)+.
EXAMPLE 60
5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-ox0pentanoic acid A solution of EXAMPLE 3 ID (0.077 g, 0.020 mmol), pent-4-ynoic acid (0.040 g, 0.040 mmol) and triethylamine (0.21 g, 2.0 mmol) in N,N-dimethylamine (0.75 ml) was degassed and then bis(triphenylphosphine)palladium(II) chloride (0.014 g, 0.020 mmol) and copper iodide (3.89 mg, 0.020 mmol) were added under nitrogen. The reaction mixture was irradiated with microwaves (Biotage Initiator) at 120°C for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated and the crude material was purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um lOOA AXIA column (30mm x 75mm), 10-95% (0.1% trifluoroacetic acid in water) to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 11.75 (s, 1 H) 7.50 (s, 1 H) 7.40 (s, 1 H) 4.59 (s, 2 H) 3.97 (s, 2 H) 3.55 (q, J = 7.11 Hz, 4 H) 2.83 (t, J = 6.62 Hz, 2 H) 2.53 (t, J = 6.62 Hz, 2 H) 1.24 - 1.41 (m, 6 H). MS ESI(+) m/z 365.0 (M+H)+.
EXAMPLE 61
4-[7-chloro-3-(ethylammo)-2-{[3-(4-methylpiperazin-l-yl)propyl]amino}qumoxalin-6-yl]but-3- yn-l-ol
EXAMPLE 61A
3,6-dichloro-N-ethyl-7-iodoquinoxalin-2-amine
The title compound was prepared as described in EXAMPLE 1 except substituting 2,3- dichloro-6,7-dimethoxyquinoxaline with EXAMPLE 3 IB. !H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.28 (s, 1 H) 7.80 - 7.89 (m, 1 H) 7.79 (s, 1 H) 3.40 - 3.58 (m, 2 H) 1.20 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 376.8 (M+H)+.
EXAMPLE 6 IB
6-chloro-N2-ethyl-7-iodo-N3-(3-(4-methylpiperazin-l-yl)propyl)quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting
EXAMPLE 3C with EXAMPLE 61A and pyridin-3-ylmethanamine with 3-(4-methylpiperazin- l-yl)propan-l -amine. lU. NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.84 - 7.93 (m, 1 H) 7.49 - 7.56 (m, 1 H) 7.37 (s, 1 H) 7.20 (d, J = 4.04 Hz, 1 H) 3.41 - 3.57 (m, 6 H) 3.32 (s, 4 H) 3.02 (s, 4 H) 2.81 (s, 3 H) 1.82 - 2.09 (m, 2 H) 1.24 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 489.0 (M+H)+.
EXAMPLE 61C
The title compound was prepared as described for EXAMPLE 3 IE except substituting EXAMPLE 31 D with EXAMPLE 6 IB. H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.43 (s, 1 H) 7.39 (s, 1 H) 7.16 (t, J = 4.78 Hz, 1 H) 7.07 (t, J = 4.60 Hz, 1 H) 4.90 (s, 1 H) 3.61 (t, J = 6.99 Hz, 2 H) 3.37 - 3.54 (m, 6 H) 2.60 (t, J = 6.99 Hz, 2 H) 2.24 - 2.44 (m, 6 H) 2.15 (s, 3 H) 1.70 - 1.85 (m, 2 H) 1.24 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 431.1 (M+H)+.
EXAMPLE 62
4-(7-chloro-2,3-bis{[2-(4-methylpiperazin-l-yl)emyl]amino}quinoxalin-6-yl)but-3-yn-l-ol EXAMPLE 62A6-chloro-7-iodo-N,N'-bis[2-(4-methylpiperazin- 1 -yl)ethyl]quinoxaline-2,3- diamine
The title compound was prepared as described in EXAMPLE 15G except substituting EXAMPLE 15F with EXAMPLE 31C and ethanamine with 2-(4-methylpiperazin-l- yl)ethanamine. !HNMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.86 (s, 1 H) 7.50 (s, 1 H) 7.08 - 7.26 (m, 2 H) 3.56 (q, J = 5.52 Hz, 4 H) 2.52 - 2.63 (m, 4 H) 2.39 - 2.48 (m, 8 H) 2.32 (s, 8 H) 2.14 (s, 6 H). MS ESI(+) m/z 574.1 (M+H)+.
EXAMPLE 62B
The title compound was prepared as described for EXAMPLE 3 IE except substituting EXAMPLE 3 ID with EXAMPLE 62A. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.44 (s, 1 H) 7.39 (s, 1 H) 7.18 (t, J= 4.96 Hz, 1 H) 7.08 (t, J= 4.78 Hz, 1 H) 3.58 - 3.67 (m, 2 H) 3.51 - 3.59 (m, 4 H) 3.49 (t, J= 6.62 Hz, 1 H) 2.53 - 2.64 (m, 4 H) 2.45 (s, 8 H) 2.36 - 2.43 (m, 2 H) 2.32 (s, 8 H) 2.15 (s, 6 H). MS ESI(+) m/z 515.2(M+H)+. EXAMPLE 63
4-[7-chloro-3-(ethylamino)-2-{[2-(4-methylpiperazin-l-yl)ethyl]amino}quinoxalin-6-yl]but-3- yn-l-ol
EXAMPLE 63A
6-chloro-7-iodo-N3-(2-(4-methylpiperazin-l-yl)ethyl)-N2-propylquinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 61A and pyridin-3-ylmethanamine with 2-(4-methylpiperazin- l-yl)ethanamine. MS ESI(+) m/z 475.0 (M+H)+.
EXAMPLE 63B
The title compound was prepared as described for EXAMPLE 3 IE except substituting
EXAMPLE 3 ID with EXAMPLE 63 A. Ή NMR (300 MHz, dimethylsulfoxide-d6) δ ppfn 7.44 (s, 1 H) 7.39 (s, 1 H) 7.22 (t, J = 4.78 Hz, 1 H) 7.01 - 7.11 (m, 1 H) 4.92 (s, 1 H) 3.41 - 3.71 (m, 4 H) 2.52 - 2.66 (m, 4 H) 2.46 (s, 4 H) 2.32 (s, 4 H) 2.14 (s, 3 H) 1.90 (s, 2 H) 1.23 (t, J = 7.17 Hz, 3 H). MS ESI(+) m/z 417.1(M+H)+.
EXAMPLE 64
2-{3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-l,2,4-oxadiazol-5-yl}ethanol
EXAMPLE 64A
(Z)-7-chloro-2,3-bis(ethylamino)-N'-hydroxyquinoxaline-6-carboximidamide
To a suspension of EXAMPLE 23 (0.2 g, 0.725 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (1.0 g, 14.39 mmol) and the reaction mixture was refluxed for 12 hours. The suspension was cooled to room temperature, filtered and air-dried to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 9.39 (s, 1 H) 7.37 (s, 1 H) 7.34 (s, 1 H) 7.11 (t, J = 4.78 Hz, 1 H) 7.02 (t, J = 4.78 Hz, 1 H) 5.74 (s, 2 H) 3.40 - 3.57 (m, 4 H) 1.25 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 308.9 (M+H)+.
EXAMPLE 64B
Methyl 3 -(tert-butyldiphenylsilyloxy)propanoate
To a solution of methyl 3-hydroxypropanoate (1.0 g, 9.61 mmol) and imidazole (1.308 g, 19.21 mmol) in dichloromethane (40 ml) was added tert-butylchlorodiphenylsilane (2.52 ml, 9.61 mmol) and the turbid suspension was stirred at room temperature overnight. Saturated ammonium chloride was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried with magnesium sulfate and filtered. The filtrate was concentrated to afford the title compound, which was used without further purification. MS ESI(+) m/z 360 (M+NH4)+.
EXAMPLE 64C
3 -(tert-buty ldiphenylsilyloxy)propanoic acid
To a solution of EXAMPLE 64B (3.3 g, 9.63 mmol) in ethanol (15 ml) was added sodium hydroxide (10.12 ml, 10.12 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and then treated with IN HC1, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford the title compound. MS ESI(-) m/z 326.9 (M-H)\
EXAMPLE 64D
(Z)-N'-(3-(tert-butyldiphenylsilyloxy)propanoyloxy)-7-chloro-2,3-bis(ethylamino)quinoxaline-6- carboximidamide
To a mixture of EXAMPLE 64A (0.1 lg, 0.356 mmol), EXAMPLE 64C (0.140 g, 0.428 mmol) and l-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.082 g, 0.428 mmol) in dichloromethane (2.5 ml) was added catalytical amount of 4-dimethylaminopyridine and the suspension was stirred at room temperature overnight. After the removal of solvent, the residue was purified on silica gel (15-80% ethyl acetate in hexane) to afford the title compound. 'H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.58 - 7.76 (m, 5 H) 7.39 - 7.51 (m, 6 H) 7.37 (s, 1 H) 7.17 (t, J = 4.78 Hz, 1 H) 7.08 (t, J = 4.78 Hz, 1 H) 6.83 (s, 2 H) 3.95 (t, J = 6.25 Hz, 2 H) 3.38 - 3.63 (m, 4 H) 2.74 (t, J = 6.07 Hz, 2 H) 1.13 - 1.36 (m, 6 H) 0.98 (s, 9 H). MS ESI(+) m/z 619.2 (M+H)+.
EXAMPLE 64E
2-{3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-l,2,4-oxadiazol-5-yl}ethanol To a solution of EXAMPLE 64D (150 mg, 0.242 mmol) in tetrahydrofuran (0.5 ml) was added tetrabutyl ammonium fluoride (0.606 ml, 0.606 mmol) and the mixture was stirred at room temperature for 16 hours. After an aqueous workup, the crude material was purified on silica gel (40-100% ethyl acetate in hexane) to afford the title compound. !H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.93 (s, 1 H) 7.52 (s, 1 H) 7.33 (t, J = 4.78 Hz, 1 H) 7.17 (t, J = 4.60 Hz, 1 H) 5.02 (t, J = 5.33 Hz, 1 H) 3.88 (q, J = 5.88 Hz, 2 H) 3.43 - 3.64 (m, 4 H) 3.15 (t, J = 6.25 Hz, 2 H) 1.21 - 1.39 (m, 6 H). MS ESI(+) m/z 363.0 (M+H)+. EXAMPLE 65
N-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-3-hydroxypropanamide
EXAMPLE 65 A
3-(tert-butyldiphenylsilyloxy)-N-(7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl)propanamide The title compound was prepared as described for EXAMPLE 64D except substituting
EXAMPLE 64A with EXAMPLE 21. lU NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.35 - 7.71 (m, 10 H) 7.21 (s, 1 H) 6.88 - 7.05 (m, 1 H) 6.77 (s, 1 H) 6.73 (t, J=4.78 Hz, 1 H) 6.48 (t, J=4.78 Hz, 1 H) 3.97 (t, J=5.70 Hz, 2 H) 3.34 - 3.61 (m, 4 H) 2.69 (t, J=5.88 Hz, 2 H) 1.13 - 1.37 (m, 6 H) 0.98 (s, 9 H).
EXAMPLE 65B
N-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-3-hydroxypropanamide The title compound was prepared as described for EXAMPLE 64E except substituting EXAMPLE 64 C with EXAMPLE 65A. JH NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 9.42 (s, 1 H) 7.86 (s, 1 H) 7.41 (s, 1 H) 6.88 - 7.14 (m, 2 H) 4.91 (s, 1 H) 3.64 - 3.84 (m, 2 H) 3.39 - 3.57 (m, 4 H) 2.51 - 2.62 (m, 2 H) 1.24 (t, J = 7.17 Hz, 6 H). MS ESI(+) m/z 337.9 (M+H)+.
EXAMPLE 66
4- [2,7-dichloro-3 -(ethylamino)quinoxalin-6-y l]but-3-yn- 1 -ol The title compound was prepared as described for EXAMPLE 3 IE except substituting EXAMPLE 3 ID with EXAMPLE 61A. *H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.88 (s, 1 H) 7.84 (s, 1 H) 7.72 - 7.79 (m, 1 H) 4.95 (q, J= 5.76 Hz, 1 H) 3.56 - 3.75 (m, 2 H) 3.42 - 3.56 (m, 2 H) 2.58 - 2.81 (m, 2 H) 1.20 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 309.8 (M+H)+.
EXAMPLE 67
4,4'-[7-chloro-3-(ethylamino)quinoxaline-2,6-diyl]bisbut-3-yn-l-ol The title compound was prepared as a by-product in EXAMPLE 66. !H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 8.24 (s, 1 H) 7.73 (s, 1 H) 7.34 (t, J= 5.70 Hz, 1 H) 5.13 (s, 2 H) 3.69 (t, J= 6.43 Hz, 4 H) 3.41 - 3.61 (m, 2 H) 2.65 - 2.87 (m, 4 H) 1.20 (t, J= 7.17 Hz, 3 H). MS ESI(+) m/z 401.8 (M+CH3CN+NH4)+.
EXAMPLE 68
7-chloro-2-{[2-(4-methylpiperazin-l-yl)ethyl]amino}-3-(pyridin-2-yl)quinoxaline-6-carbonitrile
EXAMPLE 68A
2,3-dibromo-7-chloroquinoxaline-6-carbonitrile The title compound was prepared as described for EXAMPLE 3B except substituting EXAMPLE 3 A with EXAMPLE 23D. Ή NM (300 MHz, dimethylsulfoxide-d6) 8 ppm 8.94 (s, 1 H) 8.54 (s, 1 H).
EXAMPLE 68B
3 -bromo-7-chloro-2-(2-(4-methylpiperazin- 1 -yl)ethylamino)quinoxaline-6-carbonitrile
The title compound was prepared as described in EXAMPLE 3C except substituting EXAMPLE 3B with EXAMPLE 68A and ethanamine with 2-(4-methylpiperazin-l- yl)ethanamine. MS ESI(-) m/z 406.9 (M-H)".
EXAMPLE 68C
7-chloro-2- { [2-(4-methylpiperazin- 1 -yl)ethyl]amino} -3 -(pyridin-2-yl)quinoxaline-6-carbonitrile A mixture of EXAMPLE 68B (50mg, 0.122 mmol), 2-(tributylstannyl)pyridine (67.4 mg, 0.146 mmol), bis(triphenyIphosphine)paIladium(II) chloride (8.57 mg, 0.012 mmol) and copper(I) iodide (1.162 mg, 6.10 μιηοΐ) in tetrahydrofuran (2.5 ml) was refluxed for 120 minutes. The solvent was removed and the residue was purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um ΙΟθΑ AXIA column (30mm x 75mm), 10- 95% (0.1% trifluoroacetic acid in water) to afford the title compound. 'H NMR (500 MHz, dimethylsulfoxide-de) δ ppm 10.87 (t, J = 4.58 Hz, 1 H) 8.78 (d, J = 4.27 Hz, 1 H) 8.64 (d, J = 7.93 Hz, 1 H) 8.49 (s, 1 H) 8.01 - 8.24 (m, 1 H) 7.78 (s, 1 H) 7.57 - 7.74 (m, 1 H) 3.57 - 3.87 (m, 2 H) 3.28 (s, 4 I-I) 2.65 (t, J = 6.10 Hz, 2 H) 2.39 (s, 4 H) 2.20 (s, 3 H). MS ESI(+) m/z 408.0 (M+H)+.
EXAMPLE 69
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-2-ol The title compound was prepared as described for EXAMPLE 3 IE except substituting but-3-yn-l-ol with but-3-yn-2-ol. !H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.49 (s, 1H), 7.45 (s, 1H), 4.64 (q, J= 6.6 Hz, 1H), 3.47 (dq, J= 5.7, 7.2 Hz, 4H), 1.43 (d, J= 6.6 Hz, 3H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 319 (M+H)+.
EXAMPLE 70
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-2-methylbut-3-yn-2-oi The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with 2-methylbut-3-yn-2-ol. ¾ NMR (400 MHz, dimethylsulfoxide-D20) 5 7.47 (s, 1H), 7.44 (s, 1H), 3.47 (dq, J= 6.0, 7.2 Hz, 4H), 1.50 (s, 6H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 333 (M+H)+.
EXAMPLE 71
1 - [7-chloro-2,3 -bis(ethy lamino)quinoxalin-6-yl]-3 -methy lpent- 1 -yn-3 -ol The title compound was prepared as described in EXAMPLE 31 E except substituting but-3-yn-l-ol with 3-methylpent-l-yn-3-ol. Ή NMR (400 MHz, dimethylsulfoxide-D20) δ 7.47 (s, 1H), 7.44 (s, 1H), 3.47 (dq, J= 6.0, 7.2 Hz, 4H), 1.77 - 1.58 (m, 2H), 1.46 (s, 3H), 1.24 (t, J= 7.2 Hz, 6H), 1.06 (d, J= 7.4 Hz, 3H). MS ESI(+) m/z 347 (M+H)+.
EXAMPLE 72
6-chIoro-N,N'-diethyI-7-(3-methoxyprop- 1-yn- l-yl)quinoxaline-2,3 -diamine
The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with 3-methoxyprop-l-yne. 1H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.53 (s, 1H), 7.46 (s, 1H), 4.37 (s, 2H), 3.47 (quin, J= 7.2 Hz, 4H), 3.38 (s, 3H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 319 (M+H)+.
EXAMPLE 73
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-yn-l-ol
The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with hex-5-yn-l-ol. Ή NMR (400 MHz, CD3OD): δ 7.49 (1H, s), 7.39 (1H, s), 3.57 (2H, t, J= 8.4 Hz), 3.44-52 (4H, m), 2.46 (2H, t, J= 8.8 Hz), 1.64-1.71 (4H, m), 1.30-1.34 (6H, t, J= 10.0). MS ESI(+) m/z 347 (M+H)+.
EXAMPLE 74
3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-yl propionate The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with prop-2-ynyl propionate. ]H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.52 (s, 1H), 7.46 (s, 1H), 4.98 (s, 2H), 3.47 (quin, J= 7.2 Hz, 4H), 2.40 (q, J= 7.5 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H), 1.07 (t, J= 7.5 Hz, 3H). MS ESI(+) m/z 361 (M+H)+.
EXAMPLE 75
6-chloro-N,N'-diethyl-7-(hex- 1 -yn- 1 -yl)quinoxaline-2,3-diamine The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with hex-l-yne. !H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.45 (s, 1H), 7.43 (s, 1H), 3.46 (dq, J= 5.3, 7.2 Hz, 4H), 2.48 (t, J= 6.7 Hz, 2H), 1.61 - 1.39 (m, 4H), 1.24 (t, J= 7.2 Hz, 6H), 0.93 (t, J= 7.2 Hz, 3H). MS ESI(+) m/z 331 (M+H)+.
EXAMPLE 76
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-ynenitrile The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with hex-5-ynenitrile. !H MR (400 MHz, dimethylsulfoxide-D20) δ 7.51 (s, 1H), 7.44 (s, 1H), 3.47 (dq, J= 5.9, 7.2 Hz, 4H), 2.68 (t, J= 7.0 Hz, 2H), 2.61 (t, J= 7.0 Hz, 2H), 1.89 (quin, J= 7.0 Hz, 2H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 342 (M+H)+.
EXAMPLE 77
5- [7-chloro-2,3 -bis(ethylamino)quinoxalin-6-y 1] pent-4-ynenitrile
The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with pent-4-ynenitrile. 1H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.50 (s, 1H), 7.45 (s, 1H), 3.47 (dq, J = 6.1, 7.2 Hz, 4H), 2.90 - 2.75 (m, 4H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 328 (M+H)+.
EXAMPLE 78
3-{[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]ethynyl}phenol The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with 3-ethynylphenol. !H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.61 (s, 1H), 7.50 (s, 1H), 7.25 (t, J= 7.8 Hz, 1H), 7.02 (dt, J= 1.7, 7.8 Hz, 1H), 6.95 (dd, J= 1.7, 2.3Hz, 1H), 6.85 (ddd, J= 1.2, 2.3, 7.8 Hz, 1H), 3.49 (dq, J= 6.4, 7.2 Hz, 4H), 1.25 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 367 (M+H)+.
EXAMPLE 79
3 -[7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]prop-2-yn- 1 -ol The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with prop-2-yn-l-ol. *H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.46 (s, 1 H) 7.42 (s, 1 H) 7.20 (t, J= 4.75 Hz, 1 H) 7.06 (t, J= 4.58 Hz, 1 H) 5.36 (t, J= 5.93 Hz, 1 H) 4.35 (d, J= 5.76 Hz, 2 H) 3.42 - 3.62 (m, 4 H) 1.24 (t, J= 7.29 Hz, 6 H). MS ESI(+) m/z 305 (M+H)+
EXAMPLE 80
1 -[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex- 1 -yn-3-ol The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with hex-5-yn-3-ol. *H NMR (400 MHz, dimethylsulfoxide-D20) S 7.48 (s, 1H), 7.44 (s, 1H), 4.50 (t, J= 6.6 Hz, 1H), 3.47 (dq, J= 5.6, 7.2 Hz, 4H), 1.75 - 1.59 (m, 2H), 1.56 - 1.44 (m, 2H), 1.24 (t, J= 7.2 Hz, 6H), 0.94 (t, J= 13 Hz, 3H). MS ESI(+) m/z 347 (M+H)+.
EXAMPLE 81
2-({3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-yl}oxy)ethanol The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with 2-(prop-2-ynyloxy)ethanol. lH NMR (400 MHz, dimethylsulfoxide-D20) δ 7.53 (s, 1H), 7.46 (s, 1H), 4.45 (s, 2H), 3.64 - 3.53 (m, 4H), 3.54 - 3.39 (m, 4H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 349 (M+H)+.
EXAMPLE 82
6-chloro-N,N'-diethyl-7-(3-furylethynyl)quinoxaline-2,3-diamine
EXAMPLE 82A
3-ethynylfuran
Lithium diisopropylamide was added to a solution of CH3SiCHN2 in tetrahydrofuran (5 mL) at -78°C. After stin-ing for 30 minutes, furan-3-carbaldehyde (0.42 mL, 0.48 g, 5.0 mmol) in tetrahydrofuran was added and the stirring continued for another 1 hour. The solvent was removed and distillation of the residue gave a solution of the title compound in tetrahydrofuran.
EXAMPLE 82B
6-chloro-N,N'-diethyl-7-(3-furylethynyl)quinoxaline-2,3-diamine
The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with EXAMPLE 82A. Ή NMR (400 MHz, dimethylsulfoxide-D20) δ 8.12 (dd, J = 0.8, 1.7 Hz, 1H), 7.77 (t, J= 1.7 Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 6.71 (dd, /= 0.8, 1.7 Hz, 1H), 3.48 (dd, J= 6.7, 7.2 Hz, 4H), 1.25 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 341 (M+H)+.
EXAMPLE 83
methyl 3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2;-ynoate The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with methyl propiolate. Ή NMR (400 MHz, dimethylsulfoxide-D20) δ 7.69 (s, 1H), 7.50 (s, 1H), 3.80 (s, 3H), 3.49 (dq, J= 7.2, 11.7 Hz, 4H), 1.25 (t, J= 7.2 Hz, 6H). MS ESI(+) m/z 333 (M+H)+.
EXAMPLE 84 3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynamide
EXAMPLE 84A
propiolamide
Aqueous ammonia (14.0 mL, 29% in water) was cooled to -78°C before the stepwise addition of methyl propiolate (4.2 g, 50.2 mmol) over 15 minutes via an addition funnel. The mixture was stirred for 2 hours at -78°C before being warmed to room temperature. The solvent was removed at 25°C under vacuum to obtain the title compound.
EXAMPLE 84B
3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynamide The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with EXAMPLE 84A. Ή NMR (400 MHz, dimethylsulfoxide-D20) δ 7.66 (s, IH), 7.49 (s, IH), 3.48 (dq, J= 9.0, 7.2 Hz, 4H), 1.25 (t, J= 7.2 Hz, 6Η). MS ESI(+) m/z 318 (M+H)+.
EXAMPLE 85
6-(but-l-yn-l-yl)-7-chloro-N,N'-diethylquinoxaline-2,3-diamine
The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with but-l-yne. !H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.45 (s, IH), 7.43 (s, IH), 3.46 (dq, J= 5.2, 7.2 Hz, 4H), 2.47 (q, J= 7.5 Hz, 2H), 1.24 (t, J= 7.2 Hz, 6H), 1.20 (t, J= 7.5 Hz, 3H). MS ESI(+) m/z 303 (M+H)+.
EXAMPLE 86
1 - { 3 - [7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]prop-2-yn- 1 -y 1} urea The title compound was prepared as described in EXAMPLE 3 IE except substituting but-3-yn-l-ol with l-(prop-2-ynyl)urea. H NMR (400 MHz, dimethylsulfoxide-D20) δ 7.49 (s, IH), 7.44 (s, IH), 4.08 (s, 2H), 3.47 (dq, J= 5.6, 7.2 Hz, 4H), 1.24 (t, J= 7.2 Hz, 6H). MS ESI (+) m/z 347 (M+H)+.
EXAMPLE 87
6-chloro-N-ethyl-7-methoxy-3-(l-naphthyl)quinoxalin-2-amine The title compound was prepared as described in EXAMPLE 38C except substituting 3- chlorophenylboronic acid with naphthalen-l-ylboronic acid. !H NMR (500 MHz,
dimethylsulfoxide-d6) δ ppm 8.11 (d, J= 8.24 Hz, 1 H) 8.07 (d, J= 7.93 Hz, 1 H) 7.85 (s, 1 H) 7.66 - 7.74 (m, 1 H) 7.40 - 7.64 (m, 5 H) 7.26 (s, 1 H) 4.02 (s, 3 H) 3.39 (d, J= 5.49 Hz, 2 H) 1.07 (t, J= 7.02 Hz, 3 H). MS ESI (+) m/z 364.8 (M+H)+.
EXAMPLE 88
methyl 5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-oxopentanoate The title compound was prepared as described in EXAMPLE 60 as a by-product. !H
NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 7.50 (s, 1 H) 7.39 (s, 1 H) 4.59 (s, 2 H) 3.96 (s, 2 H) 3.64 (s, 3 H) 3.49 - 3.61 (m, 4 H) 2.86 (t, J = 6.43 Hz, 2 H) 2.56 (t, J = 6.43 Hz, 2 H) 1.24 - 1.43 (m, 6 H). MS ESI (+) m/z 364.8 (M+H)+.
EXAMPLE 89
6,7-dimethoxy-3-(pyridin-4-yl)-N-[3-(pyri lidin-l-yl)propyl]quinoxalin-2-amine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 14A and pyridin-3-ylmethanamine with 3-(pyrrolidin-l- yl)propan-l -amine. !H NMR (300 MHz, dimethylsulfoxide-d6) δ 8.82 (d, J=6.25 Hz, 2 H) 7.88 (d, J=5.88 Hz, 2 H) 7.27 (s, 1 H) 7.04 (s, 1 H) 6.69 - 6.81 (m, 1 H) 3.93 (s, 3 H) 3.87 (s, 3 H) 3.39 - 3.65 (m, 4 H) 3.14 - 3.31 (m, 2 H) 3.01 (s, 2 H) 1.78 - 2.14 (m, 6 H). MS ESI(+) m/z 394.1 (M+H)+.
EXAMPLE 90
2- { 1 - [7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]azetidin-3-yl} ethanol
EXAMPLE 90A
2-(2-(tert-butyldimethylsilyloxy)ethyl)propane- 1 ,3-diol
A solution of diethyl malonate (5.21 ml, 34.3 mmol) and sodium ethoxide (2.460 g, 34.3 mmol) in ethanol (100 ml) was heated at 80°C for 1 hour. The mixture was then cooled to room temperature and treated with (2-bromoethoxy)-tert-butyldimethylsilane (7.36 ml, 34.3 mmol). The resulting solution was stirred at 76°C overnight. The solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and used without further purification. To a solution of the crude residue(7.4 g, 23.24 mmol) in tetrahydrofuran (50 ml) was added lithium borohydride (23.82 ml, 47.6 mmol) dropwise and the reaction mixture was stirred at room temperature for 4 hours. Water was slowly added to the mixture at 4°C and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford the title compound. 1HNMR (300 MHz, dimethylsulfoxide-d6) δ 3.98 - 4.21 (m, 2 H) 3.42 - 3.76 (m, 4 H) 1.09 - 1.27 (m, 3 H) 0.76 - 0.92 (s, 9 H) 0.03 - 0.24 (s, 6 H). MS ESI (+) m/z 234.9 (M+H)+.
EXAMPLE 90B
2-{l-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]azetidin-3-yl}ethanol To a solution of EXAMPLE 90A (0.05 g, 0.213 mmol) and N,N-diisopropylethylamine
(0.2 ml, 1.14 mmol) in acetonitrile (2.5 ml) was added trifluoromethanesulfonic anhydride (0.075 ml, 0.447 mmol) dropwise at -20°C. After 20 minutes, the solution was treated with EXAMPLE 21 (0.054 g, 0.203 mmol). The reaction mixture was stirred at 70°C for 1 hour. The solvent was removed and the residue was purified by reverse phase HPLC (Waters LC4000 purification system, Phenomenex Luna C8(2) 5 um lOOA AXIA column (30mm x 75mm), 10- 95% (0.1% trifluoroacetic acid in water) in acetonitrile) to afford the title compound. ]H NMR (300 MHz, dimethylsulfoxide-de) δ ppm 4.30 (t, J = 5.33 Hz, 2 H) 3.61 (t, J = 6.80 Hz, 2 H) 3.32 - 3.38 (m, 4 H) 1.48 - 1.63 (m, 1 H) 1.41 (q, J = 6.62 Hz, 2 H) 0.85 (s, 9 H) 0.01 (s, 6 H). MS ESI (+) m/z 350.0 (M+H)+.
EXAMPLE 91
N-ethy l-6,7-dimethoxy-3 -(pyridin-4-yl)quinoxalin-2-amine The title compound was prepared as described in EXAMPLE 7 except substituting EXAMPLE 3C with EXAMPLE 14A and pyridin-3-ylmethanamine with ethanamine. Ή NMR (300 MHz, dimethylsulfoxide-de) 5ppm 7.60 (d, J=1.84 Hz, 1 H) 7.22 (s, 1 H) 7.05 (s, 1 H) 6.71 (d, J=1.84 Hz, 1 H) 6.29 (t, J=5.33 Hz, 1 H) 3.92 (s, 3 H) 3.90 (s, 3 H) 3.86 (s, 3 H) 3.36 - 3.53 (m, 2 H) 1.18 (t, J=6.99 Hz, 3 H).. MS ESI (+) m/z 310.9 (M+H)+.
Example 92
PGK1 Assay
The NADH fluorescence assay was used to evaluate inhibition of purified PGK1 activity. PGK1 is a monomer that catalyzes the interconversion of 1,3-bisphosphogylcerate and 3- phosphoglycerate. When the purified PGK1 is coupled with glyceraldehyde P-dehydrogenase in the presence of the cofactors NADH and ATP, PGK1 activity can be measured through a decrease in the NADH fluorescence signal at 340/460 (excitation/emission). The final enzyme reactions (100 μΐ) contained 50 mM triethanolamine, pH 7.5, 1 mM ATP, 50 mM MgS04, 50 mM KCl, 20 μg/ml glyceraldehyde 3-phosphate dehydrogenase, 0.2 mM NADH, 5 mM DTT, 40 mM (NH)2S04, 2 mM 3-phosphoglycerate, and 5 nM PGK1. Compounds (in 20 μΐ 5% DMSO) were mixed with the PGK1 reaction mix (75 uL) in the absence of the 3-phosphoglycerate substrate and an initial fluorescent reading was taken. Substrate (5 μΐ) was then added and the reaction was incubated for 30 minutes at room temperature at which time a final fluorescent reading was taken to assess the level of NADH. Reactions containing all components except substrate and compound were used to assess background fluorescence. Reactions containing all components except compounds were used to assess maximal reaction signal. Fluorescent signals were calibrated to NADH titration curves. IC50S were determined using a four parameter logistic function. Results are shown in Table 1 below.
Table 1:
NADH NADH
Fluor PGK1 Fluor PG 1
- IC50(uM) - IC50(uM)
EXAMPLE (IC50) [uM] EXAMPLE (IC50) |u ]
1 6.320 47 4.400
2 50.000 48 1.500
3 4.640 49 1.400
4 24.000 50 4.600
5 2.530 51 0.075
6 16.430 52 0.066
7 0.710 53 0.220
8 2.010 54 1.600
9 1.280 55 1.700
10 4.360 56 2.000
11 1.810 57 0.210
12 0.741 58 0.550
13 0.840 59 0.091
14 7.590 60 5.830
15 0.009 61 0.016 16 1.180 62 0.036
17 0.129 63 0.008
18 0.366 64 0.596
19 0.320 65 1.090
20 0.098 66 0.041
21 10.000 67 0.665
22 4.140 68 0.346
23 0.038 69 0.125
24 0.015 70 2.690
25 0.071 71 4.810
26 1.170 72 0.066
27 0.173 73 0.385
28 0.195 74 0.257
29 0.252 75 0.884
30 0.515 76 0.570
31 0.005 77 0.054
32 0.012 78 5.700
33 0.122 79 0.001
34 0.042 80 2.000
35 0.019 81 0.103
36 3.160 82 1.030
37 1.050 83 0.633
38 2.100 84 0.556
39 1.900 85 0.270 40 2.300 86 0.393
41 0.190 87 10.000
43 1.400 88 9.000
43 1.100 89 10.000
44 2.000 90 10.000
45 0.078 91 6.660
46 0.240
Compounds of the present invention assessed by the above-described assay were found to have phosphoglycerate kinase inhibiting activity.
All publication and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WE CLAIM:
1. A compound having formula (I) , or pharmaceutically acceptable salt thereof,
Figure imgf000084_0001
Formula (I);
wherein
R1 is halogen, cyano, or methoxy;
R2 is halogen, hydroxy, trifluoromethoxy, cyano, amino, nitro, R5A, R5, OR5, or
NHC(0)R5; provided that, when R2 is halogen, R1 is cyano or methoxy;
R3 is halogen, or NHR7;
R4 is R7 or NHR7;
R5A is heterocyclyl; wherein the heterocyclyl is optionally substituted with R6;
R5 is alkyl, alkenyl, or alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano, amino, NHC(0)NH2, C(0)NH2, R6, OR6, C(0)R6, C(0)OR6, or OC(0)R6;
R6 is alkyl, cycloalkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C(0)OH, or C(0)OR10; and (b) the cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more hydroxy;
each R7 is independently Q -alkyl, alkynyl, aryl, quinolinyl, 4-pyridinyl, 3-pyridinyl, 2- pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, naphthalenyl, or chromen-4-onyl; wherein (a) the alkyl and alkynyl are optionally substituted with one or more substituents selected from the group consisting of hydroxy 1, heterocyclyl, heterocyclylalkyl, and N(R8)2, (b) the aryl is optionally substituted with one substituent selected from the group consisting of halogen, R8, C(0)NH2, and C(0)NHR8; (c) the quinolinyl, 4- pyridinyl, 3-pyridinyl, pyrazolyl, thienyl, indolyl, benzodioxolyl, benzothiophenyl, benzofuranyl, and chromen-4-onyl are optionally substituted with one substituent selected from the group consisting of R8, and C(0)R8;
each R8 is independently alkyl, aryl, or heterocyclyl; wherein (a) the alkyl is optionally substituted with one or more R9, and (b) the aryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of R9, C(0)OR9, and C(0)R9; each R9 is independently alkyl, aryl, or heterocyclyl; and
R10 is alkyl.
2. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein
R1 is halogen or methoxy; and
R2 is halogen or R5, provided that, when R2 is halogen, R1 is methoxy.
3. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein
R1 is halogen or methoxy; and
R2 is R5.
4. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein
R1 is methoxy;
R2 is R5; and
R5 is alkynyl.
5. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein
R1 is halogen;
R2 is R5;
R3 is NHR7; and
R4 is NHR7.
6. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein
R1 is methoxy; R2 is halogen;
R3 is NHR7; and
R4 is R7.
A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is methoxy;
R2 is halogen;
R3 is NHR7; and
R4 is NHR7.
A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is methoxy;
R2 is methoxy;
R3 is NHR7; and
R4 is NHR7.
The compound of claim 1 which is
3-chloro-N-ethyl-6,7-dimethoxyquinoxalin-2-amine;
N,N'-diethyl-6,7-dimethoxyquinoxaline-2,3-diamine;
3-bromo-N-ethyl-6,7-dimethoxyquinoxalin-2-amine;
3-chloro-6,7-dimethoxy-N-methylquinoxalin-2-amine;
N-ethyl-6,7-dimethoxy-N'-methylquinoxaline-2,3-diamine;
3-bromo-6,7-dimethoxy-N-[2-(4-methylpiperazin-l-yl)ethyl]quinoxalin-2-amine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-3-ylmethyl)quinoxaline-2,3-diamine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-4-ylmethyl)quinoxaline-2,3 -diamine;
N-ethyl-6,7-dimethoxy-N'-(pyridin-2-ylmethyl)quinoxaline-2,3 -diamine;
N-ethyl-6,7-dimethoxy-N'-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3-diamine;
l-(3-{[3-(ethylamino)-6,7-dimethoxyquinoxalin-2-yl]amino}propyl)pyrrolidin-2-one;
N-ethyl-6,7-dimethoxy-N'-[2-(pyridin-4-yl)ethyl]quinoxaline-2,3-diamine; N-ethyl-6,7-dimethoxy-N'-[2-(pyridin-2-yl)ethyl]quinoxaline-2,3-diamine; 6,7-dimethoxy-3-(pyridin-4-yl)-N-(pyridin-3-ylmethyl)quinoxalin-2-amine;
6-chloiO-N,N'-diethyl-7-methoxyquinoxaline-2,3 -diamine;
3,6-dichloro-N-ethyl-7-methoxyquinoxalin-2-amine;
6- chloro-N2-ethyl-7-methoxy-N3-(pyridin-3-ylmethyl)quinoxaline-2,3-diamine;
7- chloro-2,3-bis(ethylamino)quinoxalin-6-ol;
6-chloro-N,N'-diethyl-7-(prop-2-yn-l-yloxy)quinoxaline-2,3-diamine;
6- chloro-N,N'-diethyl-7-nitroquinoxaline-2,3-diamine;
7- chloro-N2,N3-diethylquinoxaline-2,3,6-triamine;
N-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]acetamide;
7-chloro-2,3-bis(ethylamino)quinoxaline-6-carbonitrile;
7-chloro-2-(ethylamino)-3-[(pyridin-3-ylinethyl)amino]quinoxaline-6-carbonitrile;
7-chloro-2-(ethylamino)-3 - { [2-(4-methylpiperazin- 1 -yl)ethyl]amino} quinoxaline-6- carbonitrile;
6-chloro-N,N'-diediyl-7-(trifluoromethoxy)quinoxaline-2,3-diamine;
6-chloro-N2-ethyl-7-methoxy-N3-[2-(4-methylpiperazin-l-yl)ethyl]quinoxaline-2,3- diamine;
6-chloro-N -ethyl-7-methoxy-N3-[3-(4-methylpiperazin-l-yl)propyl]quinoxaline-2,3- diaraine;
6-chloro-N2-ethyl-7-methoxy-N3-[3-(pyrrolidin-l-yl)propyl]quinoxaline-2,3-diamine; 6-chloro-N3-[5-(diethylamino)pentan-2-yl]-N2-ethyl-7-methoxyquinoxaline-2,3-diamine^
4- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-l-ol;
6-chloro-N,N'-diethyl-7-ethynylquinoxaline-2,3-diamine;
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn-2-ol;
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-yn-l-ol;
6- chloro-7-(cyclopropylethynyl)-N,N'-diethylquinoxaline-2,3 -diamine;
2- {4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn- 1-yl} - 1 H-isoindole- 1 ,3(2H)- dione;
6-(4-aminobut-l-yn-l-yl)-7-chloro-N,N'-diethylquinoxaline-2,3-diamine; 6-chloro-3-(3-chlorophenyl)-N-ethyl-7-methoxyquinoxalin-2-amine;
6-chloro-3-(4-chlorophenyl)-N-ethyl-7-methoxyquinoxalin-2-amine;
3-(l,3-benzodioxol-5-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(2-thienyl)quinoxalin-2-amine;
3-(l-benzofuran-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
l-{5-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-2-thienyl}ethanone;
3-(l-benzothiophen-3-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3-(l-benzothiophen-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3 - [7-chloro-3 -(ethy lamino)-6-methoxyquinoxalin-2-y ljbenzamide;
6-chloro-N-ethyl-3-(lH-indol-4-yl)-7-methoxyquinoxalin-2-amine;
6-chloro-N-ethyl-3-(isoquinolin-4-yl)-7-methoxyquinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(quinolin-5-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(quinolin-3-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3 -( 1 H-pyrazol-4-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3 -( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-2-amine;
6-chloro-N-ethyl-7-methoxy-3-(l-methyl-lH-indol-5-yl)quinoxalin-2-amine;
6-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-4H-chromen-4-one;
tert-butyl 4-{5-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]pyridin-2- yl } piperazine- 1 -carboxy late;
3-(biphenyl-2-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]-N-(2-furylmethyl)benzamide;
N-benzyl-3-[7-chloro-3-(ethylamino)-6-methoxyquinoxalin-2-yl]benzamide;
3- (l -benzyl- lH-pyrazol-4-yl)-6-chloro-N-ethyl-7-methoxyquinoxalin-2-amine;
5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-oxopentanoic acid;
4- [7-chloro-3-(ethylamino)-2- { [3-(4-methylpiperazin- 1 -yl)propyl] amino} quinoxalin-6- yl]but-3-yn-l-ol;
4-(7-chloro-2,3-bis { [2-(4-methylpiperazin- 1 -yl)ethyl]amino} quinoxalin-6-yl)but-3 -yn- 1 - ol; 4- [7-chloro-3 -(ethy lamino)-2- { [2-(4-methy lpiperazin- 1 -y l)ethyl] amino } qu inoxalin-6- yl]but-3-yn-l-ol;
2- {3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-l,2,4-oxadiazol-5-yl}ethanol; N-[7-chloro-2,3-bis(ethylamino)quinoxalm-6-yl]-3-hydiOxypropanamide;
4-[2,7-dichloro-3-(ethylamino)quinoxalin-6-yl]but-3-yn-l-ol;
4,4'-[7-chloro-3-(ethylamino)quinoxaline-2,6-diyl]bisbut-3-yn-l-ol;
7-chloro-2- { [2-(4-methy lpiperazin- 1 -y l)ethyl] amino } -3 -(pyridin-2-y l)quinoxaline-6- carbonitrile;
4-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]but-3-yn-2-ol;
4- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-2-methylbut-3-yn-2-ol;
l-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-3-methylpent-l-yn-3-ol;
6-chloro-N,N'-diethyl-7-(3-methoxyprop-l-yn-l-yl)quinoxaline-2,3-diamine;
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-yn-l-ol;
3- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-yl propionate;
6-chloro-N,N'-diethyl-7-(hex- 1 -yn- l-yl)quinoxaline-2,3 -diamine;
6-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-5-ynenitrile;
5- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]pent-4-ynenitrile;
3-{[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]ethynyl}phenol;
3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-yn-l-ol;
1- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]hex-l-yn-3-ol;
2- ( { 3 - [7-chloro-2,3 -bis(ethy lamino)quinoxalin-6-yl]prop-2-yn- 1 -y 1} oxy)ethano 1;
6- chloro-N,N'-diethyl-7-(3 -fuiylethynyl)quinoxaline-2,3 -diamine;
methyl 3-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynoate;
3- [7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]prop-2-ynamide;
6-(but- 1 -yn- 1 -yl)-7-chloro-N,N'-diethylquinoxaline-2,3 -diamine;
1 - { 3 - [7-chloro-2,3 -bis(ethylamino)quinoxalin-6-yl]prop-2-yn- 1 -y 1 } urea;
6-chloro-N-ethyl-7-methoxy-3-(l-naphthyl)quinoxalin-2-amine;
methyl 5-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]-4-oxopentanoate;
6,7-dimethoxy-3-(pyridin-4-yl)-N-[3-(pyrrolidin-l-yl)propyl]quinoxalin-2-amine; 2-{l-[7-chloro-2,3-bis(ethylamino)quinoxalin-6-yl]azetidin-3-yl}ethanol; N-ethyl-6,7-dimethoxy-3-(pyridin-4-yl)quinoxalin-2-amine; or a pharmaceutically acceptable salt thereof.
10. A phannaceutical composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
11. A method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.
12. A method for decreasing tumor volume in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
13. The method of claim 11, wherein the cancer is breast cancer, colon cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, or stomach cancer.
14. A method of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of claim 1, or pharmaceutically acceptable salt thereof, in combination with radiotherapy.
International application No.
INTERNATIONAL SEARCH REPORT
PCT/CN2010/001579
Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1. Claims Nos.: 11-14
because they relate to subject matter not required to be searched by this Authority, namely:
Claims 11 -14 are directed to methods of treatment of the human/animal body (Rule 39.1 (iv) PCT).
2. □ Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:
3. □ Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
1. Π As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.
2. Π As all searchable claims could be searched without effort justifying an additional fees, this Authority did not invite payment of additional fee.
3. Π As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos. :
4. Π No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos. :
The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee.
The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation.
No protest accompanied the payment of additional search fees.
Form PCT/ISA /210 (continuation of first sheet (2)) (July 2009)
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675231A (en) * 2012-05-15 2012-09-19 江苏丰山集团有限公司 Method for removing sulfur content impurity in synthesis technology of 2, 6-dichloro-quinoxaline
CN104496919A (en) * 2015-01-13 2015-04-08 马良军 Synthetic method for quinoxaline medical intermediate compound
WO2015059088A1 (en) 2013-10-23 2015-04-30 Bayer Cropscience Ag Substituted quinoxaline derivatives as pest control agent
WO2016111991A1 (en) * 2015-01-05 2016-07-14 Board Of Regent, The University Of Texas System The protein kinase activity of phosphoglycerate kinase 1 as a target for cancer treatment and diagnosis
CN106471067A (en) * 2014-04-01 2017-03-01 霍华德休斯医学研究所 The fluorescent chemicalses that azetidine replaces
TWI660949B (en) * 2014-07-07 2019-06-01 國立台灣大學 Arylamine substututed quinoxaline and their use as anticancer drugs
CN110698418A (en) * 2019-09-11 2020-01-17 广西师范大学 3-arylamino quinoxaline-2-formamide derivative and preparation method and application thereof
CN110981819A (en) * 2019-12-24 2020-04-10 广西师范大学 Quinoxaline signal channel inhibitor and preparation method and application thereof
WO2020081446A1 (en) * 2018-10-14 2020-04-23 The University Of Chicago Compositions and methods for activating nrf2-dependent gene expression
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
WO2022253316A1 (en) * 2021-06-02 2022-12-08 上海交通大学 Quinoxaline derivative, preparation therefor and use thereof
CN117430614A (en) * 2023-12-20 2024-01-23 首都医科大学 Isoquinoline derivative and synthetic method and application thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1966500A (en) * 2005-11-17 2007-05-23 中国科学院上海药物研究所 Quinoxaline derivative, preparation method and uses
CN101602737A (en) * 2009-06-11 2009-12-16 浙江大学 Benzenesulfonyl quinoxaline compound and preparation method and purposes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1966500A (en) * 2005-11-17 2007-05-23 中国科学院上海药物研究所 Quinoxaline derivative, preparation method and uses
CN101602737A (en) * 2009-06-11 2009-12-16 浙江大学 Benzenesulfonyl quinoxaline compound and preparation method and purposes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI JIE JACK ET AL.: "Synthesis and Structure-Activity Relationship of 2-Amino-3-heteroaryl-quinoxalines as Non-peptide, Small-Molecule Antagonists for Interleukin-8 Receptor", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 11, 2003, pages 3777 - 3790 *
TENG MIN ET AL.: "Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, 4 July 2007 (2007-07-04), pages 5472 - 5478 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN105873914A (en) * 2013-10-23 2016-08-17 拜耳作物科学股份公司 Substituted quinoxaline derivatives as pest control agent
JP2016536302A (en) * 2013-10-23 2016-11-24 バイエル・クロップサイエンス・アクチェンゲゼルシャフト Substituted quinoxaline derivatives as pest control agents
US9936700B2 (en) 2013-10-23 2018-04-10 Bayer Cropscience Aktiengesellschaft Substituted quinoxaline derivatives as pest control agent
WO2015059088A1 (en) 2013-10-23 2015-04-30 Bayer Cropscience Ag Substituted quinoxaline derivatives as pest control agent
CN106471067A (en) * 2014-04-01 2017-03-01 霍华德休斯医学研究所 The fluorescent chemicalses that azetidine replaces
US9933417B2 (en) 2014-04-01 2018-04-03 Howard Hughes Medical Institute Azetidine-substituted fluorescent compounds
EP3126451A4 (en) * 2014-04-01 2017-09-20 Howard Hughes Medical Institute Azetidine-substituted fluorescent compounds
CN106471067B (en) * 2014-04-01 2020-12-08 霍华德休斯医学研究所 Azetidine substituted fluorescent compounds
TWI660949B (en) * 2014-07-07 2019-06-01 國立台灣大學 Arylamine substututed quinoxaline and their use as anticancer drugs
WO2016111991A1 (en) * 2015-01-05 2016-07-14 Board Of Regent, The University Of Texas System The protein kinase activity of phosphoglycerate kinase 1 as a target for cancer treatment and diagnosis
CN104496919B (en) * 2015-01-13 2016-08-24 *** A kind of synthetic method of quinoxaline pharmaceutical intermediate compound
CN104496919A (en) * 2015-01-13 2015-04-08 马良军 Synthetic method for quinoxaline medical intermediate compound
US11274095B2 (en) 2018-04-18 2022-03-15 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
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