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WO2012045196A1 - Inhibiteurs de la phosphoglycérate kinase - Google Patents

Inhibiteurs de la phosphoglycérate kinase 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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WIPO (PCT)
Prior art keywords
chloro
ethyl
quinoxalin
ethylamino
bis
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PCT/CN2010/001579
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English (en)
Inventor
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/fr
Publication of WO2012045196A1 publication Critical patent/WO2012045196A1/fr

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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.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I) ou des sels de ceux-ci pharmaceutiquement acceptables. Dans la formule (I), R1, R2, R3 et R4 sont tels que définis dans la description. L'invention concerne également des procédés de production de ces composés et des compositions contenant lesdits composés qui sont utilisées pour inhiber des kinases, telles que la phosphoglycérate kinase.
PCT/CN2010/001579 2010-10-09 2010-10-09 Inhibiteurs de la phosphoglycérate kinase WO2012045196A1 (fr)

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CN102675231A (zh) * 2012-05-15 2012-09-19 江苏丰山集团有限公司 一种2,6—二氯喹喔啉合成工艺中硫分杂质的脱除方法
CN104496919A (zh) * 2015-01-13 2015-04-08 马良军 一种喹喔啉类医药中间体化合物的合成方法
WO2015059088A1 (fr) 2013-10-23 2015-04-30 Bayer Cropscience Ag Dérivés de chinoxaline substitués servant d'agent de lutte antiparasitaire
WO2016111991A1 (fr) * 2015-01-05 2016-07-14 Board Of Regent, The University Of Texas System Activité de la protéine kinase de phosphoglycerate kinase 1 en tant que cible pour le traitement et le diagnostic du cancer
CN106471067A (zh) * 2014-04-01 2017-03-01 霍华德休斯医学研究所 氮杂环丁烷取代的荧光化合物
TWI660949B (zh) * 2014-07-07 2019-06-01 國立台灣大學 作為抗癌藥物之芳基胺取代的喹喔啉
CN110698418A (zh) * 2019-09-11 2020-01-17 广西师范大学 一种3-芳胺基喹喔啉-2-甲酰胺类衍生物及其制备方法和应用
CN110981819A (zh) * 2019-12-24 2020-04-10 广西师范大学 一种喹喔啉类信号通路抑制剂及其制备方法和应用
WO2020081446A1 (fr) 2018-10-14 2020-04-23 The University Of Chicago Compositions et procédés d'activation de l'expression génique dépendant de nrf2
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
CN115433173A (zh) * 2021-06-02 2022-12-06 上海交通大学 一类喹喔啉衍生物及其制备和用途
CN117430614A (zh) * 2023-12-20 2024-01-23 首都医科大学 一种异喹啉类衍生物及其合成方法和应用
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
WO2025137411A1 (fr) * 2023-12-22 2025-06-26 The Children's Medical Center Corporation Agonistes de gasdermine d non clivants

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CN102675231A (zh) * 2012-05-15 2012-09-19 江苏丰山集团有限公司 一种2,6—二氯喹喔啉合成工艺中硫分杂质的脱除方法
JP2016536302A (ja) * 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 有害生物防除剤としての置換されているキノキサリン誘導体
WO2015059088A1 (fr) 2013-10-23 2015-04-30 Bayer Cropscience Ag Dérivés de chinoxaline substitués servant d'agent de lutte antiparasitaire
US9936700B2 (en) 2013-10-23 2018-04-10 Bayer Cropscience Aktiengesellschaft Substituted quinoxaline derivatives as pest control agent
CN105873914A (zh) * 2013-10-23 2016-08-17 拜耳作物科学股份公司 作为害虫防治剂的取代的喹喔啉衍生物
EP3126451A4 (fr) * 2014-04-01 2017-09-20 Howard Hughes Medical Institute Composés fluorescents à substitution azétidine
CN106471067A (zh) * 2014-04-01 2017-03-01 霍华德休斯医学研究所 氮杂环丁烷取代的荧光化合物
CN106471067B (zh) * 2014-04-01 2020-12-08 霍华德休斯医学研究所 氮杂环丁烷取代的荧光化合物
US9933417B2 (en) 2014-04-01 2018-04-03 Howard Hughes Medical Institute Azetidine-substituted fluorescent compounds
TWI660949B (zh) * 2014-07-07 2019-06-01 國立台灣大學 作為抗癌藥物之芳基胺取代的喹喔啉
WO2016111991A1 (fr) * 2015-01-05 2016-07-14 Board Of Regent, The University Of Texas System Activité de la protéine kinase de phosphoglycerate kinase 1 en tant que cible pour le traitement et le diagnostic du cancer
CN104496919B (zh) * 2015-01-13 2016-08-24 李强 一种喹喔啉类医药中间体化合物的合成方法
CN104496919A (zh) * 2015-01-13 2015-04-08 马良军 一种喹喔啉类医药中间体化合物的合成方法
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
WO2020081446A1 (fr) 2018-10-14 2020-04-23 The University Of Chicago Compositions et procédés d'activation de l'expression génique dépendant de nrf2
US12048686B2 (en) 2018-10-14 2024-07-30 The University Of Chicago Compositions and methods for activating NRF2-dependent gene expression
CN110698418B (zh) * 2019-09-11 2022-07-01 广西师范大学 一种3-芳胺基喹喔啉-2-甲酰胺类衍生物及其制备方法和应用
CN110698418A (zh) * 2019-09-11 2020-01-17 广西师范大学 一种3-芳胺基喹喔啉-2-甲酰胺类衍生物及其制备方法和应用
CN110981819A (zh) * 2019-12-24 2020-04-10 广西师范大学 一种喹喔啉类信号通路抑制剂及其制备方法和应用
CN110981819B (zh) * 2019-12-24 2022-07-01 广西师范大学 一种喹喔啉类信号通路抑制剂及其制备方法和应用
CN115433173A (zh) * 2021-06-02 2022-12-06 上海交通大学 一类喹喔啉衍生物及其制备和用途
WO2022253316A1 (fr) * 2021-06-02 2022-12-08 上海交通大学 Dérivé de quinoxaline, sa préparation et son utilisation
CN117430614A (zh) * 2023-12-20 2024-01-23 首都医科大学 一种异喹啉类衍生物及其合成方法和应用
CN117430614B (zh) * 2023-12-20 2024-03-08 首都医科大学 一种异喹啉类衍生物及其合成方法和应用
WO2025129826A1 (fr) * 2023-12-20 2025-06-26 首都医科大学 Dérivé d'isoquinoléine, procédé pour sa synthèse et utilisation correspondante
WO2025137411A1 (fr) * 2023-12-22 2025-06-26 The Children's Medical Center Corporation Agonistes de gasdermine d non clivants

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