WO2018085348A1 - Quinoléines substituées et procédés pour traiter le cancer - Google Patents

Quinoléines substituées et procédés pour traiter le cancer Download PDF

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WO2018085348A1
WO2018085348A1 PCT/US2017/059470 US2017059470W WO2018085348A1 WO 2018085348 A1 WO2018085348 A1 WO 2018085348A1 US 2017059470 W US2017059470 W US 2017059470W WO 2018085348 A1 WO2018085348 A1 WO 2018085348A1
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compound
alkyl
optionally substituted
pharmaceutically acceptable
alkoxy
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PCT/US2017/059470
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Elena V. DNEPROVSKAIA
Michael S. HOLZWARTH
Scott D. RYCHNOVSKY
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Actavalon, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/12—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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Substituted quinoline compounds methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or ameliorate cancer are provided.
  • the aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of a diverse set of genes. AhR plays an important role in cellular proliferation and differentiation and in maintaining cellular homeostasis of the immune system. Studies have shown that the AhR plays a key role in hematopoietic stem cell (HSC) growth and differentiation. Upon ligand binding, AhR protein translocates to the nucleus, where it forms a heterodimer with the Aryl hydrocarbon Receptor Nuclear Translocator (ARNT), known as the Aryl Hydrocarbon Receptor Complex (AhRC). The AhR ARNT heterodimer activates transcription of a number of genes, but it is primarily known to be involved in systemic metabolism of xenobiotics.
  • Aryl hydrocarbon Receptor Nuclear Translocator Aryl Hydrocarbon Receptor Complex
  • AhR is activated by a wide variety of polyaromatic and polycyclic hydrocarbons (PAH) and other exogenous ligands.
  • PAH polyaromatic and polycyclic hydrocarbons
  • the exact mechanism of how the AhR actually mediates gene transcription has been the focus of recent investigations. It has been observed that, depending on the ligand, context and cellular phenotype, the AhR can either promote or inhibit cellular proliferation.
  • the AhR/ARNT complex alters transcription by binding to its specific DNA recognition sites.
  • a number of genes have been identified that are directly regulated by the AhR/ARNT complex. The most prominent of these genes involve the drug-metabolizing Cytochrome P450 (CYP1) family of enzymes - CYP1A1, CYP1A2 and CYP1B1.
  • CYP1 enzymes are involved in metabolism of xenobiotics and bioactivation of pro-drugs. By inducing the drug-metabolizing CYP1 enzymes, a large number of the AhR ligands induce their own metabolism and clearance from the body. The resulting metabolites typically are also capable of binding to the AhR protein and exhibit different selectivity in binding to the CYPl enzymes, thus further attenuating the AhR signaling. AhR can also alter transcription via physical interaction and cross-talk with other transcription factors, including NFkB, Estrogen (ER) and Androgen (AR) nuclear receptors and the retinoblastoma (pRB) tumor suppressor protein.
  • NFkB nuclear factor
  • Estrogen (ER) and Androgen (AR) nuclear receptors nuclear receptors
  • pRB retinoblastoma
  • AhR pathway appears to play a prominent role in development of breast, prostate and colon cancers. AhR mediates all major stages of cancer development - initiation, promotion, progression, and metastasis. Levels of the CYP1B1 enzymes are commonly elevated in metastatic and aggressive breast cancers and in advanced prostate cancers. Increased levels of AhR and its constitutive localization in the nucleus have been observed in several types of advanced malignant cell lines. Many of the triple negative breast cancers cells have shown increased expression of AhR protein. It has been observed that depletion of AhR in metastatic breast cancer cell line can potentiate the efficacy of chemotherapeutic agents and ionizing radiation.
  • each R 1 is selected from H, C 2 - 6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, - CN, -NO2, -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • each R 2 , R 4 and R 5 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci -6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , - C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • each R 3 and R 6 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci -6 alkyl, halo, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , - NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • each R 7 is selected from H or C 1-6 alkyl
  • each 8 is selected from C 6 -io aryl, 5 or 6 membered heteroaryl comprising one or two heteroatoms, , or 9 or 10 membered heteroaryl, each optionally substituted with one or more R A ;
  • each R 9 , R 10 , R 14 and R 15 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 ; or R 14 and R 15 together with the nitrogen atom to which they are
  • each R 11 is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 - 6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; each R 12 , R 13 and R 16 is independently selected from the group consisting of H, optionally substituted Ci- 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R A is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , -0(CH 2 ) n R 18 , and -(CH 2 ) k - S(0) 2 -R 19 ;
  • each R 17 is independently selected from 4 to 7 membered heterocyclyl, or 5 to 6
  • each R is independently selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR 9 R 10 ;
  • each R 19 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C 6 -io aryl, C 7-14 aralkyl, -NR 9 R 10 , 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more
  • each R 20 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, - (CH 2 CH 2 0) p CH 2 CH 2 N 3, halo, hydroxyl, oxo, and -CN; and
  • each k, m, n and p is independently an integer selected from 0 to 6;
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, R 8 is phenyl, then R 8 is substituted with one or more R A selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (Ci.6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , - 0(CH 2 ) n R 18 , and -(CH 2 ) k -S(0) 2 -R 19 .
  • each R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of H, Ci-6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci -6 alkyl, -0-(Ci -6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , - C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • R 6 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C ⁇ . 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • R 7 is selected from H or C 1-6 alkyl
  • Ring A is selected from C 6 -io aryl, 5 or 6 membered heteroaryl, or 9 or 10 membered heteroaryl, each optionally substituted with one or more R A ;
  • each R 9 , R 10 , R 14 and R 15 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C -w aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 ; or R 14 and R 15 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 ; each R 11 is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl
  • each R 12 , R 13 and R 16 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R A is independently selected from the group consisting of C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -O- (Ci -6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , - 0(CH 2 ) n R 18 , and -(CH 2 ) k -S(0) 2 -R 19 ;
  • each R 17 is independently selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R 20 ; each R is independently selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR 9 R 10 ;
  • each R 19 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy)Ci_6 alkyl, C3_7 cycloalkyl, C 6 -io aryl, C 7-14 aralkyl, -NR 9 R 10 , 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more
  • each R 20 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, oxo, and -CN; and
  • each m, n and k is independently an integer selected from 0 to 6;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, ring A is phenyl, then ring A is substituted with one or more R A .
  • compositions comprising a compound of formula (I) or ( ⁇ ) described herein, a specific compound selected from Compounds 1-26, 28-67, 75-80, 82-84, 86-91, 94-103, 105-152, and 159-170 of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising a compound of formula (II) described herein, a specific compound selected from Compounds 27, 70-74, 81, 85, 92, 93, 104 and 153-158 of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Some further embodiments of the present disclosure relate to methods of treating cancer, comprising administering a therapeutically effective amount of a compound of formula (I), ( ⁇ ) or (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition thereof to a subject in need thereof.
  • Some further embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (I), ( ⁇ ) or (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as described herein.
  • FIG. 1 is a plot that illustrates the abrogation of the anti-proliferative activity of Compound 1 in LS174T colon cancer cells by the addition of 10 uM of the AhR inhibitor, CH223191, and also by the addition of 10 uM of the CYP1 inhibitor, Acacetin. This plot shows that the therapeutic effect of Compound 1 in colon cancer is at least partially due to modulation of the AhR pathway.
  • FIG. 2 is a plot that illustrates the abrogation of the anti-proliferative activity of Compound 1 in the breast cancer cell line Au565 by the addition of 10 uM of the AhR inhibitor CH223191, and also by the addition of 10 uM of the CYP1 inhibitor Acacetin. This plot shows that the therapeutic effect of Compound 1 in breast cancer is at least partially due to modulation of the AhR pathway.
  • FIG. 3 illustrates the generation of ⁇ - ⁇ 2 ⁇ foci in Au565 cells treated with a conventional anti-cancer drug, Doxorubicin.
  • DNA-damage response was assessed by staining cell nuclei for phosphorylation of Serine 139 on histone H2AX.
  • ⁇ - ⁇ 2 ⁇ focus formation is considered to be a sensitive and selective signal for the existence of DNA double-strand breaks.
  • Cells were treated with 2 uM of Doxorubicin and incubated for 6 hrs. Cells were stained with goat anti- ⁇ - H2AX antibody conjugated with Alexa Fluor® 647 and nuclei were stained with DAPI. DMSO was used as a negative control.
  • the data in FIG. 3 illustrates the levels of DNA-damage induced by the positive control, Doxorubicin.
  • FIG. 4 illustrates the surprising lack of DNA-damage response in Au565 cells treated with Compound 1, as indicated by the lack of generation of ⁇ - ⁇ 2 ⁇ foci as compared to Doxorubicin (see FIG. 3).
  • Cells were treated with 4 uM of Compound 1 and incubated for 16 hrs or 24 hrs.
  • DNA-damage response was assessed by staining cell nuclei for phosphorylation of Serine 139 on histone H2AX.
  • ⁇ - ⁇ 2 ⁇ focus formation is considered to be a sensitive and selective signal for the existence of DNA double-strand breaks.
  • Cells were stained with anti-y-H2AX antibody conjugated to Alexa Fluor® 647 from ThermoFisher and nuclei were stained with DAPI.
  • DMSO was used as a negative control.
  • FIGS. 1-4 The data in FIGS. 1-4 indicates that embodiments of the compounds described herein are useful for the treatment of cancer by modulating the AhR pathway without inducing a DNA damage response typical for other known AhR modulators.
  • Novel substituted quinoline compounds including substituted quinoline-7- carboxamides and 2-(quinol-7-yl)benzimidazoles, syntheses thereof and the results of phenotypic screening for inhibition of cellular proliferation in various cancer cell lines are outlined below.
  • Solidvate refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al, published September 1 1, 1987 (incorporated by reference herein in its entirety).
  • C a to Q or “C a -t > “ in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to "b", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” or “Ci -4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • halogen or "halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g. , fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be designated as "Ci -4 alkyl” or similar designations.
  • “Ci -4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.
  • alkoxy refers to the formula -OR wherein R is an alkyl as is defined above, such as "C1-9 alkoxy", including but not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • alkylthio refers to the formula -SR wherein R is an alkyl as is defined above, such as “C ⁇ alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, and tert-butylmercapto.
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group may be designated as "C2-4 alkenyl" or similar designations.
  • C2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1 -methyl-propen-l-yl, 2-methyl-propen-l -yl, 1 -ethyl-ethen-l -yl, 2-methyl-propen-3-yl, buta-l,3-dienyl, buta-l ,2,-dienyl, and buta-l,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group may be designated as "C2-4 alkynyl" or similar designations.
  • C2-4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l -yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
  • the heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term "heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
  • the heteroalkyl group may be designated as "C1-4 heteroalkyl" or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • “Ci -4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • carbocyclic aromatic e.g., phenyl
  • heterocyclic aromatic groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as "C6-10 aryl,” “C 6 or Cio aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C6-10 aryloxy” or “C6-10 arylthio", including but not limited to phenyloxy.
  • an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as "C 7-1 4 aralkyl", including but not limited to benzyl, 2-phenylethyl, 3- phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a Ci -4 alkylene group).
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system is aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated.
  • the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
  • the heteroaryl group may be designated as "5-7 membered heteroaryl,” "5-10 membered heteroaryl,” or similar designations.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone.
  • carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
  • carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as "C3-6 carbocyclyl" or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a "(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C 4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
  • An example is cyclohexenyl.
  • heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 ,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathiinyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxany
  • a "(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • R is hydrogen, Ci-6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • R is selected from hydrogen, Ci-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a "cyano” group refers to a "-CN” group.
  • a “sulfonyl” group refers to an "-SO2R” group in which R is selected from hydrogen, C 1-6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, C3- 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • S-sulfonamido refers to a "-S02NR A R B " group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, € 3 . 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-sulfonamido refers to a “-N(R A )S0 2 R B " group in which R A and R are each independently selected from hydrogen, C 1-6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, C3- 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An “amino” group refers to a "-NR A R B " group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C2- 6 alkenyl, C2- 6 alkynyl, € 3 . 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes free amino (i.e., -NH2).
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C2- 8 alkoxyalkyl” and the like.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • substituents independently selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), C3-C7-carbocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy),
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
  • a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 - -CH 2 CH 2 -, -CH 2 CH(CI3 ⁇ 4)CH 2 -, and the like.
  • Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene” or "alkenylene.”
  • R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring.
  • the ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • ring A is a heteroaryl ring containing the depicted nitrogen.
  • R 1 2 1 2 and R and R are defined as selected from the group consisting of hydrogen and alkyl, or R and R together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • A is an aryl ring or a carbocylyl containing the depicted double bond.
  • a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
  • a substituent depicted as -AE- or 3 ⁇ 4 A ⁇ E A includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • the compounds disclosed herein may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents.
  • Isotopes can be present in the compounds described. Each chemical element as represented in a compound structure can include any isotope of said element. For example, at any position of the compound that a hydrogen atom is be present, the hydrogen atom encompasses any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Deuteration replacement of a hydrogen- 1 at a metabolically labile position of a compound may improve the pharmacokinetic properties of the compound.
  • each R 1 is selected from H, C 2 - 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, - CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • each R 2 , R 4 and R 5 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci -6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , - C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ; each R 3 and R 6 is selected from the group consisting of H, C 1-6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalk
  • each R 7 is selected from H or C 1-6 alkyl
  • each 8 is selected from C 6 -io aryl, 5 or 6 membered heteroaryl comprising one or two heteroatoms, , or 9 or 10 membered heteroaryl, each optionally substituted with one or more R A ;
  • each R 9 , R 10 , R 14 and R 15 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 ; or R 14 and R 15 together with the nitrogen atom to which they are
  • each R 11 is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R 12 , R 13 and R 16 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R A is selected from the group consisting of C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, halo, hydroxyl, -CN, - N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , -0(CH 2 ) n R 18 , and -(CH 2 ) k -S(0) 2 -R 19 ;
  • R 17 is selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl,
  • R is selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR 9 R 10 ;
  • R is selected from C 1-6 alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy)Ci-6 alkyl, C3-7 cycloalkyl, C 6 -io aryl, C 7-14 aralkyl, -NR 9 R 10 , 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R 20 ;
  • each R is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci.6 alkyl, -0-(Ci.6 alkoxy)Ci.6 alkyl, - (CH 2 CH 2 0) p CH 2 CH2N3 , halo, hydroxyl, oxo, and -CN; and
  • each k, m, n and p is independently an integer selected from 0 to 6;
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 1 is H, and R 8 is phenyl, then R 8 is substituted with one or more R A selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (Ci.6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , - 0(CH 2 ) n R 18 , and -(CH 2 ) k -S(0) 2 -R 19 .
  • R A selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C
  • R 1 is selected from H, C 2- 6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 .
  • R 1 is selected from H or Ci-6 alkoxy. In one embodiment, R 1 is H. In another embodiment, R 1 is methoxy.
  • R 2 is selected from H, halo, Ci-6 alkyl, or C 1-6 alkoxy. In one embodiment, R 2 is H.
  • R 3 is selected from H or Ci-6 alkoxy. In one embodiment, R 3 is H. In another embodiment, R 3 is methoxy.
  • R 4 is selected from H, halo, or C 1-6 alkyl. In one embodiment, R 4 is H. In another embodiment, R 4 is methyl.
  • R 5 is selected from H, halo, or C 1-6 alkyl. In one embodiment, R 5 is H. In another embodiment, R 5 is methyl. In yet another embodiment, R 5 is halo.
  • R 6 is selected from H, halo, or C 1-6 alkyl.
  • R 4 is H. In another embodiment, R 4 is methyl.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is H. In some other embodiments, at least one of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is not H.
  • R 7 is H. In some other embodiments, R is C 1-6 alkyl, for example, methyl.
  • R 8 is selected from phenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl,
  • R 8 is selected from phenyl, pyrazolyl, pyridinyl,
  • R 8 is unsubstituted.
  • R A is selected from the group consisting of halo, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci_6 haloalkoxy, -CN, -NR 9 R 10 , - C(0)NR 14 R 15 , -(CH 2 ) m R 17 , -0(CH 2 ) complicatR 18 , and -(CH 2 ) k -S(0) 2 -R 19 .
  • R A is selected from the group consisting of halo, methyl, trifluoromethyl, t-butyl, methoxy, trifluoromethoxy, and -CN.
  • R A is -C(0)NR 14 R 15 , and wherein each R 14 and R 15 is selected from H or Ci-6 alkyl. In one embodiment, both R 14 and R 15 are H. In another embodiment, both R 14 and R 15 are methyl. In some further embodiments, R A is -C(0)NR 14 R 15 , and R 14 and R 15 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 , for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • R A is -(CH 2 ) m R 17 and wherein m is selected from 0, 1 or 2. In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In some embodiments, R 17 is selected from 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O, or 5 to 6 membered heteroaryl each comprising one to three heteroatoms selected from N, S or O. In some such embodiments, m is 0 or 1 and R is selected from imidazolyl, triazolyl, I— I , ? , and wherein R a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl. In some such embodiments, R 17 is unsubstituted. In
  • R is substituted with one or more R , for example, one to three R .
  • R is -0(CH 2 ) n R and wherein n is selected from 0, 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1.
  • n is 2.
  • R is selected from Ci-6 haloalkyl, Ci-6 alkoxy, optionally substituted phenyl, optionally substituted pyridinyl, or -NR 9 R 10 .
  • R 18 is -NR 9 R 10 and wherein each R 9 and R 10 is selected from H or C 1-6 alkyl. In one such embodiment, both R 9 and R 10 are H. In another such embodiment, both R 9 and R 10 are Ci-6 alkyl, for example, methyl.
  • R 18 is -NR 9 R 10 , and R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 , for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • R 18 is selected from phenyl or pyridinyl, each substituted with one or more R 20 , for example, one to three R 20 .
  • R A is -(CI3 ⁇ 4) k - S(0) 2 -R 19 and wherein k is selected from 0, 1 or 2. In one embodiment, k is 0. In another embodiment, k is 1. In yet another embodiment, k is 2. In some such embodiments, R 19 is selected from C3-7 cycloalkyl, -NR 9 R 10 , or 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O. In some further embodiments, k is 0 and R 19 is selected from cyclopropyl, yclohexyl, + + ⁇ o
  • R a is selected from H, C 1-6 alkyl
  • p is an integer in the range of 0 to 6.
  • k is 1 and R 19 is selected from cyclopropyl, cyclopentyl,
  • R a is selected from H, Ci -6 alkyl, -(CHjCHjC pCHjCHjNs , or (Ci -6 alkoxy)Ci_6 alkyl, where p is an integer in the range of 0 to 6.
  • R a is selected from H, methyl or -(CI3 ⁇ 4)2C)CH3.
  • k is 0 or 1 and R 19 is -NR 9 R 10 , and wherein each R 9 and R 10 is independently selected from H, C 1-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl.
  • k is 0 or 1 and R 19 is In some embodiments, R a is -(CH 2 CH 2 0) p CH 2 CH 2 N 3i for example, ( ⁇ 2 ⁇ 3 ⁇ 40)5 ⁇ 3 ⁇ 4 ⁇ 3 ⁇ 4 ⁇ 3. In some such embodiments, R 9 is selected from H or methyl, and R 10 is selected from methyl, t-butyl, optionally substituted phenyl or optionally substituted C3-7 cycloalkyl.
  • the phenyl is substituted with one or more R selected from halo, C 1-6 alkyl, Ci- 6 haloalkyl, (Ci- 6 alkoxy)Ci- 6 alkyl, or -0-(Ci- 6 alkoxy)Ci- 6 alkyl.
  • the compounds are selected from Compounds 1-26, 28-67, 75-80, 82-84, 86-91 , 94-103, 105-152, and 159-170 of Table 1, or pharmaceutically acceptable salts thereof.
  • each R , R , R , R and R is independently selected from the group consisting of H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci -6 alkyl, -0-(Ci -6 alkoxy)Ci -6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -OR 11 , - C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -S0 2 R 16 ;
  • R 6 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, Ci_ 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, -CN, -NO 2 , -NR 9 R 10 , -OR 11 , -C(0)R 12 , -C(0)OR 13 , -C(0)NR 14 R 15 , -NR 14 C(0)R 12 , and -SO2R 16 ;
  • R is selected from H or C 1-6 alkyl
  • Ring A is selected from C -w aryl, 5 or 6 membered heteroaryl, or 9 or 10 membered heteroaryl, each optionally substituted with one or more R A ;
  • each R 9 , R 10 , R 14 and R 15 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally substituted with one or more R 20 ; each R is independently selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R 12 , R 13 and R 16 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2- 6 alkynyl, optionally substituted C 6 -io aryl, optionally substituted C 7-14 aralkyl, and optionally substituted C3-7 cycloalkyl;
  • each R A is selected from the group consisting of C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci-6 haloalkyl, Ci- 6 alkoxy, Ci- 6 haloalkoxy, (C 1-6 alkoxy)C 1- 6 alkyl, -0-(C 1-6 alkoxy)C 1- 6 alkyl, halo, hydroxyl, -CN, -N0 2 , -NR 9 R 10 , -C(0)NR 14 R 15 , -(CH 2 ) m R 17 , -0(CH 2 ) n R 18 , and -(CH 2 ) k - S(0) 2 -R 19 ;
  • R 17 is selected from 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more
  • R 18 is selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, optionally substituted phenyl, optionally substituted six membered heteroaryl, and -NR 9 R 10 ;
  • R 19 is selected from C 1-6 alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy)Ci_6 alkyl, C3-7 cycloalkyl, C 6 -io aryl, C 7-14 aralkyl, -NR 9 R 10 , 4 to 7 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one or more R 20 ;
  • each R 20 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (C 1-6 alkoxy)Ci_6 alkyl, -0-(Ci_6 alkoxy)Ci_6 alkyl, halo, hydroxyl, oxo, and -CN;
  • each m, n and k is independently an integer selected from 0 to 6;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is H, and ring A is phenyl, then ring A is substituted with one or more R A .
  • R 1 is selected from H or Ci-6 alkoxy. In one embodiment, R 1 is H. In another embodiment, R 1 is methoxy.
  • R 2 is selected from H, halo, Ci-6 alkyl, or C 1-6 alkoxy. In one embodiment, R 2 is H.
  • R 3 is selected from H or Ci-6 alkoxy. In one embodiment, R 3 is H. In another embodiment, R 3 is methoxy.
  • R 4 is selected from H, halo, or Ci_6 alkyl. In one embodiment, R 4 is H. In another embodiment, R 4 is methyl.
  • R 5 is selected from H, halo, or Ci_6 alkyl. In one embodiment, R 5 is H. In another embodiment, R 5 is methyl. In yet another embodiment, R 5 is halo.
  • R 6 is selected from H, halo, or C 1-6 alkyl.
  • R 4 is H. In another embodiment, R 4 is methyl.
  • each R 1 , R 2 , R 3 , R 4 , R 5 is independently selected from the group consisting of the compounds of formula (II).
  • R° is H. In some other embodiments, at least one of R , R , R R , R and R° is not H.
  • R is H. In some other embodiments, R is Ci-6 alkyl, for example, methyl.
  • ring A is selected from phenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and quinolinyl, each optionally substituted with one or more R A .
  • ring A is selected from phenyl or pyridinyl, each optionally substituted with one or more R A . In some other embodiments, ring A is unsubstituted.
  • R A is selected from the group consisting of halo, Ci_6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci_6 haloalkoxy, -CN, -NR 9 R 10 , - C(0)NR 14 R 15 , -(CH 2 ) m R 17 , -0(CH 2 ) complicatR 18 , and -(CH 2 ) k -S(0) 2 -R 19 .
  • R A is selected from the group consisting of halo, methyl, trifluoromethyl, t-butyl, methoxy, trifluoromethoxy, and -CN.
  • R A is -C(0)NR 14 R 15 , and wherein each R 14 and R 15 is selected from H or Ci-6 alkyl. In one embodiment, both R 14 and R 15 are H. In another embodiment, both R 14 and R 15 are methyl. In some further embodiments, R A is -C(0)NR 14 R 15 , and R 14 and R 15 together with the nitrogen atom to which they are attached forms a 4 to 6 membered
  • heterocyclyl optionally substituted with one or more R , for example, a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • R A is -(CH 2 ) m R 17 and wherein m is selected from 0, 1 or 2. In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In some embodiments, R 17 is selected from 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O, or 5 to 6 membered heteroaryl each comprising one to three heteroatoms selected from N, S or O.
  • m is 0 or 1 and R is selected from imidazolyl, triazolyl, , and wherein R a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl. In some such embodiments, R is unsubstituted. In some other embodiments, R 17 is substituted with one or more R 20 , for example, one to three R 20.
  • R is -0(CH 2 ) n R and wherein n is selected from 0, 1 or 2. In one embodiment, n is 0. In another embodiment, n is 1. In
  • n is 2.
  • R is selected from Ci-6 haloalkyl, Ci-6 alkoxy, optionally substituted phenyl, optionally substituted pyridinyl, or -NR 9 R 10 .
  • R 18 is -NR 9 R 10 and wherein each R 9 and R 10 is selected from H or Ci-6 alkyl. In one such embodiment, both R 9 and R 10 are H. In another embodiment, both R 9 and R 10 are Ci-6 alkyl, for example, methyl.
  • R 18 is -NR 9 R 10 , and R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocyclyl optionally
  • R 18 is selected from a 4 to 6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • R 18 is selected
  • R A is -(CH 2 ) k -S(0) 2 -R 19 and wherein k is selected from 0, 1 or 2. In one embodiment, k is 0. In another embodiment, k is 1. In yet another embodiment, k is 2. In some such embodiments, R 19 is selected from C3-7 cycloalkyl, -NR 9 R 10 , or 4 to 7 membered heterocyclyl comprising one to three heteroatoms selected from N, S or O. In some further embodiments, k is 0 or 1 and R 19 is selected from cyclopropyl, cyclopentyl,
  • R a is selected from H, Ci-6 alkyl, or (Ci-6 alkoxy)Ci_6 alkyl.
  • R is selected from H, methyl or -(CH 2 ) 2 OCH 3 .
  • k is 0 or 1 and R 19 is -NR 9 R 10 , and wherein each R 9 and R 10 is independently selected from H, Ci-6 alkyl, optionally substituted phenyl, or optionally substituted C3-7 cycloalkyl.
  • R 9 is selected from H or methyl
  • R 10 is selected from methyl, t-butyl, optionally substituted phenyl or optionally substituted C3-7 cycloalkyl.
  • the phenyl is substituted with one or more R selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy)Ci-6 alkyl, or -0-(Ci-6 alkoxy)Ci_6 alkyl.
  • the compounds are selected from Compounds 27, 70-74, 81, 85, 92, 93, 104, and 153-158 of Table 1, or pharmaceutically acceptable salts thereof.
  • the compounds of formula (II) may include tautomers thereof, depending on the specific synthetic procedures used in the preparation of the compounds.
  • Compounds 73 and 74 may also exist in their tautomeric forms:
  • Various embodiments of the present disclosure including but not limited to substituted quinoline compounds, pharmaceutical salts, compositions thereof, and methods of treating cancer do not include the specific compounds disclosed in PCT Publication Nos. WO 2003/062233 Al, WO 2011/080266 Al, WO 2012/177893 A2, WO 2014/037342 Al, and U.S. Publication No. 2007/0060567 Al, all of which are hereby incorporated by reference and particularly for the purpose of describing the specific compounds disclosed therein.
  • compositions comprising: (a) a therapeutically effective amount of a compound of formula (I), ( ⁇ ) or (II) as described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a therapeutically effective dosage e.g., a dosage sufficient to provide treatment for the disease states previously described.
  • a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives;
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • compositions described herein are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • routes for administration for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically- acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
  • Other excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al, Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-31 1 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • Some embodiments of the present disclosure relate to a method of treating cancer, comprising administering a therapeutically effective amount of a compound of formula (I), ( ⁇ ) or (II) as described herein, a specific compound selected from Table 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof.
  • Some embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (I), ( ⁇ ) or (II), a specific compound selected from Table 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Non-limiting examples of cancer that may be treated include breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non-Hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.
  • the subject is a mammal. In some further embodiments, the subject is a human.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.
  • the effect can be detected by, for example, the assays disclosed in the following examples.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., IC 50 is a measure of how effective a drug is. It indicates how much of a particular drug compound is needed to inhibit a given biological process (e.g., a cancer cell line) by half. It is commonly used as a measure of antagonist drug potency in pharmacological research.
  • EDso the dose therapeutically effective in 50% of the population
  • LD 50 the dose lethal to 50% of the population.
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED 50 /LD 50 .
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
  • compositions that exhibit narrow therapeutic indices are also within the scope of the invention.
  • the data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use.
  • the dosage contained in such compositions is preferably within a range of circulating concentrations that include an EDso with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • the exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days.
  • An increase in survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone.
  • treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • treating a condition described herein results in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells is equivalent to the mitotic index.
  • treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • the methods described herein may include identifying a subject in need of treatment.
  • the methods include identifying a mammal in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing such as genomic sequencing, or any other means known to one of skill in the art, including any combination of means for identification.
  • the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition.
  • a preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.
  • Further embodiments include administering a combination of compounds to a subject in need thereof.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • coadministration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Various embodiments provide methods of treating a cancer by administering to a subject in need thereof a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition as described herein, wherein the method further comprises co-administering to the subject an effective amount of an additional medicament that is also effective for treating the cancer.
  • the cancer is breast cancer and the additional medicament is a Selective Estrogen Receptor Modulator (SERM), Tamoxifen (oral and/or topical), Afimoxifene (4- hydroxytamoxifen) (oral and/or topical) and/or omeprazole.
  • SERM Selective Estrogen Receptor Modulator
  • Tamoxifen oral and/or topical
  • Afimoxifene (4- hydroxytamoxifen)
  • omeprazole a Selective Estrogen Receptor Modulator
  • the compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W.
  • Substituted quinoline compounds described herein can be prepared by using one or more of the following general synthetic schemes exemplified below. Those skilled in the art can develop modified synthetic schemes for particular compounds within the scope of Formulae (I), ( ⁇ ) and/or (II) by using routine experimentation guided by the detailed teachings provided herein.
  • HATU 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (228 mg, 0.6 mmol, 1.2 equiv) was added, and the reaction mixture was stirred at room temperature for 16 hours. After dilution with water, the mixture was extracted with dichloromethane (3 x 20 mL). Combined organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid).
  • reaction mixture was stirred at room temperature until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F 2 5 4 ). Then the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x 20 rriL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 20 mL).
  • HATU N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
  • HATU N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
  • reaction mixture was stirred at room temperature until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F254).
  • the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3x20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was purified on C18-silica gel (water/acetonitrile + 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and treated with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane (3 x 20 mL).
  • the residue was purified on silica gel using a mixture of dichloromethane and methanol (100:0 to 90: 10 gradient) as eluent.
  • the product was obtained as brown oil as a mixture of isomers Int-2 and Int-2A (1.5: 1) in 35% yield.
  • Lithium hydroxide monohydrate (114 mg, 2.71 mmol, 2.0 eq) was added to a solution of compound Int-4 (300 mg, 1.35 mmol, 1.0 eq) in 4:2: 1 mixture of THF/H 2 0/MeOH (1 mL), and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with DI water, acidified to pH ⁇ 4 with IN HC1 and extracted with EtOAc.
  • reaction mixture was poured into ice-cold water.
  • the formed solid was filtered, washed and dried under vacuum to give 40 mg of the desired compound 127 as a pale-yellow solid in 21% yield. 97.88% purity as determined by HPLC at 215 nm.

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Abstract

L'invention concerne des composés de quinoléine substitués, des procédés de fabrication de tels composés, des compositions pharmaceutiques, des médicaments comprenant de tels composés et des procédés d'utilisation de ces composés pour traiter, prévenir ou atténuer le cancer.
PCT/US2017/059470 2016-11-03 2017-11-01 Quinoléines substituées et procédés pour traiter le cancer WO2018085348A1 (fr)

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CN111056978A (zh) * 2019-12-13 2020-04-24 西安交通大学 一种磺酰胺类化合物及其制备方法和应用
WO2020231739A3 (fr) * 2019-05-10 2020-12-24 Antidote Ip Holdings, Llc Composés et méthodes de traitement du cancer
EP3668496A4 (fr) * 2017-08-17 2021-07-14 Ikena Oncology, Inc. Inhibiteurs d'ahr et leurs utilisations
WO2021142180A1 (fr) 2020-01-10 2021-07-15 Ikena Oncology, Inc. Inhibiteurs d'ahr et leurs utilisations
US11390621B2 (en) 2019-04-15 2022-07-19 Ariagen, Inc. Chiral indole compounds and their use
US11427576B2 (en) 2017-11-20 2022-08-30 Ariagen, Inc. Indole compounds and their use
WO2022183963A1 (fr) * 2021-03-05 2022-09-09 朗捷睿(苏州)生物科技有限公司 Composé de coumarine à substitution 8-(picolinamide), son procédé de préparation et son utilisation
US11547698B2 (en) 2016-12-26 2023-01-10 Ariagen, Inc. Aryl hydrocarbon receptor modulators

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11547698B2 (en) 2016-12-26 2023-01-10 Ariagen, Inc. Aryl hydrocarbon receptor modulators
EP3668496A4 (fr) * 2017-08-17 2021-07-14 Ikena Oncology, Inc. Inhibiteurs d'ahr et leurs utilisations
US11555026B2 (en) 2017-08-17 2023-01-17 Ikena Oncology, Inc. AHR inhibitors and uses thereof
US11427576B2 (en) 2017-11-20 2022-08-30 Ariagen, Inc. Indole compounds and their use
US11459322B2 (en) 2017-11-20 2022-10-04 Ariagen, Inc. Indole compounds and their use
US11891386B2 (en) 2017-11-20 2024-02-06 Ariagen, Inc. Indole compounds and their use
US11390621B2 (en) 2019-04-15 2022-07-19 Ariagen, Inc. Chiral indole compounds and their use
WO2020231739A3 (fr) * 2019-05-10 2020-12-24 Antidote Ip Holdings, Llc Composés et méthodes de traitement du cancer
CN111056978A (zh) * 2019-12-13 2020-04-24 西安交通大学 一种磺酰胺类化合物及其制备方法和应用
CN111056978B (zh) * 2019-12-13 2021-01-19 西安交通大学 一种磺酰胺类化合物及其制备方法和应用
WO2021142180A1 (fr) 2020-01-10 2021-07-15 Ikena Oncology, Inc. Inhibiteurs d'ahr et leurs utilisations
WO2022183963A1 (fr) * 2021-03-05 2022-09-09 朗捷睿(苏州)生物科技有限公司 Composé de coumarine à substitution 8-(picolinamide), son procédé de préparation et son utilisation

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