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WO2018103058A1 - Inhibiteurs de tyrosine kinase de bruton et leurs procédés d'utilisation - Google Patents

Inhibiteurs de tyrosine kinase de bruton et leurs procédés d'utilisation Download PDF

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Publication number
WO2018103058A1
WO2018103058A1 PCT/CN2016/109134 CN2016109134W WO2018103058A1 WO 2018103058 A1 WO2018103058 A1 WO 2018103058A1 CN 2016109134 W CN2016109134 W CN 2016109134W WO 2018103058 A1 WO2018103058 A1 WO 2018103058A1
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Prior art keywords
oxo
thia
dihydro
carboxamide
triazaacenaphthylene
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PCT/CN2016/109134
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English (en)
Inventor
Min Cai
Nidhi Arora
Genesis M. Bacani
Joseph Kent Barbay
Scott D. Bembenek
Wei Chen
Charlotte Pooley DECKHUT
James P. Edwards
Brahmananda GHOSH
Baoyu HAO
Kevin D. Kreutter
Gang Li
Mark S. Tichenor
Jennifer D. Venable
Jianmei Wei
John J. M. Wiener
Yao Wu
Yaoping Zhu
Feihuang ZHANG
Zheng Zhang
Kun Xiao
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Priority to PCT/CN2016/109134 priority Critical patent/WO2018103058A1/fr
Publication of WO2018103058A1 publication Critical patent/WO2018103058A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/16—Peri-condensed systems

Definitions

  • the present disclosure is directed to small molecule tyrosine kinase inhibitors.
  • RA Rheumatoid arthritis
  • RA is a chronic, autoimmune, inflammatory disorder that affects the lining of the joints, causing painful swelling that can result in bone erosion and joint deformation.
  • RA presents a significant societal impact –it has a relatively high prevalence (about 1%of the United States population suffers from RA) , produces irreversible joint damage, and has a widespread occurrence of co-morbities. While many patients benefit from currently marketed biologic and small molecule medicines, most patients still suffered from the chronic pain and inflammation of the disease.
  • Cancer in particular mantle cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia, and multiple myeloma, continues to afflict patients. Alternative, effective treatments of cancer are still needed.
  • tyrosine kinase Human Bruton’s tyrosine kinase ( “Btk” ) is a ⁇ 76 kDa protein belonging to the Tec family of non-receptor tyrosine kinases.
  • Tec kinases form the second largest family of cytoplasmic tyrosine kinases in mammalian cells, which consists of four other members in addition to BTK: the eponymous kinase TEC, ITK, TXK/RLK and BMX.
  • Tec kinases are evolutionarily conserved throughout vertebrates. They are related to, but structurally distinct from, the larger Src and Syk kinase families. Tec family proteins are abundantly expressed in hematopoietic tissues and play important roles in the growth and differentiation of blood and endothelial cells in mammals.
  • Btk inhibition has the potential to modulate biology associated with B cells, macrophages, mast cells, osteoclasts, and platelet microparticles.
  • the role of B cells in RA is supported by the therapeutic benefit exhibited in the clinic upon B cell depletion with Rituximab TM . Since auto-reactive antibodies play such a critical role in synovial inflammation, therapeutic modulation of the B cell compartment is an attractive mechanism to treat early RA and potentially modulate disease at the earliest stages.
  • Btk inhibitors block antigen receptor-induced signaling at the earliest stages and subsequent B cell proliferation.
  • critical aspects of antigen presentation function such as antigen internalization and upregulation of co-stimulation molecules such as CD80 and CD86 and MHC-IIs can be blocked with Btk inhibitors (Kenny, E.F., et al. (2013) PLoS One 8, e74103) .
  • Btk inhibitors exhibit efficacy in a variety of rodent arthritis models, whether dosed prophylactically or fully therapeutically (Di Paolo, J.A., et al.
  • Btk inhibition decreases autoantibody production and isotype switching, as well as epitope spreading from bovine collagen to rodent collagen.
  • Btk inhibition shows significant reductions in inflammation scores as assessed by inflamed paw histopathology.
  • Btk is a clinically validated target for the treatment of hematological malignancies, with the irreversible covalent inhibitor (ICI) ibrutinib approved for treatment of B cell malignancies such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL) and macroglobulinemia (Hendriks, R.W., et al. (2014) Nat Rev Cancer 14, 219-232) .
  • ICI irreversible covalent inhibitor
  • R 1 is H or C 1-6 alkyl
  • R 2 is –C 0-6 alk-piperidinyl; –C 0-6 alk-pyrrolidinyl; –C 0-6 alk-oxazepanyl; –C 0-6 alk-azetidinyl;
  • R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
  • -C 1-6 haloalkyl -C 1-6 alkaryl; -SO 2 -C 1-6 alkyl; -SO 2 -C 2-6 alkenyl; -C (O) H;
  • R 3 is H; -CN; halogen; -C 1-6 haloalkyl; or -C 1-6 alkyl;
  • R 4 and R 5 are each independently H; halogen; -C 1-6 alkyl;
  • R 6 and R 7 are each independently H; -C 1-6 alkyl; -C 3-6 cycloalkyl;
  • R 8 is H or C 1-6 alkyl
  • A is a bond, pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl;
  • E is –O-; a bond; -C (O) -NH-; -CH 2 -; or -CH 2 -O-;
  • G is H; -C 3-6 cycloalkyl; -phenyl; -thiophenyl; -C 1-6 alkyl; -pyrimidinyl; -pyridyl; -pyridazinyl;
  • compositions comprising compounds of formula I are also described. Methods of using compounds of formula I are also within the scope of the disclosure.
  • compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.
  • alkyl when used alone or as part of a substituent group, refers to a straight-or branched-chain alkyl group having from 1 to 12 carbon atoms ( “C 1-12 ” ) , preferably 1 to 6 carbons atoms ( “C 1-6 ” ) , in the chain.
  • alkyl groups include methyl (Me, C 1 alkyl) ethyl (Et, C 2 alkyl) , n-propyl (C 3 alkyl) , isopropyl (C 3 alkyl) , butyl (C 4 alkyl) , isobutyl (C 4 alkyl) , sec-butyl (C 4 alkyl) , tert-butyl (C 4 alkyl) , pentyl (C 5 alkyl) , isopentyl (C 5 alkyl) , tert-pentyl (C 5 alkyl) , hexyl (C 6 alkyl) , isohexyl (C 6 alkyl) , and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • C 1-3 includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 , and C 3 .
  • C 1-6 alk refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, –CH 2 -, –CH (CH 3 ) -, -CH (CH 3 ) -CH 2 -, and –C (CH 3 ) 2 -.
  • -C 0 alk- refers to a bond.
  • the C 1-6 alk can be substituted with an oxo group or an –OH group.
  • alkenyl when used alone or as part of a substituent group, refers to straight and branched carbon chains having from 2 to 12 carbon atoms ( “C 2-12 ” ) , preferably 2 to 6 carbon atoms ( “C 2-6 ” ) , wherein the carbon chain contains at least one, preferably one to two, more preferably one double bond.
  • alkenyl moieties include, but are not limited to allyl, 1-propen-3-yl, 1-buten-4-yl, propa-1, 2-dien-3-yl, and the like.
  • alkynyl when used alone or as part of a substituent group, refers to straight and branched carbon chains having from 2 to 12 carbon atoms ( “C 2-12 ” ) , preferably 2 to 6 carbon atoms ( “C 2-6 ” ) , wherein the carbon chain contains at least one, preferably one to two, more preferably one triple bond.
  • alkynyl moieties include, but are not limited to vinyl, 1-propyn-3-yl, 2-butyn-4-yl, and the like.
  • aryl refers to carbocylic aromatic groups having from 6 to 10 carbon atoms ( “C 6-10 ” ) such as phenyl, naphthyl, and the like.
  • cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ( “C 3-10 ” ) , preferably from 3 to 6 carbon atoms ( “C 3-6 ” ) .
  • Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ) , cyclobutyl (C 4 ) , cyclopentyl (C 5 ) , cyclohexyl (C 6 ) , 1-methylcyclopropyl (C 4 ) , 2-methylcyclopentyl (C 4 ) , adamantanyl (C 10 ) , and the like.
  • heterocycloalkyl refers to any four to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahyofuranyl, tetrahydropyranyl, piperazinyl, hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrolyl, benzo [d] [1, 3] dioxolyl, and the like.
  • heteroaryl refers to a mono-or bicyclic aromoatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms ( “C 5-10 ” ) .
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl) , oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • haloalkyl refers to an alkyl moiety wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • One exemplary substitutent is fluoro.
  • Preferred haloalkyl groups of the disclosure include trihalogenated alkyl groups such as trifluoromethyl groups.
  • an oxo-substituted pyrrolidinyl moiety could be a pyrrolidin-2-one moiety or a pyrrolidin-3-one moiety.
  • the benzofuranyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7-carbon atoms.
  • the benzo [d] [1, 3] dioxolyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, or 7-carbon atoms.
  • the “benzo [d] [1, 3] dioxolyl moiety is substituted with halogen, ” the following moieties are preferred:
  • the benzothiophenyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7-carbon atoms.
  • phenyl represents the following moiety:
  • the phenyl moiety can be attached through any of the carbon atoms.
  • naphthyl i.e., naphthyl
  • the naphthalenyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.
  • the pyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position carbon atoms.
  • pyrimidinyl represents the following moiety:
  • the pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms.
  • pyrazinyl represents the following moiety:
  • the pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.
  • the pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms.
  • pyrazolyl represents the following moiety:
  • the pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position carbon atoms.
  • thiophenyl represents the following moiety:
  • the thiophenyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.
  • linker-PEG-Biotin refers to a moiety comprising –linker-PEG-CH 2 -NH-biotinyl.
  • Compounds of the disclosure that include a linker-PEG-Biotin moiety can be used according to any of the methods described herein.
  • compounds of the disclosure that include a linker-PEG-Biotin moiety can be used as diagnostic probes according to methods known in the art.
  • Preferred linkers are known in the art, with the linker –CH 2 -NHC (O) - (CH 2 ) 3 -C (O) -NH-CH 2 -being particularly preferred.
  • Preferred PEG moieties include at least two or three repeating –CH 2 -CH 2 -O-moieties.
  • a preferred linker-PEG-Biotin moiety is
  • R 2 when R 2 is a C 0 alk-piperidinyl moiety, it can be attached to the compound of formula I through any one of the 2-, 3-, 4-, 5-, or 6-position atoms. In other aspects, when R 2 is a C 0 alk-piperidinyl moiety, it can be attached to the compound of formula I through any ring atom. Within the disclosure, when R 2 is a C 1-6 alk-piperidinyl moiety, it can be attached to the compound of formula I through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms. When the piperidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms.
  • R 2 when R 2 is a C 0 alk-pyrrolidinyl moiety, it can be attached to the compound of formula I through any one of the 2-, 3-, 4-, or 5-position atoms. In other aspects, when R 2 is a C 0 alk-pyrrolidinyl moiety, it can be attached to the compound of formula I through any ring atom. Within the disclosure, when R 2 is a C 1-6 alk-pyrrolidinyl moiety, it can be attached to the compound of formula I through any one of the 1-, 2-, 3-, 4-, or 5-position atoms. When the pyrrolidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position atoms.
  • oxazepanyl refers to a 7-membered heterocycloalkyl moiety having one ring nitrogen atom and one ring oxygen atom. Examples include 1, 3-oxazepanyl and 1, 4-oxazepanyl moieties
  • R 2 when R 2 is a C 0 alk-oxazepanyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms. In other aspects, when R 2 is a C 0 alk-oxazepanyl moiety, it can be attached to the compound of formula I through any ring nitrogen or carbon atom. Within the disclosure, when R 2 is a C 1-6 alk-oxazepanyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or nitrogen ring atom. When the oxazepanyl moiety is a substituent, it can be attached through any ring carbon atom or through the nitrogen atom.
  • aziridinyl represents a 3-membered heterocycloalkyl moiety having one ring nitrogen.
  • R 2 when R 2 is a C 0 alk-aziridinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms.
  • R 2 when R 2 is a C 1-6 alk-aziridinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom.
  • the aziridinyl moiety is a substituent, it can be attached through any carbon atom or through the nitrogen atom.
  • azetidinyl represents a 4-membered heterocycloalkyl moiety having one ring nitrogen.
  • R 2 when R 2 is an C 0 alk-azetidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms.
  • R 2 when R 2 is a C 1-6 alk-azetidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom.
  • R 2 is an C 1-6 alk-azetidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom.
  • the azetidinyl moiety when the azetidinyl moiety is a substituent, it can be attached through any carbon atom or through the nitrogen atom.
  • azepanyl represents a 7-membered heterocycloalkyl moiety having one ring nitrogen.
  • R 2 when R 2 is an C 0 alk-azepanyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms.
  • R 2 when R 2 is a C 1-6 alk-azepanyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom.
  • R 2 is an C 1-6 alk-azepanyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or nitrogen ring atom.
  • the azepanyl moiety when the azepanyl moiety is a substitutent, it can be attached through any carbon atom or through the nitrogen atom.
  • R 2 when R 2 is a quinuclidinyl moiety, or when the quinuclidinyl moiety is a substituent, it can be attached to the compound of formula I through any one of the ring carbon atoms.
  • imidazolidinyl represents the following moiety:
  • R 2 when R 2 is an C 0 alk-imidazolidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms. In other aspects, when R 2 is a C 1-6 alk-imidazolidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom. Within the disclosure, when R 2 is an C 1- 6 alk-imidazolidinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or any nitrogen ring atom. When the imidazolidinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position atoms.
  • R 2 when R 2 is a C 0 alk-piperazinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms. In other aspects, when R 2 is a C 1-6 alk-piperazinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom. Within the disclosure, when R 2 is a C 1-6 alk-piperazinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or nitrogen ring atoms. When the piperazinyl moiety is a substituent, it can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms.
  • morpholinyl represents the following moiety:
  • R 2 when R 2 is a C 0 alk-morpholinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms. In other aspects, when R 2 is a C 1-6 alk-morpholinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or the nitrogen ring atom. Within the disclosure, when R 2 is a C 1-6 alk-morpholinyl moiety, it can be attached to the compound of formula I through any one of the ring carbon atoms or nitrogen ring atom. When the morpholinyl moiety is a substituent, it can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position atoms.
  • tetrahydropyranyl represents a 6-membered heterocycloalkyl moiety having one ring oxygen.
  • the tetrahydropyranyl moiety can be attached through any carbon atom on the ring.
  • tetrahydrofuranyl represents a 5-membered heterocycloalkyl moiety having one ring oxygen.
  • the tetrahydrofuranyl moiety can be attached through any carbon atom on the ring.
  • compound (s) of formula I includes those compounds of “formula I, ” as well as compounds of any of the formula I subgenera.
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE) , diisopropyl ether (DIPE) , ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK) , methyl ethyl ketone (MEK) , acetone, nitromethane, tetrahydrofuran (THF) , dichloromethane (DCM) , dioxane, heptanes, toluene, anisole, acetonitrile, and the like.
  • solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE) , diisopropyl ether (D
  • solvates are formed using, but not limited to, Class 3 solvent (s) . Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) , “Impurities: Guidelines for Residual Solvents, Q3C (R3) , (November 2005) . Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the described compounds, or pharmaceutically acceptable salts thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of the compounds described herein are anhydrous. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof, exist in unsolvated form. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, exist in unsolvated form and are anhydrous.
  • s Class 3 solvent
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • non toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • Subject includes humans.
  • the terms “human, ” “patient, ” and “subject” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D) , carbon-13 ( 13 C) , nitrogen-15 ( 15 N) , or the like.
  • Radiolabeled compounds of the disclosure can be used in diagnostic methods such as Single-photon emission computed tomography (SPECT) .
  • SPECT Single-photon emission computed tomography
  • positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers. ” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers, ” for example, diastereomers, enantiomers, and atropisomers.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers. ”
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture. ”
  • “Atropisomers” refer to stereoisomers that arise because of hindered rotation around a single bond.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H) .
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers or as mixtures thereof.
  • any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom.
  • a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, separately or as a mixture, are encompassed by that structure.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • L is -C (O) NR 1 -, –C 1-6 alk-NR 1 -, a bond, or -NR 1 -C (O) -.
  • L is -C (O) NR 1 -, corresponding to compounds of formula I’ :
  • L is –C 1-6 alk-NR 1 -, corresponding to compounds of formula I” :
  • L is a bond, corresponding to compounds of formula I” ’ :
  • L is -NR 1 -C (O) -, corresponding to compounds of formula I” ” :
  • a preferred embodiment of the disclosure is a compound of Formula (I) having the Formula (I’) :
  • R 1 is H or C 1-6 alkyl
  • R 2 is –C 0-6 alk-piperidinyl; –C 0-6 alk-pyrrolidinyl; –C 0-6 alk-oxazepanyl; –C 0-6 alk-azetidinyl;
  • R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
  • -C 1-6 haloalkyl -C 1-6 alkaryl; -SO 2 -C 1-6 alkyl; -SO 2 -C 2-6 alkenyl; -C (O) H;
  • R 3 is H; -CN; halogen; -C 1-6 haloalkyl; or -C 1-6 alkyl;
  • R 4 and R 5 are each independently H; halogen; -C 1-6 alkyl;
  • R 6 and R 7 are each independently H; -C 1-6 alkyl; -C 3-6 cycloalkyl;
  • R 8 is H or C 1-6 alkyl
  • A is a bond, pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl;
  • substituents independently selected from the group consisting of -C 1-6 alkyl; halogen; -SF 5 ; -OC 1-6 alkyl; -C (O) -C 1-6 alkyl; and -C 1-6 haloalkyl;
  • E is –O-; a bond; -C (O) -NH-; -CH 2 -; or -CH 2 -O-; and
  • G is H; -C 3-6 cycloalkyl; -phenyl; -thiophenyl; -C 1-6 alkyl; -pyrimidinyl; -pyridyl; -pyridazinyl;
  • R 1 is H or C 1-6 alkyl
  • R 2 is selected from the group consisting of: C 0-2 alk-piperidinyl; C 0-2 alk-pyrrolidinyl; oxazepanyl; azetidinyl; azepanyl; quinuclidinyl; C 2 alk-imidazolidinyl; C 2 alk-piperazinyl; C 2 alk-morpholinyl; tetrahydropyranyl; and C 0-1 alk-tetrahydrofuranyl; wherein the R 2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of:
  • R 3 is selected from the group consisting of: H, CN, halogen, C 1-6 haloalkyl, and C 1-6 alkyl;
  • R 4 and R 5 are each independently selected from the group consisting of: H; halogen; C 1-6 alkyl; CH 2 OH; C 1-6 alk-OC 1-6 alkyl; OC 1-6 alkyl; C 1-4 alk-NR 6 R 7 ; C 3-6 cycloalkyl substituted with NH 2 or CH 3 ; oxetanyl substituted with CH 3 ; 1-acetylpyrrolidin-2-yl; CH 2 -pyrrolidinyl; CH 2 -piperidinyl; C (CH 3 ) 2 -piperidinyl; CH 2 -morpholinyl; C (CH 3 ) 2 -morpholinyl; CH 2 - (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl; C (CH 3 ) 2 NH (CH 2 CH 2 OCH 3 ) ; CH 2 SO 2 CH 3 ; CH 2 NHSO
  • G is selected from the group consisting of: H, C 1-6 alkyl; C 1-6 haloalkyl; C 1-6 alk-OC 1-6 alkyl;
  • NR 6 R 7 SO 2 C 1-6 alkyl; OH; C 3-6 cycloalkyl; phenyl; thiophenyl; pyrimidinyl; pyridyl; pyridazinyl; benzofuranyl; ; heterocycloalkyl that contains an oxygen heteroatom; phenyl-CH 2 -O-phenyl; wherein the phenyl, thiophenyl, pyrimidinyl, pyridyl, pyridazinyl, or benzofuranyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 alkyl-OC 1-6 alkyl, C 3-6 cycloalkyl, CN, OH, NH 2 , N (CH 3 ) 2 , C 1-6
  • Stereoisomers and isotopic variants, pharmaceutically acceptable salts, N-oxides, and solvates of Formula I’a re also within the scope of the disclosure.
  • An additional embodiment of the disclosure is directed to compounds of Formula (II’) , as well as the stereoisomers, isotopic vairants, and pharmaceutically acceptable salt thereof:
  • R a is independently selected from the group consisting of: H, Cl, F, CH 3 , and CF 3 ;
  • n 0-2;
  • Ring B is selected from the group consisting of:
  • R d is selected from the group consisting of: H, F, OH, and OCH 3 ;
  • R e is H or C 1-6 alkyl
  • R d is selected from the group consisting of: H, F, OH, and OCH 3 ;
  • R 3 is selected from the group consisting of: H, CN, halogen, C 1-6 haloalkyl, and C 1-6 alkyl;
  • R 4 and R 5 are each independently selected from the group consisting of: H; halogen; C 1-6 alkyl; CH 2 OH; C 1-6 alk-OC 1-6 alkyl; OC 1-6 alkyl; C 1-4 alk-NR 6 R 7 ; C 3-6 cycloalkyl substituted with NH 2 or CH 3 ; oxetanyl substituted with CH 3 ; 1-acetylpyrrolidin-2-yl; CH 2 -pyrrolidinyl; CH 2 -piperidinyl; C (CH 3 ) 2 -piperidinyl; CH 2 -morpholinyl; C (CH 3 ) 2 -morpholinyl; CH 2 - (4aR, 7aS) -tetrahydro-2H- [1, 4] dioxino [2, 3-c] pyrrol-6 (3H) -yl; C (CH 3 ) 2 NH (CH 2 CH 2 OCH 3 ) ; CH 2 SO 2 CH 3 ; CH 2 NHSO
  • R 6 and R 7 are each independently selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl, and CN;
  • R g is selected from the group consisting of: H, C 1-6 alkyl, and CN;
  • R h is selected from the group consisting of: H, CN, CH 3 , and CH 2 phenyl.
  • An additional embodiment of the disclosure is directed to compounds of Formula (III’) , as well as the stereoisomers, isotopic vairants, and pharmaceutically acceptable salt thereof:
  • G-A is selected from the group consisting of:
  • G is phenyl; or phenyl substituted with one or two members independently selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, pyridyl, oxetan-3-yl, and tetrahydro-2H-pyran-4-yl;
  • R a is H or CH 3 ;
  • Ring B is selected from the group consisting of:
  • An additional embodiment of the disclosure is directed to compounds of Formula (IV’) , as well as the stereoisomers, isotopic vairants, and pharmaceutically acceptable salt thereof:
  • G-E-A is selected from the group consisting of:
  • G is selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, tetrahydro-2H-pyran-4-yl, pyridazin-3-yl, phenyl, and phenyl substituted with F;
  • R a is H or CH 3 ;
  • Ring B is selected from the group consisting of:
  • An additional embodiment of the disclosure is directed to compounds of Formula (V’) , as well as the stereoisomers, isotopic vairants, and pharmaceutically acceptable salt thereof:
  • Ring B is selected from the group consisting of:
  • R d is H or OH.
  • R 1 is H or C 1-6 alkyl.
  • R 1 is C 1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or t-butyl.
  • R 1 is H.
  • R 2 is a C 0-6 alk-heterocycloalkyl moiety that is unsubstituted or substituted with 1, 2, or 3 substituents.
  • the heterocycloalkyl is directly attached to the compound of formula I through a bond.
  • R 2 is a -C 1-6 alk-heterocycloalkyl moiety
  • the heterocycloalkyl moiety is attached to the compound of formula I through an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms
  • the C 1-6 alk includes, for example, –CH 2 -, –CH(CH 3 ) -, -CH (CH 3 ) -CH 2 -, and –C (CH 3 ) 2 -.
  • the C 1-6 alk linker is substituted by oxo, e.g, -CH 2 -C (O) -.
  • R 2 is -C 0-1 alk-heterocycloalkyl, for example -C 0 alk-heterocycloalkyl (i.e., -heterocycloalkyl) or -C 1 alk-heterocycloalkyl (i.e., -CH 2 -heterocycloalkyl) .
  • the R 2 heterocycloalkyl moiety is a 3-, 4-, 5-, or 6-membered heterocycloalkyl, preferably a 5-or 6-membered heterocycloalkyl, with a 6-membered heterocycloalkyl being most preferred.
  • the heterocycloalkyl moiety can include one nitrogen atom, two nitrogen atoms, one nitrogen atom and one oxygen atom, or one oxygen atom.
  • Preferred one nitrogen-containing heterocycloalkyl groups for R 2 are piperidinyl; pyrrolidinyl; azetidinyl; azepanyl; aziridinyl; and quinuclidinyl, with piperidinyl and pyrrolidinyl being preferred and piperidinyl being more preferred.
  • Preferred two nitrogen-containing heterocycloalkyl groups for R 2 are imidazolidinyl and piperazinyl.
  • Preferred one nitrogen, one oxygen containing heterocycloalkyl groups for R 2 are oxazepanyl, with 1, 4-oxazepanyl being preferred; and morpholinyl.
  • Preferred one oxygen-containing heterocycloalkyl groups for R 2 are tetrahydropyranyl and tetrahydrofuranyl.
  • R 2 is –C 0-6 alk-piperidinyl, preferably –C 0 alk-piperidinyl or –C 1 alk-piperidinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-piperidinyl, preferably –C 0 alk-piperidinyl or –C 1 alk-piperidinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the piperidinyl ring. In preferred aspects, at least one substituent is attached through the piperidinyl nitrogen atom.
  • R 2 is –C 0-6 alk-pyrrolidinyl, preferably –C 0 alk-pyrrolidinyl or –C 1 alk-pyrrolidinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-pyrrolidinyl, preferably –C 0 alk-pyrrolidinyl or –C 1 alk-pyrrolidinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the pyrrolidinyl ring. In preferred aspects, at least one substituent is attached through the pyrrolidinyl nitrogen atom.
  • R 2 is –C 0-6 alk-oxazepanyl, preferably –C 0 alk-oxazepanyl or –C 1 alk-oxazepanyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-oxazepanyl, preferably –C 0 alk-oxazepanyl or –C 1 alk-oxazepanyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the oxazepanyl ring. In some aspects, at least one substituent is attached through the oxazepanyl nitrogen atom.
  • R 2 is –C 0-6 alk-azetidinyl, preferably –C 0 alk-azetidinyl or –C 1 alk-azetidinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-azetidinyl, preferably –C 0 alk-azetidinyl or –C 1 alk-azetidinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the azetidinyl ring. In some aspects, at least one substituent is attached through the azetidinyl nitrogen atom.
  • R 2 is –C 0-6 alk-azepanyl, preferably –C 0 alk-azepanyl or –C 1 alk-azepanyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-azepanyl, preferably –C 0 alk-azepanyl or –C 1 alk-azepanyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the azepanyl ring. In some aspects, at least one substituent is attached through the azepanyl nitrogen atom.
  • R 2 is –C 0-6 alk-aziridinyl, preferably –C 0 alk-aziridinyl or –C 1 alk-aziridinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-aziridinyl, preferably –C 0 alk-aziridinyl or –C 1 alk-aziridinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the aziridinyl ring. In some aspects, at least one substituent is attached through the azepanyl nitrogen atom.
  • R 2 is –C 0-6 alk-quinuclidinyl, preferably –C 0 alk-quinuclidinyl or –C 1 alk-quinuclidinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-quinuclidinyl, preferably –C 0 alk-quinuclidinyl or –C 1 alk-quinuclidinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the quinuclidinyl ring.
  • R 2 is –C 0-6 alk-imidazolidinyl, preferably –C 0 alk-imidazolidinyl or –C 1 alk-imidazolidinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-imidazolidinyl, preferably –C 0 alk-imidazolidinyl or –C 1 alk-imidazolidinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the imidazolidinyl ring. In some aspects, at least one substituent is attached through one of the imidazolidinyl nitrogen atoms.
  • R 2 is –C 0-6 alk-piperazinyl, preferably –C 0 alk-piperazinyl or –C 1 alk-piperazinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-piperazinyl, preferably –C 0 alk-piperazinyl or –C 1 alk-piperazinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the piperazinyl ring. In some aspects, at least one substituent is attached through one of the piperazinyl nitrogen atoms.
  • R 2 is –C 0-6 alk-morpholinyl, preferably –C 0 alk-morpholinyl or –C 1 alk-morpholinyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-morpholinyl, preferably –C 0 alk-morpholinyl or –C 1 alk-morpholinyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any position on the morpholinyl ring. In some aspects, at least one substituent is attached the morpholinyl nitrogen atom.
  • R 2 is –C 0-6 alk-tetrahydropyranyl, preferably –C 0 alk-tetrahydropyranyl or –C 1 alk-tetrahydropyranyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-tetrahydropyranyl, preferably –C 0 alk-tetrahydropyranyl or –C 1 alk-tetrahydropyranyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any carbon atom on the tetrahydropyranyl ring.
  • R 2 is –C 0-6 alk-tetrahydrofuranyl, preferably –C 0 alk-tetrahydrofuranyl or –C 1 alk-tetrahydrofuranyl, optionally substituted with 1, 2, or 3 substituents as recited herein.
  • R 2 is –C 0-6 alk-tetrahydrofuranyl, preferably –C 0 alk-tetrahydrofuranyl or –C 1 alk-tetrahydrofuranyl, substituted with 1 or 2 substituents as recited herein.
  • the substituents can be attached through any carbon atom on the tetrahydrofuranyl ring.
  • R 2 is piperidinyl, CH 2 CH 2 -piperidinyl, pyrrolidinyl, CH 2 -pyrrolidinyl, or CH 2 CH 2 -pyrrolidinyl.
  • R 2 is azetidinyl; azepanyl; quinuclidinyl; CH 2 CH 2 -imidazolidinyl; or CH 2 CH 2 -piperazinyl.
  • R 2 is tetrahydropyranyl or tetrahydrofuranyl, or CH 2 -tetrahydrofuranyl.
  • R 2 moiety can be defined as “Ring B. ”
  • R d is selected from the group consisting of: H, F, OH, and OCH 3 ; and R e is H or C 1-6 alkyl.
  • Ring B is selected from the group consisting of
  • R d is selected from the group consisting of: H, F, OH, and OCH 3 ;
  • R 6 and R 7 are each independently selected from the group consisting of: H, C 1-6 alkyl, C 3- 6 cycloalkyl, and CN; and R g is selected from the group consisting of: H, C 1-6 alkyl, and CN.
  • Ring B is selected from the group consisting of
  • R h is selected from the group consisting of: H, CN, CH 3 , and CH 2 phenyl.
  • Ring B is selected from the group consisting of
  • R 2 moiety can be defined as “Ring B. ”
  • Ring B is selected from the group consisting of
  • Ring B is selected from the group consisting of
  • R 2 moiety can be defined as “Ring B. ”
  • Ring B is selected from the group consisting of
  • Ring B is selected from the group consisting of
  • R 2 moiety can be defined as “Ring B. ”
  • Ring B is selected from the group consisting of
  • R d is H or OH.
  • the R 2 heterocycloalkyl is unsubstituted.
  • the R 2 heterocycloalkyl is substituted with 1, 2, or 3 substituents.
  • the R 2 heterocycloalkyl is substituted with 1 or 2 substituents, more preferably 1 substituent.
  • the substituents may be independently selected from the group consisting of
  • R 2 heterocycloalkyl is substituted, the substituents are preferably independently selected from the group consisting of
  • the R 2 heterocycloalkyl is substituted with an oxo moiety, for example one oxo moiety.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with a halogen, for example a fluorine or chlorine. In some aspects, the R 2 heterocycloalkyl is substituted with one or two halogens, preferably one halogen. In those aspects wherein the R 2 heterocycloalkyl is substituted with a halogen, the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –CN. In some aspects, the R 2 heterocycloalkyl is substituted with one or two -CN, preferably one -CN. In those aspects wherein the R 2 heterocycloalkyl is substituted with -CN, the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –OH. In some aspects, the R 2 heterocycloalkyl is substituted with one or two -OH, preferably one -OH. In those aspects wherein the R 2 heterocycloalkyl is substituted with -OH, the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –NR 6 R 7 wherein R 6 and R 7 are each independently H; -C 1-6 alkyl, -C 3-6 cycloalkyl; –C (O) H; or –CN. In preferred aspects, R 6 and R 7 are each independently H or -C 1-6 alkyl. In those aspects wherein the R 2 heterocycloalkyl is substituted with –NR 6 R 7 , the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two -C 1-6 alkyl, preferably one -C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C 1-6 alk-OH, for example, -C 1-5 alk-OH, -C 1-4 alk-OH, -C 1-3 alk-OH, -C 1-2 alk-OH, or -C 1 alk-OH, wherein the —OH moiety can be attached to any carbon of the –C 1-6 alk group, preferably the ⁇ carbon.
  • the R 2 heterocycloalkyl is substituted with one or two -C 1-6 alk-OH, preferably one -C 1-6 alk-OH.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -OC 1-6 alkyl, for example, -O-C 1-5 alkyl, -O-C 1-4 alkyl, -O-C 1-3 alkyl, -O-C 1-2 alkyl, or -O-C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two -OC 1-6 alkyl, preferably one -OC 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the R 2 heterocycloalkyl is substituted with one or two -C 3-6 cycloalkyl, preferably one -C 3-6 cycloalkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , –CH 2 CH 2 F, and the like.
  • the R 2 heterocycloalkyl is substituted with one or two -C 1-6 haloalkyl, preferably one -C 1-6 haloalkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C 1-6 alkaryl, for example, benzyl (i.e., -CH 2 -phenyl) .
  • the R 2 heterocycloalkyl is substituted with one or two -C 1-6 alkaryl, preferably one -C 1-6 alkaryl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -SO 2 C 1-6 alkyl, for example, -SO 2 -C 1-5 alkyl, -SO 2 -C 1-4 alkyl, -SO 2 -C 1-3 alkyl, -SO 2 -C 1-2 alkyl, or -SO 2 -C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two -SO 2 C 1-6 alkyl, preferably one -SO 2 C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -SO 2 C 2-6 alkenyl, for example, -SO 2 C 2-5 alkenyl, -SO 2 C 2-4 alkenyl, -SO 2 C 2-3 alkenyl, or -SO 2 C 2 alkenyl.
  • the R 2 heterocycloalkyl is substituted with one or two -SO 2 C 2-6 alkenyl, preferably one -SO 2 C 2-6 alkenyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) H. In some aspects, the R 2 heterocycloalkyl is substituted with one or two –C (O) H, preferably one –C (O) H. In those aspects wherein the R 2 heterocycloalkyl is substituted with –C (O) H, the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -C 1-6 alkyl, preferably one –C (O) -C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -C 3-6 cycloalkyl, for example, –C (O) -cyclopropyl, –C (O) -cyclobutyl, –C (O) -cyclopentyl, or –C (O) -cyclohexyl.
  • the R 2 heterocycloalkyl is substituted with one or two -–C (O) -C 3-6 cycloalkyl, preferably one -–C (O) -C 3-6 cycloalkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -C 1-6 haloalkyl, for example, –C (O) –C 1-5 haloalkyl, –C (O) –C 1-4 haloalkyl, –C (O) –C 1-3 haloalkyl, –C (O) –C 1-2 haloalkyl, or –C (O) –C 1 haloalkyl, including –C (O) –CF 3 , –C (O) –CH 2 CH 2 F, and the like.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -C 1-6 haloalkyl, preferably one –C (O) -C 1-6 haloalkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -C 2-6 alkynyl, for example, –C (O) -C 2-5 alkynyl, –C (O) -C 2-4 alkynyl, –C (O) -C 2-3 alkynyl, or –C (O) -C 2 alkynyl.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -C 2-6 alkynyl, preferably one -C (O) -C 2-6 alkynyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -C 6-10 aryl, for example, –C (O) -phenyl or –C (O) -napthalenyl.
  • the R 2 heterocycloalkyl is substituted with one or two ––C (O) -C 6-10 aryl, preferably one –C (O) -C 6-10 aryl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -heteroaryl, for example, –C (O) -pyrrolyl, –C (O) -thienyl, –C (O) -oxazolyl, –C (O) -pyrazolyl, –C (O) -pyridyl, –C (O) -pyrimidinyl, and the like.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -heteroaryl, preferably one –C (O) -heteroaryl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-CN, for example, -C (O) -C 1-5 alk-CN, -C (O) -C 1-4 alk-CN, -C (O) -C 1-3 alk-CN, -C (O) -C 1-2 alk-CN, or -C (O) -C 1 alk-CN.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -C 1-6 alk-CN, preferably one – (C (O) -C 1-6 alk-CN.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-OH, for example, -C (O) -C 1-5 alk-OH, -C (O) -C 1-4 alk-OH, -C (O) -C 1-3 alk-OH, -C (O) -C 1-2 alk-OH, or -C (O) -C 1 alk-OH.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -C 1-6 alk-OH, preferably one –C (O) -C 1-6 alk-OH.
  • the –OH moiety can be attached to any carbon of the –C 1-6 alk group, preferably the ⁇ carbon.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-SO 2 -C 1-6 alkyl, for example, -C (O) -C 1-5 alk-SO 2 -C 1-5 alkyl, -C (O) -C 1-4 alk-SO 2 -C 1-4 alkyl, -C (O) -C 1-3 alk-SO 2 -C 1-3 alkyl, -C (O) -C 1-2 alk-SO 2 -C 1-2 alkyl, or -C (O) -C 1 alk-SO 2 -C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two -C (O) -C 1-6 alk-SO 2 -C 1-6 alkyl, preferably one -C (O) -C 1-6 alk-SO 2 -C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with –C (O) -O-C 1-6 alkyl, for example, –C (O) -O-C 1-5 alkyl, –C (O) -O-C 1-4 alkyl, -–C (O) -O-C 1-3 alkyl, –C (O) -O-C 1-2 alkyl, or –C (O) -O-C 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two –C (O) -O-C 1-6 alkyl, preferably one -–C (O) -O-C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-NR 6 R 7 , for example, -C (O) -C 1-5 alk-NR 6 R 7 , -C (O) -C 1-4 alk-NR 6 R 7 , -C (O) -C 1-3 alk-NR 6 R 7 , -C (O) -C 1-2 alk-NR 6 R 7 , or -C (O) -C 1 alk-NR 6 R 7 , wherein R 6 and R 7 are each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R 6 and R 7 are each independently H, -C 1-6 alkyl; or -C 3-6 cycloalkyl, with H and -C 1-6 alkyl being preferred, and H and –C 1-2 alkyl being more preferred.
  • the R 2 heterocycloalkyl is substituted with one or two -C (O) -C 1-6 alk-NR 6 R 7 , preferably one -C (O) -C 1-6 alk-NR 6 R 7 .
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-O-C 1-6 alkyl, for example, -C (O) -C 1-5 alk-O-C 1-5 alkyl, -C (O) -C 1-4 alk-O-C 1-4 alkyl, -C (O) -C 1-3 alk-O-C 1-3 alkyl, -C (O) -C 1-2 alk-O-C 1-2 alkyl, or -C (O) -C 1 alk-O-C 1 alkyl.
  • the –C 1-6 alk- is optionally substituted with –OH; -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl; or -NR 6 R 7 (wherein R 6 and R 7 are each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; -C 3-6 cycloalkyl; –C (O) H; or –CN) .
  • R 6 and R 7 are each independently H, -C 1-6 alkyl; or -C 3-6 cycloalkyl, with H and -C 1-6 alkyl being preferred, and H and –C 1-2 alkyl being more preferred.
  • the –C 1-6 alk-of the -C (O) -C 1-6 alk-O-C 1-6 alkyl moiety is substituted with –OH.
  • the –C 1-6 alk- is substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the R 2 heterocycloalkyl is substituted with one or two -C (O) -C 1-6 alk-O-C 1-6 alkyl, preferably one -C (O) -C 1-6 alk-O-C 1-6 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 0-6 alk-heterocycloalkyl, for example, -C (O) -C 0-5 alk-heterocycloalkyl, -C (O) -C 0-4 alk-heterocycloalkyl, -C (O) -C 0-3 alk-heterocycloalkyl, -C (O) -C 0-2 alk-heterocycloalkyl, -C (O) -C 0-1 alk-heterocycloalkyl, -C (O) -C 1 alk-heterocycloalkyl, or -C (O) -C 0 alk-heterocycloalkyl.
  • -C (O) -C 0-6 alk-heterocycloalkyl for example, -C (O) -C 0-5 alk-heterocyclo
  • Preferred substituent heterocycloalkyl groups include tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and the like.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-heterocycloalkyl
  • the -C 1-6 alk- is optionally substituted with oxo.
  • the substituent heterocycloalkyl moiety can be unsubstituted or substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the R 2 heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • R 8 is H.
  • R 3 is H; -CN; halogen; -C 1-6 haloalkyl; or -C 1-6 alkyl.
  • R 3 is H.
  • R 3 is –CN. In still other aspects, R 3 is halogen, for example F or Cl. In yet other aspects, R 3 is -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, -C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , –CH 2 CH 2 F, and the like.
  • R 3 is -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • R 3 is H; -CN; halogen; -C 1-6 haloalkyl; or -C 1-6 alkyl.
  • R 3 is H.
  • R 3 is –CN.
  • R 3 is halogen, for example F or Cl.
  • R 3 is -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, -C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , –CH 2 CH 2 F, and the like.
  • R 3 is -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the heterocycloalkyl ring may optionally be substituted with one or two additional substituents as defined herein for the R 2 substituents.
  • the R 2 heterocycloalkyl is substituted with -C (O) -C 1-6 alk-NR 6 R 7 ; -C (O) -C 1-6 alkyl; or –NR 6 R 7 ; wherein R 6 and R 7 are each independently H or C 1-6 alkyl.
  • the R 2 is substituted with halogen; CN; OH; C 1-6 alkyl; C 1-6 haloalkyl; C 1- 6 alk-OH; OC 1-6 alkyl; C 3-6 cycloalkyl; NH 2 ; or C 1-2 alkaryl.
  • R 4 and R 5 are each independently H; halogen; -C 1-6 alkyl; -OC 1-6 alkyl; -C 0-6 alk-C 3-6 cycloalkyl optionally substituted with -C 1-6 alkyl; -C 1-6 alk-OH; -C 0-6 alk-NR 6 R 7 ;
  • -C 1-6 alk-O-C 1-6 alkyl -C 1-6 alk-NH-C 0-6 alk-O-C 1-6 alkyl; -C 0-6 alk-heterocycloalkyl optionally substituted with –C (O) C 1-6 alkyl or -C 1-6 alkyl; -C 1-6 alk-NHSO 2 -C 1-6 alkyl; -C 1-6 alk-SO 2 -C 1-6 alkyl;
  • neither R 4 nor R 5 is H.
  • each of R 4 and R 5 is H.
  • one of R 4 and R 5 is H. In certain of these aspects, the other of R 4 and R 5 is halogen, for example F or Cl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 0-6 alk-C 3-6 cycloalkyl, for example, -C 0-5 alk-C 3-5 cycloalkyl, -C 0-4 alk-C 3-4 cycloalkyl, -C 0-3 alk-C 3 cycloalkyl, -C 0-2 alk-C 3-6 cycloalkyl, -C 0-1 alk-C 3-6 cycloalkyl, –C 0 alk-C 3-6 cycloalkyl or –C 1 alk-C 3-6 cycloalkyl.
  • the cycloalkyl moiety can be unsubstituted or can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the substitution can be a spiro-substitution or a non-spiro-substitution.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 0-6 alk-heterocycloalkyl, for example, -C 1-6 alk-heterocycloalkyl, -C 0-4 alk-heterocycloalkyl, -C 0-3 alk-heterocycloalkyl, -C 0-2 alk-heterocycloalkyl, -C 0-1 alk-heterocycloalkyl, -C 1 alk-heterocycloalkyl, or -C 0 alk-heterocycloalkyl.
  • the substituent heterocycloalkyl is preferably an oxygen-containing heterocycloalkyl, for example, tetrahydropyranyl, tetrahydrofuranyl, or oxetanyl.
  • the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, for example, pyrrolidinyl, aziridinyl, or piperidinyl.
  • the substituent heterocycloalkyl can be substituted with –C (O) C 1-6 alkyl, for example, –C (O) C 1-5 alkyl, –C (O) C 1-4 alkyl, -C (O) C 1-3 alkyl, -C (O) C 1-2 alkyl, or -C (O) C 1 alkyl.
  • the substituent heterocycloalkyl can be substituted with –C 1-6 alkyl, for example, –C 1-5 alkyl, –C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alk-OH, for example, -C 1-5 alk-OH, -C 1-4 alk-OH, -C 1-3 alk-OH, -C 1-2 alk-OH, or -C 1 alk-OH.
  • the —OH moiety can be attached to any carbon of the –C 1-6 alk group, preferably the ⁇ carbon.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 0-6 alk-NR 6 R 7 , for example, -C 0-5 alk-NR 6 R 7 , -C 0-4 alk-NR 6 R 7 , -C 0-3 alk-NR 6 R 7 , -C 0-2 alk-NR 6 R 7 , -C 0-1 alk-NR 6 R 7 , C 1 alk-NR 6 R 7 , or -C 0 alk-NR 6 R 7 , wherein R 6 and R 7 are each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alk-NH-C 0-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-NH-C 0-6 alk-O-C 1-5 alkyl,
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alk-NHSO 2 -C 1-6 alkyl, for example, -C 1-5 alk-NHSO 2 -C 1-5 alkyl -C 1-4 alk-NHSO 2 -C 1-4 alkyl, -C 1-3 alk-NHSO 2 -C 1-3 alkyl, -C 1-2 alk-NHSO 2 -C 1-2 alkyl, or -C 1 alk-NHSO 2 -C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -C 1-6 alk-SO 2 -C 1-6 alkyl, for example, -C 1-5 alk-SO 2 -C 1-5 alkyl, -C 1-4 alk-SO 2 -C 1-4 alkyl, -C 1-3 alk-SO 2 -C 1-3 alkyl, -C 1-2 alk-SO 2 -C 1-2 alkyl, or -C 1 alk-SO 2 -C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is -NHC (O) -C 1-6 alkyl, for example, -NHC (O) -C 1-5 alkyl, -NHC (O) -C 1-4 alkyl, -NHC (O) -C 1-3 alkyl, -NHC (O) -C 1-2 alkyl, or -NHC (O) -C 1 alkyl.
  • one of R 4 and R 5 is H.
  • the other of R 4 and R 5 is linker-PEG-Biotin, preferably
  • one of R 4 and R 5 is H and the other of R 4 and R 5 is C 1-6 alkyl (e.g., methyl, t-butyl) ; cycloalkyl (e.g., cyclopropyl) ; -C 1-6 alk-NR 6 R 7 (e.g., -CH 2 -NH 2 , -CH 2 -NHCH 3 , -CH 2 -N (CH 3 ) 2 , -C (CH 3 ) 2 -NH 2 , -C (CH 3 ) 2 -NHCH 3 , -C (CH 3 ) 2 -N (CH 3 ) 2 ; -C1-6alk-O-C1-6alkyl (e.g., -C (CH 3 ) 2 -OCH 3 , -C (CH 3 ) 2 -OCH 2 CH 3 ) ; -C 0-6 alk-heterocycloalkyl substituted with -C 1-6 alkyl (
  • a preferred subgenus of formula I is:
  • piperidinyl ring is substituted at the ring nitrogen with any 1 or 2 of the R 2 substituents defined herein.
  • Additional embodiments of the disclosure include compounds of Formula (I) having the subgenera of Formula (I-B-1) and Formula (I-B-2) :
  • A can be a bond. Also within the scope of the disclosure, A can be pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzo [d] [1, 3] dioxolyl optionally substituted with halogen, preferably F; benzothiophenyl; or pyrazolyl. Also within the scope of the disclosure, A can be pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzothiophenyl; or pyrazolyl.
  • any of the A moieties can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; halogen, for example F or Cl; -SF 5 ; -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl; -C (O) -C 1-6 alkyl, for example, -C (O) -C 1- 5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl,
  • A is pyridyl.
  • the pyridyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom, but preferably it attached through the 2-or 3-position carbon.
  • the pyridyl is substituted with one or two substituents, preferably one substituent.
  • the pyridyl substituent can be attached to any ring carbon atom of the pyridyl ring. In those embodiments wherein the pyridyl is attached to the compound of formula I through the 3-position carbon, the substituent is preferably attached to the pyridyl at the 2-or 4-position.
  • the pyridyl can be substituted at any available ring carbon atom with -C 1- 6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the pyridyl can be substituted at any available ring carbon atom with -SF 5 .
  • the pyridyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyridyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the pyridyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • Preferred substituents wherein A is pyridyl include -C 1-6 alkyl, with -C 1 alkyl being most preferred, and with one –C 1 alkyl substituent being more preferred.
  • Other preferred substituents include halogen, in particular F and Cl.
  • A is phenyl.
  • the phenyl is substituted with one or two substituents, preferably one substituent.
  • the phenyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the phenyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the phenyl can be substituted at any available ring carbon atom with -SF 5 .
  • the phenyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the phenyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the phenyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • the phenyl’s substituent can be attached to any ring carbon atom of the phenyl ring, preferably ortho to the phenyl moiety’s point of attachment to the compound of formula I.
  • Preferred substituents wherein A is phenyl include -C 1-6 alkyl, with -C 1 alkyl being most preferred.
  • Other preferred substituents include halogen, in particular F and Cl.
  • A is napthalenyl.
  • the napthalenyl is substituted with one or two substituents, preferably one substituent.
  • the napthalenyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the napthalenyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the napthalenyl can be substituted at any available ring carbon atom with -SF 5 .
  • the napthalenyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the napthalenyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the napthalenyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • the napthalenyl can be attached through any of its carbon atoms to the compound of formula I.
  • the napthalenyl substituent can be attached to any ring carbon atom of the napthalenyl ring, preferably ortho to the napthalenyl moiety’s point of attachment to the compound of formula I.
  • Preferred substituents wherein A is napthalenyl include -C 1-6 alkyl, with -C 1 alkyl being most preferred.
  • Other preferred substituents include halogen, in particular F and Cl.
  • A is pyrimidinyl.
  • the pyrimidinyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom through any ring carbon atom.
  • the pyrimidinyl is substituted with one or two substituents, preferably one substituent.
  • the pyrimidinyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyrimidinyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the pyrimidinyl can be substituted at any available ring carbon atom with -SF 5 .
  • the pyrimidinyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyrimidinyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the pyrimidinyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • Preferred substituents wherein A is pyrimidinyl include -C 1-6 alkyl, with -C 1 alkyl being most preferred. Other preferred substituents include halogen, in particular F and Cl.
  • A is pyrazinyl.
  • the pyrazinyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom.
  • the pyrazinyl is substituted with one or two substituents, preferably one substituent.
  • the pyrazinyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyrazinyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the pyrazinyl can be substituted at any available ring carbon atom with -SF 5 .
  • the pyrazinyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyrazinyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the pyrazinyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • Preferred substituents wherein A is pyrazinyl include -C 1-6 alkyl, with - C 1 alkyl being most preferred.
  • Other preferred substituents include halogen, in particular F and Cl.
  • A is pyridazinyl.
  • the pyridazinyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom.
  • the pyridazinyl is substituted with one or two substituents, preferably one substituent.
  • the pyridazinyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridazinyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the pyridazinyl can be substituted at any available ring carbon atom with -SF 5 .
  • the pyridazinyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyridazinyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1- 3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the pyridazinyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • Preferred substituents wherein A is pyridazinyl include -C 1-6 alkyl, with -C 1 alkyl being most preferred. Other preferred substituents include halogen, in particular F and Cl.
  • A is benzo [d] [1, 3] dioxolyl.
  • the benzo [d] [1, 3] dioxolyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom.
  • the benzo [d] [1, 3] dioxolyl can be unsubstituted or can be substituted with one or two halogen, preferably F.
  • the benzo [d] [1, 3] dioxolyl is substituted with one or two other substituents.
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with -SF 5 .
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the benzo [d] [1, 3] dioxolyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • A is benzothiophenyl.
  • the benzothiophenyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom.
  • the benzothiophenyl is substituted with one or two substituents, preferably one substituent.
  • the benzothiophenyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the benzothiophenyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the benzothiophenyl can be substituted at any available ring carbon atom with -SF 5 .
  • the benzothiophenyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the benzothiophenyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the benzothiophenyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • A is pyrazolyl.
  • the pyrazolyl can be attached to any of the compounds of formula I (or its subgenera) through any ring carbon atom.
  • the pyrazolyl is substituted with one or two substituents, preferably one substituent.
  • the pyrazolyl can be substituted at any available ring carbon atom with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyrazolyl can be substituted at any available ring carbon atom with halogen, for example F or Cl.
  • the pyrazolyl can be substituted at any available ring carbon atom with -SF 5 .
  • the pyrazolyl can be substituted at any available ring carbon atom with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyrazolyl can be substituted at any available ring carbon atom with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-5 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • the pyrazolyl can be substituted at any available ring carbon atom with -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , CH 2 CH 2 F, and the like.
  • A is an unsubstituted or substituted phenyl, pyridyl, pyrimidyl, or pyrazinyl moiety, with pyridinyl being particularly preferred.
  • the preferred substituents include –C 1-6 alkyl (e.g., methyl) and halogen (e.g., F or Cl) , with methyl being particularly preferred.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-D) :
  • phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-E) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-F) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • E is –O-; a bond; -C (O) -NH-; -CH 2 -; or -CH 2 -O-.
  • the E moiety can be attached through any available carbon atom on the A moiety.
  • the E moiety can also be attached through any available carbon atom on the G moiety.
  • E is –O-. In other preferred aspects, E is a bond.
  • E is -C (O) -NH-, wherein the A-E-G moiety is A-C (O) -NH-G.
  • E is -CH 2 -.
  • E is -CH 2 -O-, wherein the A-E-G moiety is A-CH 2 -O-G.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-G-1) :
  • phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-G-2) :
  • phenyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-H-1) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-H-2) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-J-1) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • Additional embodiments of the disclosure are compounds of Formula (I) having the subgenera of Formula (I-J-2) :
  • pyridyl moiety can be unsubstituted or substituted with 1 or 2 substituents at any available carbon atom.
  • G is H; -C 3-6 cycloalkyl; -phenyl; -thiophenyl; -C 1-6 alkyl; -pyrimidinyl; -pyridyl; -pyridazinyl; -benzofuranyl; -C 1-6 haloalkyl; -heterocycloalkyl that contains an oxygen heteroatom; -phenyl-CH 2 -O-phenyl; -C 1-6 alk-O-C 1-6 alkyl; -NR 6 R 7 ; -SO 2 C 1-6 alkyl; or –OH; wherein the phenyl; pyridyl; pyridazinyl; pyrimidinyl; benzofuranyl; or thiophenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl;
  • G is H.
  • G is -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • G is -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 lkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • G is -C 1-6 haloalkyl, for example, –C 1-5 haloalkyl, –C 1-4 haloalkyl, –C 1-3 haloalkyl, –C 1-2 haloalkyl, or –C 1 haloalkyl, including –CF 3 , –CH 2 CH 2 F, and the like.
  • G is a -heterocycloalkyl that contains an oxygen heteroatom, for example, tetrahydropyranyl, tetrahydrofuranyl, or oxetanyl.
  • G is -phenyl-CH 2 -O-phenyl.
  • the -phenyl-CH 2 -O-phenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with halogen, for example F or Cl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with –CN.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with –OH.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1- 4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the one or both of the phenyl rings of the -phenyl-CH 2 -O-phenyl moiety can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or-C (O) -C 1 alkyl.
  • G is -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • G is -NR 6 R 7 , wherein R 6 and R 7 are each independently H; -C 1-6 alkyl;-C 3-6 cycloalkyl; –C (O) H, or –CN.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • G is -SO 2 C 1-6 alkyl, for example, -SO 2 C 1-5 alkyl, -SO 2 C 1-4 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 1-2 alkyl, or -SO 2 C 1 alkyl.
  • G is —OH.
  • G is phenyl.
  • the phenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the phenyl can be substituted with halogen, for example F or Cl.
  • the phenyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the phenyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the phenyl can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the phenyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the phenyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the phenyl can be substituted with –CN.
  • the phenyl can be substituted with –OH.
  • the phenyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the phenyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohe
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the phenyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is pyridyl.
  • the pyridyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the pyridyl can be substituted with halogen, for example F or Cl.
  • the pyridyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the pyridyl can be substituted with -OC 1- 6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the pyridyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the pyridyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyridyl can be substituted with –CN.
  • the pyridyl can be substituted with –OH.
  • the pyridyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the pyridyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cycl
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is pyridazinyl.
  • the pyridazinyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the pyridazinyl can be substituted with halogen, for example F or Cl.
  • the pyridazinyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridazinyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the pyridazinyl can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the pyridazinyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the pyridazinyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyridazinyl can be substituted with –CN.
  • the pyridazinyl can be substituted with –OH.
  • the pyridazinyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the pyridazinyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyridazinyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is pyrimidinyl.
  • the pyrimidinyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the pyrimidinyl can be substituted with halogen, for example F or Cl.
  • the pyrimidinyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyrimidinyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the pyrimidinyl can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the pyrimidinyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the pyrimidinyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the pyrimidinyl can be substituted with –CN.
  • the pyrimidinyl can be substituted with –OH.
  • the pyrimidinyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the pyrimidinyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cycl
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the pyrimidinyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is benzofuranyl.
  • the benzofuranyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the benzofuranyl can be substituted with halogen, for example F or Cl.
  • the benzofuranyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the benzofuranyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the benzofuranyl can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the benzofuranyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the benzofuranyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the benzofuranyl can be substituted with –CN.
  • the benzofuranyl can be substituted with –OH.
  • the benzofuranyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the benzofuranyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclo
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the benzofuranyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is thiophenyl.
  • the thiophenyl can be unsubstituted or substituted with 1, 2, or 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of halogen; -C 1-6 alkyl; -C 1-6 haloalkyl; -OC 1-6 haloalkyl; -C 3-6 cycloalkyl; -OC 1-6 alkyl; -CN; -OH; -C 1-6 alk-O-C 1-6 alkyl; -C (O) -NR 6 R 7 (wherein R 6 and R 7 are as previously described herein) ; and -C (O) -C 1-6 alkyl.
  • the thiophenyl can be substituted with halogen, for example F or Cl.
  • the thiophenyl can be substituted with -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the thiophenyl can be substituted with -C 1-6 haloalkyl, for example, -C 1-5 haloalkyl, -C 1-4 haloalkyl, -C 1-3 haloalkyl, -C 1-2 haloalkyl, or -C 1 haloalkyl.
  • the thiophenyl can be substituted with -OC 1-6 haloalkyl, for example, -OC 1-5 haloalkyl, -OC 1-4 haloalkyl, -OC 1-3 haloalkyl, -OC 1-2 haloalkyl, or -OC 1 haloalkyl.
  • the thiophenyl can be substituted with -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the thiophenyl can be substituted with -OC 1-6 alkyl, for example, -OC 1-5 alkyl, -OC 1-4 alkyl, -OC 1-3 alkyl, -OC 1-2 alkyl, or -OC 1 alkyl.
  • the thiophenyl can be substituted with –CN.
  • the thiophenyl can be substituted with –OH.
  • the thiophenyl can be substituted with -C 1-6 alk-O-C 1-6 alkyl, for example, -C 1-5 alk-O-C 1-5 alkyl, -C 1-4 alk-O-C 1-4 alkyl, -C 1-3 alk-O-C 1-3 alkyl, -C 1-2 alk-O-C 1-2 alkyl, or -C 1 alk-O-C 1 alkyl.
  • the thiophenyl can be substituted with -C (O) -NR 6 R 7 , wherein R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 and R 7 are preferably each independently H; -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl; or -C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cycl
  • R 6 and R 7 are each independently H or -C 1-6 alkyl, for example, -C 1-5 alkyl, -C 1-4 alkyl, -C 1-3 alkyl, -C 1-2 alkyl, or -C 1 alkyl.
  • the thiophenyl can be substituted with -C (O) -C 1-6 alkyl, for example, -C (O) -C 1-65 alkyl, -C (O) -C 1-4 alkyl, -C (O) -C 1-3 alkyl, -C (O) -C 1-2 alkyl, or -C (O) -C 1 alkyl.
  • G is unsubstituted or substituted phenyl, pyridyl, pyridizinyl, or pyrazinyl.
  • preferred substituents include C 1-6 alkyl (e.g., methyl) .
  • G is C 1-6 alkyl (e.g., -isopropyl) .
  • G is unsubstituted or substituted phenyl, pyridyl, pyridizinyl, or pyrazinyl and E is –CH 2 -or O.
  • preferred substituents include C 1-6 alkyl (e.g., methyl) .
  • G is C 1-6 alkyl (e.g., -isopropyl) and E is –CH 2 -or O.
  • G-A is selected from the group consisting of
  • G is phenyl; or phenyl substituted with one or two members independently selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, pyridyl, oxetan-3-yl, and tetrahydro-2H-pyran-4-yl; and R a is H or CH 3 .
  • G-A is phenyl; or phenyl substituted with one or two members independently selected from the group consisting of: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, pyridyl, oxetan-3-yl, and tetrahydro-2H-pyran-4-yl; and R a is H or CH 3 .
  • G-A is
  • G is phenyl, or phenyl substituted with C 1-6 alkyl.
  • G-E-A is selected from the group consisting of:
  • G is selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, tetrahydro-2H-pyran-4-yl, pyridazin-3-yl, phenyl, and phenyl substituted with F; and R a is H or CH 3 .
  • G-E-A is R a is CH 3 ; and G is phenyl.
  • Preferred subgenera of formula I include:
  • a phenyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • a pyridyl is unsubstituted or substituted, preferably with –C 1-6 alkyl.
  • R a is H or CH 3 ; n is 1; E is O; G is phenyl or phenyl substituted with C 1-6 alkyl;
  • G-A is G is phenyl, or phenyl substituted with C 1- 6 alkyl;
  • Ring B is:
  • G-E-A is R a is CH 3 ;
  • G is phenyl;
  • a further embodiment of the present disclosure is a compound selected from the group consisting of:

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Abstract

La présente invention concerne des composés de formule I' et leurs procédés d'utilisation et de préparation, ainsi que des compositions comprenant des composés de formule I'.
PCT/CN2016/109134 2016-12-09 2016-12-09 Inhibiteurs de tyrosine kinase de bruton et leurs procédés d'utilisation Ceased WO2018103058A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10689396B2 (en) 2015-12-10 2020-06-23 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and methods of their use
US10717745B2 (en) 2015-12-10 2020-07-21 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and method of their use
WO2021043200A1 (fr) * 2019-09-04 2021-03-11 正大天晴药业集团股份有限公司 Procédé de préparation d'un dérivé de quinazoline et cristallisation de ce dernier

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092879A2 (fr) * 2006-02-08 2007-08-16 Janssen Pharmaceutica, N.V. Inhibiteurs de kinase thiatriazaacénaphthylène-6-carbonirile substitués
CN101056639A (zh) * 2004-09-15 2007-10-17 詹森药业有限公司 噻唑并吡啶激酶抑制剂
CN105026400A (zh) * 2013-03-15 2015-11-04 詹森药业有限公司 用于制备药物的方法和中间体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101056639A (zh) * 2004-09-15 2007-10-17 詹森药业有限公司 噻唑并吡啶激酶抑制剂
WO2007092879A2 (fr) * 2006-02-08 2007-08-16 Janssen Pharmaceutica, N.V. Inhibiteurs de kinase thiatriazaacénaphthylène-6-carbonirile substitués
CN105026400A (zh) * 2013-03-15 2015-11-04 詹森药业有限公司 用于制备药物的方法和中间体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THOMAS P. SELBY: "Synthesis of a Novel Thiadiazacyclazine", JOURNAL OF ORGANIC CHEMISTRY, vol. 53, no. 10, 31 December 1988 (1988-12-31), pages 2386 - 2388, XP055509093 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10689396B2 (en) 2015-12-10 2020-06-23 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and methods of their use
US10717745B2 (en) 2015-12-10 2020-07-21 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and method of their use
US10800792B2 (en) 2015-12-10 2020-10-13 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and method of their use
US10822348B2 (en) 2015-12-10 2020-11-03 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and methods of their use
US10934310B2 (en) 2015-12-10 2021-03-02 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and method of their use
US11319329B2 (en) 2015-12-10 2022-05-03 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and methods of their use
US12065446B2 (en) 2015-12-10 2024-08-20 Janssen Pharmaceutica Nv Inhibitors of Bruton's tyrosine kinase and method of their use
WO2021043200A1 (fr) * 2019-09-04 2021-03-11 正大天晴药业集团股份有限公司 Procédé de préparation d'un dérivé de quinazoline et cristallisation de ce dernier

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