WO2012174312A2 - Dérivés de benzimidazole en tant qu'agents antiviraux - Google Patents

Dérivés de benzimidazole en tant qu'agents antiviraux Download PDF

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WO2012174312A2
WO2012174312A2 PCT/US2012/042558 US2012042558W WO2012174312A2 WO 2012174312 A2 WO2012174312 A2 WO 2012174312A2 US 2012042558 W US2012042558 W US 2012042558W WO 2012174312 A2 WO2012174312 A2 WO 2012174312A2
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group
butyl
hydrogen
nitrile
methyl
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PCT/US2012/042558
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WO2012174312A3 (fr
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Janos Botyanszki
Scott Howard Dickerson
Martin Robert Leivers
Xiaofei Li
Robert Blount Mcfadyen
Aniko Maria REDMAN
John Bradford SHOTWELL
Jianjun Xue
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Glaxosmithkline Llc
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Publication of WO2012174312A2 publication Critical patent/WO2012174312A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • HCV hepatitis C virus
  • HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans.
  • the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ⁇ 3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
  • the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
  • HCV polyprotein The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b- NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
  • HCV is major causative agent for post-transfusion and for sporadic hepatitis.
  • Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
  • An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, ef a/. , Pathol. Oncol. Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S.
  • In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV- related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
  • IFN- alpha interferon alpha
  • ribavirin the standard treatment for chronic HCV.
  • IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
  • IFN-alpha is an important regulator of growth and differentiation affecting cellular
  • HCV Hastolic hypertension
  • interferon Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune
  • Ribavirin an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV.
  • IFN interferon-alpha
  • ribavirin standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN-alpha plus ribavirin.
  • a number of patients still have significant side effects, primarily related to ribavirin.
  • Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.
  • a number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
  • the viral targets the NS3/4a protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in
  • antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
  • antiviral activity can be achieved by inhibiting host cell cyclophilins.
  • a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans.
  • Flaviviridae family of viruses and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (C C 6 )alkylene;
  • X is selected from the group consisting of hydrogen, (CrC 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 14 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 1 (R 6 ) n , -NHSO 2 R 10 (R 6 ) n ,
  • R 1 is selected from the group consisting of hydrogen, -R 5 R 14 , -C(0)R 9 , -R 5 R 10 ,
  • R 2 is selected from the group consisting of hydrogen, , halo, (d-C 6 )alkyl, (C
  • fused heterocyclic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 3 is selected from the group consisting of hydrogen, nitrile, halo, and (Ci-C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, (C CeJalkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) n , -OR 7 , -R 2 , and halo;
  • R 5 is a branched or straight chain (d-CeJalkylene
  • R 6 is independently selected from the group consisting of ⁇ C ⁇ rC 6 )a ⁇ ky ⁇ , oxo, (C
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (Ci-C 7 )alkyl, -R 10 ,
  • R 9 is (Ci-C 7 )alkyl
  • R 1 is selected from the group consisting of nitrile, halo, (Ci-C 6 )alkyl, (CrC 6 )alkoxy, and -R 14 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 3 is (C 3 -C 12 )cycloalkyl
  • R 14 is selected from (Ci-C jheterocycle or (CVCi heteroaryl, each having one to three heteroatoms selected from S, N and O;
  • R 15 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any of Formulas I, II , III, IV, V, or a pharmaceutically acceptable salt or solvate thereof.
  • a method for treating a viral infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to said patient a composition comprising a compound of any of Formulas I, II, III, IV, V, or a pharmaceutically acceptable salt or solvate thereof.
  • the viral infection is mediated by hepatitis C virus.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C x .C y )alkyl refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH2-), n-propyl
  • Alkylidene or “alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u . v )alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups.
  • (Ci_ 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methypropylene, pentylene, and so forth.
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, and n-pentoxy.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-.
  • Acyl includes the "acetyl” group CH 3 C(0)-.
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)cycloalkyl,
  • R 20 is hydrogen or alkyl
  • Acyloxy refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-, alkynyl-C(0)0-, aryl-C(0)0-, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-.
  • Amino refers to the group -NR 21 R 22 where R 2 and R 22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, -S0 2 -alkyl, -S0 2 -alkenyl, -S0 2 -cycloalkyl, -S0 2 -aryl, -S0 2 -heteroaryl, and -S0 2 -heterocyclic, and wherein R 2 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 2 is hydrogen and R 22 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl, the amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 21 nor R 22 are hydrogen.
  • Hydroxyamino refers to the group -NHOH.
  • Alkoxyamino refers to the group -NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group -C(0)NR 6 R 27 where R 26 and R 27 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R 26 and R 27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • Aryl refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl).
  • a single ring e.g., phenyl
  • multiple condensed (fused) rings e.g. , naphthyl or anthryl.
  • Aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8
  • tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Cycloalkyi refers to a saturated or partially saturated cyclic group of from 3 to
  • cycloalkyi 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyi applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5-yl and 2,3- dihydro-1 H-inden-1-yl).
  • cycloalkyi includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyi groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • Examples of cycloalkyi groups that include multiple bicycloalkyi ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, dihydroindenyl, and the like. Two such bicycloalkyi multiple ring structures are exem lified and named below:
  • (C u .C v )cycloalkyl refers to cycloalkyi groups having u to v carbon atoms.
  • Spiro cycloalkyi refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyi group:
  • Fused cycloalkyi refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyi group:
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl,
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g.
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2- pyrrolidon-1 -yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (e.g. , C3-C10) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetra
  • fused heterocyclic refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Oxazolidinone refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains two carbons and is substituted at one of the two carbons by a carbonyl group as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Pyrrolidione refers to a 5-membered heterocyclic ring containing one nitrogen as a heteroatom and also contains three carbons and is substituted at one of the three carbons by a carbonyl group as exemplified by any of the following structures, wherein the pyrrolidione group exemplified here is bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formula I, II, III, IV or V, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and
  • salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.
  • Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1 ) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)-.
  • C(R X ) 2 it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as -R x R y , where the "-" indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (Ci- C 6 )alkylene;
  • X is selected from the group consisting of hydrogen, (CrC 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 14 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 14 (R 6 ) n , -NHSO 2 R 10 (R 6 ) n ,
  • R 1 is selected from the group consisting of hydrogen, -R R 14 , -C(0)R 9 , -R 5 R 10 ,
  • R 2 is selected from the group consisting of hydrogen, , halo, (Ci-C 6 )alkyl, (C C 6 )alkoxy, nitrile, oxo, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 5 R 1 (R 6 ) W , -R 10 R 5 R 14 , -R 2 , - R 14 , -R 10 R 6 , -R 10 (R 6 )n, -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R , -R 3 R 14 , -R 9 R 10 , - R 10 R 14 , -(R 4 R 12 ), -R 13 R 6 , -R 14 R 6 , -C0 2 R 7 , (C 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein A and Q are independently chosen from
  • fused heterocyclic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 3 is selected from the group consisting of hydrogen, nitrile, halo, and (C C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (d-CeJalkyl, (CVCe alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) N , -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (Ci-C 6 )alkylene
  • R 6 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, (C r
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (Ci-C 7 )alkyl, -R 0 ,
  • R 9 is (Ci-C 7 )alkyl
  • R 1 is selected from the group consisting of nitrile, halo, (Ci-C 6 )alkyl, (CrC 6 )alkoxy, and -R 14 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -C 12 )cycloalkyl
  • R 4 is selected from (Ci-Cn)heterocycle or (Ci-Cn)heteroaryl, each having one to three heteroatoms selected from S, N and O;
  • R 5 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3; and each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R 1 is selected from the group consisting of hydrogen, -R 5 R 14 , -R 5 R 10 , -C(0)R 10 ,
  • -C(0)R 14 and -C(0)R 9 ; selected from the group consisting of hydrogen, , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 0 R 5 R 14 , -R 12 , -R 4 , -(R 1 ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 13 R 14 , -R 10 R 14 , -R 3 R 6 , - R 1 R 6 , -(R 14 R 12 ), cyclopentyl,
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl;
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 11 ) M , -R 5 R 14 , and -
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 1 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 14 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 5 is selected from the group consisting of fluoro, chloro, and iodo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is a bond or methylene
  • X is selected from the group consisting of hydrogen, (Ci-C 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 4 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 1 (R 6 ) n , -NHSO 2 R 0 (R 6 ) n ,
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, , halo, (d-C 6 )alkyl, (C C 6 )alkoxy, nitrile, oxo, hydroxyl, -NH R 5 R 14 , -OR 7 , -R R 14 (R 6 ) W , -R 10 R 5 R 14 , -R 12 , - R 14 , -R 0 R 6 , -R 0 (R 6 )n, -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 13 R 14 , -R 9 R 10 , - R i o R i4 .( ⁇ R ⁇ _ R 13 R 6 _ R i R e (c 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein A and Q are independently chosen from -(CH 2 ) W R 10
  • fused heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 3 is selected from the group consisting of hydrogen, halo, and (C 1 -C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (CrC 6 )alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 5 )n, -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (CrC 6 )alkylene
  • R 6 is independently selected from the group consisting of (CrC 6 )alkyl, oxo, (Cr
  • R 7 is selected from the group consisting of hydrogen and (CrC 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (CrC 7 )alkyl, -R 0 ,
  • R 9 is (d-CyJalkyl
  • R 0 is (C 4 -C 14 )aryl
  • R 11 is selected from the group consisting of nitrile, halo, (CrC 6 )alkyl, (Ci-C 6 )alkoxy, and -R 14 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -Ci 2 )cycloalkyl
  • R 4 is selected from (Ci-Cn)heterocycle or (d-di)heteroaryl, each having one to three heteroatoms selected from N and O;
  • R 15 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen, , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 12 , -R 14 , -(R 14 ) 2 , -
  • R 14 R 6 -(R 14 R 12 ), cyclopentyl, dihydroindenyl, and phenyl, wherein A and Q are independently chosen from -(CH 2 ) W R 1Q or -(CH 2 ) w R 14 ;
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 0 (R 1 and -R 5 R 0 (R 1 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, hexyl, heptyl, neopentyl, dimethylbutanyl, and dimethylpentanyl;
  • R 0 is phenyl;
  • R 1 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 14 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is a bond or methylene
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 2 , -R 14 , -(R 14 ) 2 , -S0 2 R 10 , - S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 3 R 14 , -R 10 R 14 , -R 13 R 6 , -R 14 R 6 , - (R 14 R 12 ), cyclopentyl, dihydroindenyl, and phenyl;
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl;
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 11 ) M , and -R 5 R 0 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 0 is phenyl
  • R 1 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, and
  • R 2 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 14 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 5 is selected from the group consisting of fluoro, chloro, and iodo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 12 , -R 4 , -(R 14 ) 2 , -S0 2 R 10 , - S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 0 R 6 , -R 3 R 14 , -R 10 R 14 , -R 13 R 6 , -R 14 R 6 , - (R 14 R 12 ), cyclopentyl, dihydroindenyl, and phenyl;
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 0 (R 11 ) , and -R 5 R 10 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, and
  • R 2 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (C-i- C 6 )alkylene;
  • X is selected from the group consisting of hydrogen, (d-C 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 1 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 14 (R 6 ) n , -NHSO 2 R 10 (R 6 ) lake,
  • R is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen,
  • fused heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 4 is selected from the group consisting of hydrogen, (d-C 6 )alkyl, (d-C 6 )alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) lake, -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (CrC 6 )alkylene
  • R 6 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, (d-
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (Ci-C 7 )alkyl, -R 10 ,
  • R 9 is (d-d)alkyl
  • R 0 is (d-C 14 )aryl; selected from the group consisting of nitrile, halo, (Ci-C 6 )alkyl, (CrC 6 )alkoxy, and
  • R 2 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 3 is (C 3 -Ci 2 )cycloalkyl
  • R 14 is selected from (CrCn)heterocycle or (d-CuJheteroaryl, each having one to three heteroatoms selected from N and O;
  • R 5 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen, , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 12 , -R 14 , -(R 14 ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 3 R 14 , -R 0 R 14 , -R 13 R 6 , - R 14 R 6 , -(R 14 R
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 1 ) Ml and -R 5 R 0 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 4 R 12 ;
  • R 2 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 14 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (d- C 6 )alkylene;
  • X is selected from the group consisting of hydrogen, (CrC 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 14 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 1 (R 6 ) n , -NHSO 2 R 0 (R 6 ) n ,
  • R is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, , halo, (Ci-C 6 )alkyl, (d- C 6 )alkoxy, nitrile, oxo, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 5 R (R 6 ) W , -R 10 R 5 R 14 , -R 12 , - R 14 , -R 0 R 6 , -R 0 (R 6 ) n , -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 13 R 14 , -R 9 R 1 °, - R 0 R 14 , -(R 4 R 12 ), -R 13 R 6 , -R 1 R 6 , -C0 2 R 7 , (C 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein
  • fused heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 3 is selected from the group consisting of hydrogen, halo, and (C C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (CrC 6 )alkyl, (CrC 6 )alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) n , -OR 7 , and -R 12 ;
  • R 5 is a branched or straight chain (Ci-C 6 )alkylene
  • R 6 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, (Ci-
  • R 7 is selected from the group consisting of hydrogen and (C ⁇ CeJalkyl
  • R 8 is independently selected from the group consisting of hydrogen, (Ci-C 7 )alkyl, -R 0 ,
  • R is (Ci-C 7 )alkyl
  • R 10 is (C 4 -C 14 )aryl
  • R 1 is selected from the group consisting of nitriie, halo, (d-C ⁇ alky!, (d-C 6 )alkoxy, and
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -C 12 )cycloalkyl
  • R 14 is selected from (d-CuJheterocycle or (Ci-C )heteroaryl, each having one to three heteroatoms selected from N and O;
  • R 15 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of hydrogen, methoxy, nitriie, -C(0)R 12 ,
  • R is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ;
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, and trifluoromethyl;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 11 ) M , and -R 5 R 10 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 1 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 4 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 14 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (C r
  • X is selected from the group consisting of -R 0 , -R 10 (R 6 ) n , -R 13 , -R 14 , -R 5 R 14 , -R 9 (R 6 ) n , - R 9 , and -R 1 (R 6 ) n ;
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, , halo, (C C 6 )alkyl, (C r C 6 )alkoxy, nitrile, oxo, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 5 R 4 (R 6 ) W , -R 0 R 5 R 14 , -R 12 , - R 14 , -R 0 R 6 , -R 10 (R 6 ) n , -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 13 R 14 , -R 9 R 10 , - R 10 R 14 , -(R 14 R 12 ), -R 13 R 6 , -R 14 R 6 , -C0 2 R 7 , (C 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein A and
  • R 3 is selected from the group consisting of hydrogen, halo, and (d-C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (CrC 6 )alkyl, (CrC 6 )alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 5 )n, -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (Ci-C 6 )alkylene
  • R 6 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, (C-p
  • R 7 is selected from the group consisting of hydrogen and (C C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (C C 7 )alkyl, -R 10 ,
  • R 9 is (d-CyJalkyl
  • R 10 is (C 4 -C 14 )aryl
  • R 11 is selected from the group consisting of nitrile, halo, (CrC 6 )alkyl, (Ci-C 6 )alkoxy, and R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately chosen from among the possible R 8 substituents;
  • R 3 is (C 3 -C 12 )cycloalkyl
  • R 14 is selected from (Ci-Cn)heterocycle or (CrCn)heteroaryl, each having one to three heteroatoms selected from N and O;
  • R 5 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of X is selected from the group consisting of -R 0 ,
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen, , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 0 R 5 R 14 , -R 2 , -R 14 , -(R 14 ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 13 R 14 , -R 0 R 14 , -R 13 R 6 , - R 4 R 6 , -(R 14
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl;
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 1 ) M , and -R 5 R 0 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 4 R 12 ;
  • R 12 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 14 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (d- C 6 )alkylene;
  • X is selected from the group consisting of -R 6 , -R 12 , -R 14 , and -R 1 (R 6 ) n ;
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ,
  • R 2 is selected from the group consisting of hydrogen, , halo, (Ci-C 6 )alkyl, (C C 6 )alkoxy, nitrile, oxo, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 5 R 14 (R 6 ) W , -R 10 R 5 R 14 , -R 12 , - R 14 , -R 0 R 6 , -R 10 (R 6 )n, -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 13 R 14 , -R 9 R 10 , - R 0 R 14 , -(R 14 R 12 ), -R 13 R 6 , -R 1 R 6 , -C0 2 R 7 , (C 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein A and Q are
  • R 3 is selected from the group consisting of hydrogen, halo, and (Ci-C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (Ci-CeJalkyl, (d-CeJalkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) admir, -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (C C 6 )alkylene
  • R 6 is independently selected from the group consisting of (C t -CeJalkyl, oxo, (d-
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (CrC 7 )alkyl, -R 10 ,
  • R 9 is (d-C 7 )alkyl
  • R 0 is (C 4 -C 14 )aryl
  • R 1 is selected from the group consisting of nitrile, halo, (C C 6 )alkyl, (Ci-C 6 )alkoxy, and -R 14 R 12 ;
  • R 2 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -C 12 )cycloalkyl
  • R 14 is selected from (d-di)heterocycle or (d-di)heteroaryl, each having one to three heteroatoms selected from N and O;
  • R 15 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene, dimethylmethylene, methylmethylene, ethylmethylene, propylmethylene, methylpropylene, methylcyclopropylmethyl, and isopropylmethylene;
  • X is selected from the group consisting of -R 6 , -R 2 , -R 14 , and -R 14 (R 6 ) n , -C(0)R 12 , and -C(0)R 14 ;
  • R is selected from the group consisting of hydrogen, R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen,
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl;
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 0 (R 1 ) M , and -R 5 R 0 (R 1 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 1 R
  • R 12 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl, tetrahydropyranyl, imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 15 is selected from the group consisting of fluoro, chloro, and iodo;
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (C r C 6 )alkylene;
  • X is selected from the group consisting of hydrogen, (d-C 6 )alkoxy, nitrile, -C(0)R 12 , and
  • R 2 is selected from the group consisting of hydrogen, , halo, (Ci-C 6 )alkyl, (C C 6 )alkoxy, nitrile, oxo, hydroxyl, -NHR R 14 , -OR 7 , -R 5 R 1 (R 6 ) W , -R 10 R 5 R 14 , -R 12 , - R14 _ R io R 6_ _ R i° ( R 6 )n i _so 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 13 R 14 , -R 9 R 10 , - Rio R i4 .(R1 R12) _ R 13 R 6 .
  • R 3 is selected from the group consisting of hydrogen, halo, and (C ⁇ -C 6 )a ⁇ ky ⁇ ;
  • R 4 is selected from the group consisting of hydrogen, (CrC 6 )alkyl, (CrC 6 )alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (Ci-C 6 )alkylene; R 6 is independently selected from the group consisting of (d-C 6 )alkyl, oxo, (Ci-
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (Ci-C 7 )alkyl, -R 0 ,
  • R 9 is (Ci-C 7 )alkyl
  • R 10 is (C 4 -C 14 )aryl
  • R 11 is selected from the group consisting of nitrile, halo, (CrC 6 )alkyl, (C C 6 )alkoxy, and
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -C 12 )cycloalkyl
  • R 14 is selected from (Ci-Cn)heterocycle or (CrCn)heteroaryl, each having one to three heteroatoms selected from N and O;
  • R 15 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of hydrogen, (C C 6 )alkoxy, nitrile, -C(0)R 12 , and -C(0)R 14 ;
  • R is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen, , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 2 , -R 14 , -(R 1 ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 13 R 14 , -R 10 R 14 , -R 13 R 6 , - R 14 R 6 , -(R R 12 ),
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 1 ) M , and -R 5 R 10 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyi, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 10 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 14 R 12 ;
  • R 2 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl;
  • R 5 is selected from the group consisting of fluoro, chloro, and iodo
  • each m is independently zero or an integer from 1 to 3;
  • n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond and a (branched or straight chain) (C
  • X is selected from the group consisting of hydrogen, (CrC 6 )alkoxy, nitrile, -C(0)R 12 , -C(0)R 14 , -S0 2 R 6 , -S0 2 R 12 , -S0 2 R 14 , -S0 2 R 1 (R 6 ) n , -NHSO 2 R 10 (R 6 ) n ,
  • R is selected from the group consisting of hydrogen, -R 5 R 14 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, , halo, (d-C 6 )alkyl, (Ci- C 6 )alkoxy, nitrile, oxo, hydroxy!, -NHR 5 R 14 , -OR 7 , -R 5 R (R 6 ) W , -R 10 R 5 R 14 , -R 12 , - R 14 , -R 10 R 6 , -R 10 (R 6 )n, -S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -R 3 R 14 , -R 9 R 10 , - Rio R i4 .(R14R12) _ R 13 R 6 _ COzR 7 (C 3 -C 12 )cycloalkyl, and (C 4 -C 14 )aryl, wherein A and Q are independently chosen from -(CH 2 ) W R 10 or -(
  • fused heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused heterocyclic ring can also be optionally substituted with one to two R 6 groups;
  • R 3 is selected from the group consisting of hydrogen, halo, and (C C 6 )alkyl;
  • R 4 is selected from the group consisting of hydrogen, (C C 6 )alkyl, (C C6)alkoxy, nitrile, oxo, -C(0)R 12 , -S0 2 R 9 , -R 9 (R 15 ) n , -OR 7 , -R 12 , and halo;
  • R 5 is a branched or straight chain (d-CeJalkylene
  • R 6 is independently selected from the group consisting of (d-CeJalkyl, oxo, (C
  • R 7 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl
  • R 8 is independently selected from the group consisting of hydrogen, (CrC 7 )alkyl, -R 10 ,
  • R 9 is (d-C 7 )alkyl
  • R 10 is (C 4 -C 14 )aryl
  • R is selected from the group consisting of nitrile, halo, (Ci-C 6 )alkyl, (C C 6 )alkoxy, and
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 13 is (C 3 -C 12 )cycloalkyl
  • R 1 is selected from (d-C Jheterocycle or (CrCuJheteroaryl, each having one to three heteroatoms selected from N and O;
  • R 5 is halo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • Z is selected from the group consisting of a bond, methylene, ethylene,
  • X is selected from the group consisting of hydrogen, methoxy, nitrile, -C(0)R 12 ,
  • R 1 is selected from the group consisting of hydrogen, 5 R 14 , and -C(0)R 9 ; selected from the group consisting of hydrogen,
  • R 3 is selected from the group consisting of hydrogen, chloro, iodo, fluoro, and methyl
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, iodo, and chloro;
  • R 5 is selected from the group consisting of methylene, ethylene, and propylene
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl,
  • propyl isopropyl, butyl, t-butyl, heptyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 11 ) M , and -R 5 R 10 (R 11 ) M ;
  • R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, heptyl, dimethylbutanyl, and dimethylpentanyl;
  • R 0 is phenyl
  • R 11 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, methoxy, and -R 14 R 12 ;
  • R 2 is -N(R 8 ) 2 , wherein each R 8 may be independently chosen from among the R 8
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl;
  • R 4 is selected from the group consisting of morpholinyl, thiomorpholinyl,
  • tetrahydropyranyl imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidione, piperidinyl, and pyridinyl;
  • R 5 is selected from the group consisting of fluoro, chloro, and iodo
  • each m is independently zero or an integer from 1 to 3;
  • each n is independently zero or an integer from 1 to 3;
  • each w is independently zero or an integer from 1 to 3.
  • X is selected from -NHSO 2 R 10 (R 6 ) n or -S0 2 R 12 ;
  • R is selected from the group consisting of hydrogen, -C0 2 R 7 , -C(0)R 10 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, -R 10 R 12 , -R 0 R 14 , -R 10 , -R 15 , and -R 10 R 6 ;
  • R 4 is selected from hydrogen or (C C 6 )alkoxy
  • R 6 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, (C
  • R 7 is selected from hydrogen or (CrC 6 )alkyl
  • R 8 is selected from hydrogen or (Ci-C 7 )alkyl
  • R 9 is (C C 7 )alkyl
  • R 0 is (C 4 -C 14 )aryl
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 4 is selected from (Ci-C )heterocycle or (d-CuJheteroaryl, each having one to three heteroatoms selected from N and O;
  • R 15 is halo
  • each n is independently zero or an integer from 1 to 3.
  • X is selected from -NHSO 2 R 0 (R 6 ) 2 or -S0 2 R 12 ;
  • R 1 is selected from the group consisting of hydrogen, -C0 2 R 7 , -C(0)R 10 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of hydrogen, -R 0 R 12 , -R 10 R 14 , -R 10 , -R 15 , and -R 10 R 6 ;
  • R 4 is selected from hydrogen or methoxy
  • R 6 is independently selected from the group consisting of methyl, oxo, methoxy, fluoro, bromo, nitrile, and -C0 2 R 7 ;
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and butyl
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, heptyl, hexyl, and heptyl;
  • R 9 is selected from the group consisting of methyl, ethyl, propyl, butyl heptyl, hexyl, and heptyl;
  • R 10 is phenyl
  • R 12 is -N(R 8 ) 2 , wherein each instance of R 8 may be independently and separately
  • R 14 is morpholinyl
  • R 5 is selected from fluoro or bromo.
  • R 1 is selected from the group consisting of hydrogen, -R 5 R 14 , and -C(0)R 9 ;
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 10 R 5 R 14 , -R 12 , -R 14 , -(R ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 0 R 6 , -R 13 R 14 , -R 10 R 14 , -R 13 R 6 , -R 14 R 6 , -(R 4 R 12 ), (C 3 -C 13 )cyclo
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, nitrile, fluoro, chloro, iodo, methoxy, ethoxy, propoxy, hydroxyl, -NHR 5 R 14 , -OR 7 , -R 9 R 10 , -R 0 R 5 R 14 , -R 12 , -R 14 , -(R 14 ) 2 , - S0 2 R 10 , -S0 2 R 12 , -S0 2 R 13 , -S0 2 R 14 , -C0 2 R 7 , -R 10 R 6 , -R 13 R 14 , -R 10 R 14 , -R 3 R 6 , -R 4 R 6 , -(R 1 R 12 ), cyclopentyl, dihydro
  • R 4 is selected from the group consisting of hydrogen, -C(0)R 12 , -S0 2 R 9 , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, amino, nitrile, oxo, methylamino, dimethylamino, trifluoromethyl, fluoro, and iodo.
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, oxo, methoxy, ethoxy, propoxy, hydroxy, fluoro, chloro, iodo, nitrile, and -C0 2 R 7 .
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl;
  • R 8 is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, heptyl, hexyl, heptyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -R 5 R 10 , -R 5 R 13 , -R 10 (R 11 ) M , and -R 5 R 0 (R 11 ) M .
  • R 9 is independently selected from the group consisting of R 9 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopropyl, pentyl, t-pentyl, neopentyl, hexyl, and heptyl.
  • Formula (I), or a pharmaceutically acceptable salt thereof wherein R 1 is selected from the group consisting of methyl, nitrile, fluoro, iodo, chloro, and methoxy.
  • R 13 is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclohexyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein R 14 is selected from the group consisting of morpholinyl, thiomorpholinyl, tetrahydropyranyl, imidazolyl, quinolinyl, oxazepinyl, pyrimidinyl, pyrazolyl, indolyl, thiophenyl, tetrahydrofuranyl, piperazinyl, pyrrolidinyl, pyrrolidinone, piperidinyl, and pyridinyl.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in any of Formulas I, II, III, IV, and V.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, and V.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI, wherein said virus is hepatitis C virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, I II, IV, and V, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, and V, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine ⁇ -monophosphate dehydrogenase.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, and V, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, and V, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is ribavirin.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, and V, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
  • the compound of the present invention is chosen from the compounds set forth in Table 1 .

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Abstract

L'invention concerne des composés des formules I, II, III, IV, V et des sels de qualité pharmaceutique de ceux-ci, leur compositions pharmaceutiques, leurs procédés de préparation et leur utilisation pour le traitement d'infections virales à médiation par un élément de la famille des virus Flaviviridae, tels que le virus de l'hépatite C (VHC).
PCT/US2012/042558 2011-06-15 2012-06-15 Dérivés de benzimidazole en tant qu'agents antiviraux WO2012174312A2 (fr)

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US9573953B2 (en) 2013-02-21 2017-02-21 Calitor Sciences, Llc Heteroaromatic compounds as PI3 kinase modulators and methods of use
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WO2019031990A1 (fr) * 2017-08-07 2019-02-14 Закрытое Акционерное Общество "Биокад" Nouveaux composés hétérocycliques comme inhibiteurs de cdk8/19
AU2016315881B2 (en) * 2015-09-03 2019-09-19 The Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of DYRK1A and uses thereof
CN110551101A (zh) * 2019-08-28 2019-12-10 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途
RU2739489C2 (ru) * 2018-03-06 2020-12-24 Закрытое Акционерное Общество "Биокад" Новые гетероциклические соединения как ингибиторы CDK8/19
WO2021180219A1 (fr) * 2020-03-13 2021-09-16 挪贝肽医药科技(上海)有限公司 Effet anti-coronavirus et application d'inhibiteur de pi4k
JP2021529200A (ja) * 2018-06-26 2021-10-28 昆薬集団股▲フン▼有限公司Ｋｐｃ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． ベンズイミダゾール誘導体及びそのｉｄｈ１阻害剤としての応用
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US9926324B2 (en) 2012-11-14 2018-03-27 Calitor Sciences, Llc Heteroaromatic compounds as PI3 kinase modulators and methods of use
US9573953B2 (en) 2013-02-21 2017-02-21 Calitor Sciences, Llc Heteroaromatic compounds as PI3 kinase modulators and methods of use
CN103435618A (zh) * 2013-08-22 2013-12-11 中国药科大学 一种合成稠杂环化合物的方法
CN103435618B (zh) * 2013-08-22 2016-03-23 中国药科大学 一种合成稠杂环化合物的方法
US9926307B2 (en) 2014-09-23 2018-03-27 Mission Therapeutics Ltd Compounds
EP3828179A1 (fr) 2014-09-23 2021-06-02 Mission Therapeutics Limited Cyanopyrrolidines comme régulateurs de dub
US10392380B2 (en) 2014-09-23 2019-08-27 Mission Therapeutics Limited Compounds
CN105218413A (zh) * 2015-08-12 2016-01-06 诚达药业股份有限公司 制备芳香磺酸类化合物的方法
AU2016315881B2 (en) * 2015-09-03 2019-09-19 The Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of DYRK1A and uses thereof
US10730842B2 (en) 2015-09-03 2020-08-04 Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of DYRK1A and uses thereof
US11352328B2 (en) 2016-07-12 2022-06-07 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus
WO2019031990A1 (fr) * 2017-08-07 2019-02-14 Закрытое Акционерное Общество "Биокад" Nouveaux composés hétérocycliques comme inhibiteurs de cdk8/19
AU2018312836B2 (en) * 2017-08-07 2022-12-08 Joint Stock Company "Biocad" Novel heterocyclic compounds as CDK8/19 inhibitors
RU2739489C2 (ru) * 2018-03-06 2020-12-24 Закрытое Акционерное Общество "Биокад" Новые гетероциклические соединения как ингибиторы CDK8/19
JP2021529200A (ja) * 2018-06-26 2021-10-28 昆薬集団股▲フン▼有限公司Ｋｐｃ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． ベンズイミダゾール誘導体及びそのｉｄｈ１阻害剤としての応用
JP7258059B2 (ja) 2018-06-26 2023-04-14 昆薬集団股▲フン▼有限公司 ベンズイミダゾール誘導体及びそのｉｄｈ１阻害剤としての応用
CN110551101A (zh) * 2019-08-28 2019-12-10 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途
CN110551101B (zh) * 2019-08-28 2020-11-24 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途
WO2021180219A1 (fr) * 2020-03-13 2021-09-16 挪贝肽医药科技(上海)有限公司 Effet anti-coronavirus et application d'inhibiteur de pi4k

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