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WO2015038660A1 - Pyridazinone compounds and uses thereof - Google Patents

Pyridazinone compounds and uses thereof Download PDF

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Publication number
WO2015038660A1
WO2015038660A1 PCT/US2014/055018 US2014055018W WO2015038660A1 WO 2015038660 A1 WO2015038660 A1 WO 2015038660A1 US 2014055018 W US2014055018 W US 2014055018W WO 2015038660 A1 WO2015038660 A1 WO 2015038660A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
substituted
alkyl
heterocyclyl
Prior art date
Application number
PCT/US2014/055018
Other languages
French (fr)
Inventor
Leonid Beigelman
Robert Than Hendricks
Antitsa Dimitrova Stoycheva
Jerome Deval
Sarah Katherine STEVENS
Original Assignee
Alios Biopharma, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EA201690371A priority Critical patent/EA034868B1/en
Priority to DK14843298.2T priority patent/DK3030549T3/en
Application filed by Alios Biopharma, Inc. filed Critical Alios Biopharma, Inc.
Priority to AU2014318837A priority patent/AU2014318837B2/en
Priority to ES14843298T priority patent/ES2724581T3/en
Priority to NZ717586A priority patent/NZ717586B2/en
Priority to JP2016542074A priority patent/JP6360176B2/en
Priority to EP14843298.2A priority patent/EP3030549B8/en
Priority to CN201480061772.4A priority patent/CN105722831B/en
Priority to US15/021,073 priority patent/US10364226B2/en
Priority to CA2922943A priority patent/CA2922943A1/en
Priority to SI201431180T priority patent/SI3030549T1/en
Priority to MX2016003135A priority patent/MX370085B/en
Priority to LTEP14843298.2T priority patent/LT3030549T/en
Priority to KR1020167008927A priority patent/KR102286860B1/en
Publication of WO2015038660A1 publication Critical patent/WO2015038660A1/en
Priority to IL244434A priority patent/IL244434B/en
Priority to PH12016500492A priority patent/PH12016500492B1/en
Priority to HRP20190822TT priority patent/HRP20190822T1/en

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are pyridazinone compounds, pharmaceutical compositions that include one or more pyridazinone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating an orthomyxovirus viral infection with one or more pyridazinone compounds.
  • the viruses of the Orthomyxoviridae family are negative-sense, single- stranded RNA viruses.
  • the Orthomyxoviridae family contains several genera including Influenzavirus A, Influenzavirus B, Influenzavirus C. Isavirus and Thogotovirus.
  • Influenzaviruses can cause respiratory viral infections, including upper and lower respiratory tract viral infections. Respiratory viral infections are a leading cause of death of millions of people each year. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory system below the vocal cords, including the trachea, primary 7 bronchi and lungs.
  • Some embodiments disclosed herein relate to a compound of Formula (T), or a pharmaceutically acceptable salt thereof.
  • Other embodiments disclosed herein relate to a compound of Formula (11). or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating an orthomyxovirus viral infection that can include administering to a subject suffering from the orthomyxovirus viral infection an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing.
  • Other embodiments described herein relate to using one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, in the manufacture of a medicament for ameliorating and/or treating an orthomyxovirus viral infection.
  • Still other embodiments described herein relate to compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, that can be used for ameliorating and/or treating an orthomyxovirus viral infection.
  • methods of ameliorating and/or treating an orthomyxovirus viral infection can include contacting a cell infected with the orthomyxovirus with an effective amount of one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing.
  • Some embodiments disclosed herein relate to methods of preventing an orthomyxovirus infection that can include administering to a subject an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing.
  • the orthomyxovirus viral infection can be an influenza viral infection (such as influenza A, B and/or C).
  • Some embodiments disclosed herein relate to methods of inhibiting the replication of an orthomyxovirus that can include contacting a cell infected with the
  • the orthomyxovirus viral infection can be an influenza viral infection (such as influenza A. B and/or C).
  • influenza viral infection such as influenza A. B and/or C.
  • Other embodiments disclosed herein relate to a method for inhibiting endonuclease activity of an influenza endonuclease that can include contacting the active site of the endonuclease with an effective amount of one or more compounds of Formulae (1) and/or (II).
  • Figure 1 show s example anti-influenza agents.
  • Influenza is a negative sense, single stranded RNA virus and a member of the Orthomyxoviridae family.
  • influenza A influenza B
  • influenza C influenza A
  • Influenza A has a lipid membrane derived from the host cell, which contains the hemagglutinin, neuramididase and M2 proteins that project from the surface of the virus.
  • Influenza A has been further classified based the hemagglutinin (H or HA) and the neuramididase (N).
  • H or HA hemagglutin
  • N neuramididase
  • Influenza A includes several subtypes, including H1 N1. H1 N2. H2N2. H3N1.
  • influenza virus polymerase is a heterotrimer composed of three subunits, polymerase acid (PA), polymerase basic 1 (PB 1 ) and polymerase basic 2 (PB2). This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells.
  • PA polymerase acid
  • PB 1 polymerase basic 1
  • PB2 polymerase basic 2
  • This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells.
  • the PA subunit contains the endonuclease active site. The endonuclease activity of the PA cleaves the cellular mRNA. which is then used by the PB 1 subunit as a primer for the viral mRNA synthesis.
  • Influenza viruses can be transmitted from person to person via direct contact with infected secretions and/or contaminated surfaces or objections.
  • Complications from an influenza viral infection include pneumonia, bronchitis, dehydration, and sinus and ear infections.
  • Medications currently approved by the FDA against an influenza infection include a limited number of neuraminidase inhibitors and M2 protein inhibitors. Examples of approved neuraminidase inhibitors and M2 protein inhibitors include amantadine, rimantadine, Relenza® (zanamivir. GlaxoSmithKline) and Tamiflu® (oseltamivir. Genentech).
  • any "R" group(s) such as, without limitation, R 1 , R 2 , R', R 4 , and R 6 represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstitutcd. If two "R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl. ary l, heteroaryl or heterocycle.
  • R a and R b of an NR a R b group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
  • R groups may not be limited to the variables or substituents defined previously.
  • heterocyclyl aryl(alkyl), heteroaryl(alkyl), (heterocyclyl )alkyl, hydroxy, alkoxy. acyl. cyano. halogen, thiocarbonyl, O-carbamyl, N-carbamyl. O-thiocarbamy l, N-thiocarbamyl. C-amido. N-amido, S-sulfonamido. N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato. isothiocyanato, nitro. azido, silyl, sulfenyl, sulfinyl.
  • sulfonyl haloalkyl. haloalkoxy. trihalomethanesulfonyl. trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
  • C a to Ct in which "a” and “b” are integers refer to the number of carbon atoms in an alkyl. alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroyclyl group. That is, the alkyl.
  • alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl, ring(s) of the heteroaryl or ring(s) of the heterocyclyl can contain from “a” to "b", inclusive, carbon atoms.
  • a "C ( to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH -, CH CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH CH 2 CH 2 CH 2 -. CH 3 CH 2 CH(CH 3 )- and (CH ) 3 C-.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g. , "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom. 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as "C
  • -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl. butyl, isobutyl. tertiary butyl, penty l (straight and branched) and hexyl (straight and branched).
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyp refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl.” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) mono-cyclic or multi-cyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C 6 -C i 4 aryl group, a C 6 -C
  • aryl groups include, hut are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a mono-cyclic or multi-cyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms. that is. an element other than carbon, including but not limited to. nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroary l group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s). 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryf includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan. furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, thiazole, 1 ,2.3-thiadiazole.
  • 1,2,4-thiadiazole benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole. isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine.
  • a heteroaryl group may be substituted or unsubstituted.
  • heterocyclyl' or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 1 8-membered mono-cyclic, bicyclic. and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to. oxygen, sulfur, and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • thiobarbituric acid dioxopiperazine. hydantoin, dihydrouracil, trioxane. hexahydro-1.3,5-triazine. imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline. thiazolidine, morpholine, oxirane, piperidine A -Oxide, piperidine. piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine.
  • alkylene refers to a straight or a branched tethering fully saturated (no double or triple bonds) hydrocarbon group that connect molecular fragments via its terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -). ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and butylene (-(CH 2 ) 4 -) groups.
  • a "lower alkylene group” refers to an alkylene group containing 1 to 6 carbons. A lower alkylene and alkylene group can be substituted by replacing one or more hydrogen of the lower alky lene group or alky lene group with a substituent(s) listed under the definition of "substituted.”
  • An alkenylene group may be substituted or unsubstituted.
  • heteroalkylene refers to an alkylene containing one or more heteroatom groups or heteroatom containing groups in the carbon back bone (i.e., an alkylene group in which one or more carbon atoms is replaced with a heteroatom group or heteroatom containing group).
  • heteroalkyls may be substituted or unsubstituted.
  • Heteroalkyls include, but are not limited to ether, thioether, amino-alkylene, and alkyiene-amino-alkylene moieties.
  • heteroalkyls include, but are not limited to, -CH 2 0-, -CH 2 CH 2 CH 2 CH 2 0-, -CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, - CH2CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2OCH2CH2-, -(CH 2 ) 2 0(CH 2 )2-, -CH2S-, - CH2CH2CH2CH2S-, -CH2SCH2-.
  • heteroalkenylene refers to an alkenylene containing one or more heteroatoms in the carbon back bone (i.e., an alkenylene group in which one or more fully saturated carbon atoms (i.e. CH 2 ) is replaced with a heteroatom group or a heteroatom containing group).
  • heteroalkenyls may be substituted or unsubstituted.
  • -CH 2 CH 2 CH CHCH 2 S-.
  • aralkyl and aryl(alkyl) refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and/or aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
  • heteroarylkvl and “heteroaryl(alkyr)'” refer to a heteroarvl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and/or heteroarvl group of heteroaralkvl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzo-fused analogs.
  • a "(heteroalicyclyl)alkyl " and "(heterocyclyl ⁇ lkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
  • the lower alky lene and/or heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methy l, (piperidin-4-yl)ethyl. (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1 ,3-thiazinan-4-yl)methyl.
  • alkoxy refers to the formula -OR wherein R is alkyl. alkenyl. alkynyl, cycloalkyl, cycloalkenyl. aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyi or (heterocyclyl )alkyl is defined herein.
  • R is alkyl. alkenyl. alkynyl, cycloalkyl, cycloalkenyl. aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyi or (heterocyclyl )alkyl is defined herein.
  • alkoxys are methoxy, ethoxy. n-propoxy. 1 -methyl ethoxy (isopropoxy), n-butoxy. iso-butoxy, sec-butoxy. tert-butoxy, phenoxy and benzoxy.
  • An alkoxy may be substituted or unsub
  • acyl refers to a hydrogen, alkyi, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl, 3 -hydroxy propyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.
  • a hydroxyalkyl may be substituted or unsubstituted.
  • haloalky l refers to an alky l group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalky l, di-haloalky l and tri- haloalkyl).
  • a halogen e.g., mono-haloalky l, di-haloalky l and tri- haloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl. difluoromethyl, trifluoromethyl, l -chloi -2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group of the formula -O- alkyl in which one or more of the hydrogen atoms are replaced by a halogen (e.g.. mono- haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g.. mono- haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • Such groups include but are not limited to. chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l -chloro-2- fluoromethoxy and 2-fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, alkyl. alkenyl. alkynyl. cycloalkyl. cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.
  • a "sulfony l" group refers to an "SO 2 R" group in which R can be the same as defined with respect to sulfenyl.
  • a sulfony l may be substituted or unsubstituted.
  • R can be hydrogen, alkyl. alkenyl. alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl. aralkyl, (heteroaryl )alkyl or (heterocyclyl)alkyl. as defined herein.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a "trihalome hanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein each X is a halogen.
  • a "trihalomethanesulfonamido” group refers to an "X 3 CS(0) 2 N(RA)-' " group wherein each X is a halogen, and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • amino refers to a -NH? group.
  • hydroxy refers to a -OH group.
  • a "cyano" group refers to a "-CN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • An "S-sulfonamido” group refers to a "-S0 2 N(RARB) " group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a "RSO?N(RA)-" group in which R and RA can be independently hydrogen, alkyl, alkeny l, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • R and RA can be independently hydrogen, alkyl, alkeny l, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • N-carbamyf group refers to an group in which R and RA can be independently hydrogen, alkyl. alkenyl. alkynyl, cycloalkyl. cycloalkenyl. aryl, heteroaryl. heterocyclyl. aralkyl, (heteroaryl )alkyl or (heterocyclyl)alkyl.
  • R and RA can be independently hydrogen, alkyl. alkenyl. alkynyl, cycloalkyl. cycloalkenyl. aryl, heteroaryl. heterocyclyl. aralkyl, (heteroaryl )alkyl or (heterocyclyl)alkyl.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl. cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl. (heteroaryl )alkyl or (heterocyclyl)alkyl.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • N-amido group refers to a group in which R and RA can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl. aryl, heteroaryl. heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl.
  • An N-amido may be substituted or unsubstituted.
  • halogen atom " or "halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • substituents e.g. haloalkyl
  • substituents there may be one or more substituents present.
  • haloalky l may include one or more of the same or different halogens.
  • C i-C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unw anted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way.
  • protecting groups include benzyl; substituted benzyl: alkylcarbonyls and alkoxycarbonyls (e.g.. t-butoxycarbonyl (BOC). acetyl and isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g.
  • methoxymethyl ether and tetrahydropyranyl ether substituted ethyl ether; a substituted benzyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tn-iso- propylsilyloxymethyi. [2-(trimethylsilyl)ethoxy]methyi and t-butyldiphenyisilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g.
  • acyclic ketal e.g. dimethyl acetal and diisopropyl acetal
  • cyclic ketals e.g., 1 ,3- dioxane and 1 ,3-dioxolane
  • leaving group refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, 'leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates, mesylates and halogens (e.g., 1, Br, and CI).
  • Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331 ; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock ( 1981), pages 169- 171 ; and Organic Chemistry, 5 lh ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulionic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-gliicamine, tris(hydroxymethyl)methylamine, C
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-gliicamine, tris(hydroxymethyl)methylamine, C
  • the term “'comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or ' unless expressly stated otherwise.
  • a group of items linked with the conjunction 'or ' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or ' unless expressly stated otherwise.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol. or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
  • G 1 can be s can be hydrogen, halogen. -CN. an optionally substituted C
  • Y' and Y' can be independently an optionally substituted Ci -6 alkyl or an optionally substituted aryl;
  • R 1 can be selected from OR 6 , NH 2 , an optionally substituted mono-substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocyclyl, an optionally substituted N-sulfonamido and an optionally substituted alkoxyamine, or R' ";
  • R ⁇ can be hydrogen, C
  • R J can be hydrogen or C
  • R 4 can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl.
  • an optionally substituted heteroaryl and an optionally substituted heterocyclyl or R can be A'R A4 R LI4 .
  • A can be CH or N; and R A4 and R B4 can be each independently an optionally substituted phenyl; R 3 can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; R 6 can be selected from hydrogen. C
  • R 7 can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(Ct -6 alkyl), heteroaryl(Ci -6 alkyl) and heterocyclyl(C
  • R 8 and R 9 can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C
  • R 10 and R 4 can be taken together and include L 1 .
  • O oxygen
  • S sulfur
  • NR 1 1 wherein R 1 1 can be hydrogen or C i -6 alkyl; and Z 1 and Z 2 can be independently 0, 1 , 2, 3 or 4.
  • G J can be hydrogen.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a prodrug in which G J can be selected from -C(0)Y 2 , -C(0)0-Y ⁇ -(CH 2 )-0(CO)Y 2 , -(CH 2 )-0(CO)OY 2 , - (CHCH 3 )-0(CO)Y 2 . and -(CHCH 3 )-0(CO)OY 2 .
  • G 2 can be hydrogen.
  • G can be halogen.
  • G" can be -CN.
  • G" can be an optionally substituted aryl.
  • G" can be an optionally substituted heteroaryl.
  • G ⁇ can be -CH?OH.
  • G ' can be -CH(Y )(OH).
  • G ⁇ can be - C(0)Y .
  • G ' can be an optionally substituted C]_ f , alkyl.
  • G ⁇ can be an unsubstituted Ci -6 alkyl, such as methyl.
  • Y and Y ⁇ can be independently an optionally substituted Ci -6 alkyl or an optionally substituted aryl (such as an optionally substituted phenyl).
  • R 1 can be OR 6 .
  • R 1 can be hydroxy.
  • R 6 when R 1 is OR 6 .
  • R 6 when R 1 is OR 6 .
  • R 6 when R 1 is OR 6 , R 6 can be C
  • R 6 when R 1 is OR 6 , R 6 can be - C(0)R 7 .
  • suitable R 7 groups include, but are not limited to.
  • R 6 when R 1 is OR 6 , R 6 can be -C(0)NR 8 R 9 .
  • R 8 and R 9 can be independently various substituents, such as hydrogen, alkyl, alkenyl, alkynyi, cycloalkyl, cycloalkenyl, cycloalkynyl. aryl. heteroaryl.
  • R 6 can be hydrogen, Ci -6 alkyl, an acy or C-amido. In some embodiments. R 6 can be hydrogen. -C(0)R 7 and -C(0)NR 8 R 9 . In other embodiments. R 6 can be -C(0)R 7 and - C(0)NR 8 R 9 .
  • R 1 can be H 2 . In other embodiments. R 1 can be an optionally substituted mono-substituted amine.
  • An example of a suitable mono- substituted amine is a group having the formula of -NHR , wherein R ' can be selected from alkyl, alkenyl, alkynyi, cycloalkyl, cycloalkenyl. cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C
  • R I AA can be selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl. aryl(C
  • R 1 AA can be selected from alkyl, aryl, and aryl(C
  • R 1 is a mono-substituted amine having the formula -NHR I AA .
  • R I AA can be a substituted or unsubstituted group.
  • R 1 can be an optionally substituted di-substituted amine.
  • R 1 can be a group having the formula of -NR I BB R I C C , wherein R I B and R I CC can be independently selected from alkyl, alkenyl, alkynyl. cycloalkyl. cycloalkenyl. cycloalkynyl. aryl. heteroaryl, heterocyclyl, aryl(Ci_ 6 alkyl). heteroaryl(Ci-6 alkyl) and heterocyclyl(C i.6 alkyl).
  • R I B and R I CC can be independently selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C [ -6 alkyl), heteroaryl(C
  • R I BB and R C can be independently selected from alkyl, aryl, and aryl(C
  • R I BB and R I CC can be the same.
  • R 1 is a di-substituted amine having the formula -NR I BB R l ct
  • R 1 BB and R I CC can be substituted or unsubstituted groups.
  • R 1 can be an optionally substituted heterocyclyl.
  • Various heterocyclyls can be used and can be connected either through a ring carbon or a ring heteroatom.
  • the heterocyclyl can be a 5 to 6 membered heterocyclyl.
  • the heterocyclyl can include 1 heteroatom.
  • the heterocyclyl can include 2 heteroatoms. wherein the heteroatoms can be the same or different.
  • R 1 can be an optionally substituted heterocyclyl that contains at least one nitrogen in the ring and is an N-linked heterocyclyl.
  • R 1 can be an unsubstituted heterocyclyl.
  • R 1 can be a substituted heterocyclyl.
  • R 1 can be an optionally substituted N-sulfonamido.
  • the groups attached to the sulfur can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C
  • R I DD can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C
  • R I DD can be selected from alkyl. alkenyl, cycloalkyl, aryl, heteroaryl.
  • R I UU can be selected from alkyl. aryl. and aryl(C] _6 alkyl).
  • R I DD can be a substituted or unsubstituted group.
  • R 1 can be an optionally substituted alkoxyamine.
  • an optionally substituted alkoxyamine include, but are not limited to, the following: -NH(C
  • G 1 can be .
  • R 2 can be hydrogen.
  • R 2 can be a C
  • R 2 can be an optionally substituted C 3- cycloalkyl.
  • R 2 can be an optionally substituted C5-6 cycloalkyl, such as an optionally substituted monocyclic C 5-6 cycloalkyl or an optionally substituted fused, bicyclic C5- cycloalkyl.
  • R " can be an optionally substituted aryl, such as an optionally substituted phenyl.
  • R can be an optionally substituted aryl(C i -6 alkyl), for example, an optionally substituted benzyl.
  • R " can be an optionally substituted C-amido.
  • R '1 can be hydrogen.
  • R J can be a C i_6 alkyl.
  • R 2 and R J can be the same. In other embodiments. R " and R can be different. In some embodiments, R' and R can both be hydrogen. In other embodiments, R 2 and R "1 can both be a C
  • R 2 and R' can be taken together to form an optionally substituted C 3- 6 cycloalkyl.
  • Suitable cycloalkyls include cyclopropyl. cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl group can be unsubstituted.
  • the cycloalkyl group can be substituted with one or more substituents.
  • R' and R can be taken together to form an optionally substituted C 5 cycloalkyl.
  • R 2 and R 1 can be taken together to form an unsubstituted C 5 cycloalkyl.
  • R 2 and R '1 can be taken together to form a mono-substituted or di-substituted C5 cycloalkyl.
  • R" and R can be taken together to form an optionally substituted 5 to 6 membered heterocyclyi.
  • heterocyclyls that can be formed include, but are not limited to, optionally substituted nitrogen containing 5 to 6 membered heterocyclyls.
  • R 2 and R J can be taken together to form an optionally substituted 5 to 6 membered N-linked heterocyclyi, for example, an optionally substituted piperdino or an optionally substituted pyrrolidino.
  • R 4 can be an optionally substituted ary l. In some embodiments, R 4 can be an optionally substituted naphthyl. In other embodiments. R 4 can be an optionally substituted phenyl. In some embodiments, R 4 can be an unsubstituted phenyl. In other embodiments, R 4 can be a substituted phenyl. One or more groups can be present on a substituted phenyl.
  • the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl.
  • the substituted phenyl can be a di- substituted phenyl, such as a 2,5-di-substituted phenyl, 2,4-di-substituted phenyl and 2,3-di- substituted phenyl.
  • the substituted phenyl can be substituted with 3 or more substituent.
  • R 4 can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 4 can be an optionally substituted C -6 cycloalkyl.
  • R 4 can be an unsubstituted cycloalkyl.
  • R 4 can be a substituted cycloalkyl.
  • R 4 can be an optionally substituted heteroaryl. In some embodiments. R 4 can be an unsubstituted heteroaryl. In other embodiments, R 4 can be a substituted heteroaryl. Examples of suitable heteroaryls are described herein. In some embodiments, R 4 can be an optionally substituted monocyclic heteroaryl. In other embodiments, R 4 can be an optionally substituted bicyclic heteroaryl, for example, an optionally substituted lH-pyrrolo[2,3-b]pyridine.
  • R 4 can be an optionally substituted heterocyclyl. In some embodiments, R 4 can be an unsubstituted heterocyclyl. In other embodiments, R 4 can be a substituted heterocyclyl. In some embodiments, R 4 can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R 4 can be an optionally substituted bicyclic heterocyclyl.
  • R 4 When R 4 is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R 4 , at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R 4 are different. In some embodiments, R 4 can be substituted with one or more substituents selected from halogen. Ci -6 alkyl. alkoxy, aryloxy. haloalkyl.
  • haloalkoxy hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl. an optionally substituted heterocyclyl, carbonyl. C- carboxy, -CH 2 -(mono-substituted amine) and CH 2 -(di-substituted amine).
  • R 4 when R 4 is a substituted aryl, the aryl can be substituted with one or more groups selected from C i .6 alkyl, alkoxy, aryl (for example, phenyl), cyano.
  • halogen, haloalkyl and haloalkoxy when R 4 is a substituted cycloalkyl, the cycloalkyl can be substituted with C i -6 alkyl, alkoxy, halogen and haloalkyl.
  • R 4 when R 4 is a substituted heterocyclyl, the heterocyclyl can be substituted with C
  • the substituted heterocyclyl of R 4 can be substituted with a substituted or an unsubstituted benzyl.
  • the pyridazinone ring can be connected to R 4 via a substituted or unsubstituted alky lene.
  • Z 1 can be 0. In other embodiments, Z 1 can be 1. In still other embodiments, Z 1 can be 2. In yet still other embodiments, Z 1 can be 3. In some embodiments, Z 1 can be 4. In some embodiments, Z 2 can be 0. In other embodiments. Z" can be 1. In still other embodiments, Z" can be 2. In yet still other embodiments. Z can be 3. In some embodiments, r can be 4. In some embodiments, Z can be 1. and Z ⁇ can be 0. In other embodiments, Z and Z " can be both 1. In still other embodiments. Z and Z ⁇ can be both >1. In yet still other embodiments, at least one of Z and 7s can be 1. In some embodiments, at least one of Z and Z " can be 1 , and the other of Z and Z ⁇ can be > 1.
  • R 4 can be A*R A4 R B4 , wherein A 1 can be CH or N; and R A4 and R B4 can be each independently an optionally substituted phenyl.
  • R 4 can be CHR A4 R B4 or NR A4 R B4 .
  • the phenyl groups can be the same or different, and can be substituted or unsubstituted.
  • G can be R 5 .
  • R 5 can be a variety of groups.
  • R ? can be an optionally substituted aryl.
  • R ⁇ can be an optionally substituted naphthyl.
  • R ⁇ can be an optionally substituted phenyl.
  • R ⁇ can be an unsubstituted phenyl.
  • R ⁇ can be a substituted pheny l.
  • One or more groups can be present on a substituted phenyl.
  • the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl.
  • the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di- substituted phenyl. 2.4-di -substituted phenyl and 2.3-di-substituted phenyl.
  • the substituted phenyl can be substituted with 3 or more substituents.
  • R ? can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R ⁇ can be a substituted or an unsubstituted C4 cycloalkyl.
  • R ""1 can be an unsubstituted cycloalkyl. In other embodiments.
  • R ""1 can be a substituted cycloalkyl.
  • R J can be an optionally substituted heteroaryl.
  • R ⁇ can be an unsubstituted heteroaryl.
  • R ""1 can be a substituted heteroaryl.
  • R ⁇ can be an optionally substituted monocyclic heteroaryl.
  • R/ can be an optionally substituted bicyclic heteroaryl.
  • R " ⁇ can be an optionally substituted heterocyclyl.
  • R ? can be an unsubstituted heterocyclyl.
  • R ⁇ can be a substituted heterocyclyl.
  • R 5 can be an optionally substituted monocyclic heterocyclyl.
  • R ? can be an optionally substituted bicyclic heterocyclyl.
  • R ? When R ? is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R ' ⁇ at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R s are different.
  • R 3 can be substituted with one or more substituents selected from halogen, C i -6 alkyl, alkoxy, aryloxy, haloalkyl, haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl. carbonyl, C- carboxy, -CH 2 -(mono-substituted amine) and CH2-(di-substituted amine).
  • substituents selected from halogen, C i -6 alkyl, alkoxy, aryloxy, haloalkyl, haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalky
  • the aryl can be substituted with one or more groups selected from Ci_ 6 alkyl. alkoxy, halogen and haloalky l.
  • R ? when R ? is a substituted ary l. the aryl can be substituted with one or more groups selected from Ci -6 alkyl, alkoxy. aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy.
  • R 5 is a substituted cycloalkyl
  • the cycloalkyl can be substituted with C i -6 alkyl, alkoxy, halogen and haloalkyl.
  • R ? when R ?
  • the heterocyclyl can be substituted with C i -6 alkyl. alkoxy. halogen, haloalkyl. aryl(C i-6 alkyl) and C-carboxy.
  • the substituted heterocyclyl of R ⁇ can be substituted with a substituted or an unsubstituted benzyl.
  • R 1 is not mono-substituted amine, such as -NH- alkyl. In other embodiments, R 1 is not di-substituted amine. For example, in some embodiments, R 1 is not -N(alkyl) 2 , including -N(CH 3 )2. In some embodiments, R 6 is not C
  • the pyridazinone ring can be connected to R 4 to form a cyclic compound, for example, a compound of Formula (Ih)
  • the pyridazinone ring can be connected to to form a cyclic compound, such as a compound of Formula (Ij).
  • R 10 and R 4 can be taken together and include L 1 , where L 1 connects R 10 and R 4 to form an 1 1 - to 20-membered ring, or wherein when R 1 is R 10 .
  • R can be NR" .
  • R 10 can be NH.
  • R 1 0 can be an optionally substituted -CH 2 -.
  • R 10 can be O (oxygen).
  • R 10 can be S (sulfur).
  • L 1 can be -L 2 -.
  • L 2 when L 1 is -L 2 -, L 2 can be selected from an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted heteroalkylene and an optionally substituted heteroalkenylene.
  • L 2 can be an optionally substituted alkylene, for example, an optionally substituted C4-7 alkylene.
  • L can be an optionally substituted alkenylene. such as an optionally substituted C4-7 alkenylene.
  • Lr can be an optionally substituted heteroalkylene.
  • optionally substituted heteroalkylenes include the following: an optionally substituted -(CH 2 ) 3 -0- an optionally substituted -(CH 2 ) 4 -0- an optionally substituted -(CH 2 ) 5 -0-, an optionally substituted -(CH 2 ) 3 -S-, an optionally substituted -(CH 2 ) 4 -S-, an optionally substituted -(CH 2 ) 5 -S-, an optionally substituted -(CH 2 ) -NH-, an optionally substituted -(CH 2 ) 4 -NH-. and an optionally substituted -(CH 2 ) 5 -NH-.
  • L 2 can be an optionally substituted -(CH 2 ) 3 -0-, an optionally substituted -(CH 2 ) 4 -0-, or an optionally substituted -(CH 2 ) 5 -0-.
  • L " can be an optionally substituted C 3 oxygen-containing heteroalkenylene, an optionally substituted C 4 oxygen-containing heteroalkenylene. or an optionally substituted Q oxygen-containing heteroalkenylene.
  • L 1 can be -L '-L 4 -! -, wherein L 3 can be an optionally substituted Ci -6 alkylene; L 4 can be an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyi, O (oxygen), S (sulfur), or NR 1 1 ; and can be an optionally substituted C i -6 alkylene or an optionally substituted heteroalkylene.
  • L can be an optionally substituted C i- alkylene; L 4 can be optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and can be an optionally substituted C
  • L J can be an optionally substituted C
  • L 3 can be optionally substituted C 2 -4 alkylene
  • L 4 can be optionally substituted cycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocyclyi, O (oxygen), S (sulfur), or NR 1 1
  • L ? can be optionally substituted C 2 - 4 alkylene.
  • a compound of Formula (I) can be a compound selected from Formula (la).
  • Formula (If) and Formula (Ig) can be a compound selected from Formula (la).
  • Formula (If) and Formula (Ig) can be a compound selected from Formula (la).
  • Formula (If) and Formula (Ig) can be a compound selected from Formula (la).
  • G 1 . R 1 , R 2 , R 3 . R 4 , R and z 1 are as defined above with respect to Formula (1).
  • the phenyl ring can be substituted or unsubstituted; for Formula (Id), R l a can be an optionally substituted N-linked heterocyclyl; for Formula (It), R 6 is not hydrogen; and for Formula (If), R 1 is not OR 6 .
  • R 6 is not hydrogen and/or not a C
  • Examples of compounds of Formula (I) include the following:
  • G I A can be selected f rom and R 5A ;
  • R I A can be selected from OR 6A .
  • NHi- an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted mono-substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocyclyl and an optionally substituted N-sulfonamido, or R I 0A
  • W A can be - CH- or -N-;
  • R 2A can be hydrogen or C i -6 alkyl;
  • R 3A can be hydrogen or C i -6 alkyl; or
  • R 2A and R " ' A can be taken together to form an optionally substituted C 3-6 cycloalkyl or an optionally substituted 5 to 6 membered heterocyclyl;
  • R 4A can be selected from an optionally substituted aryl.
  • R ' A can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryi and an optionally substituted heterocyclyl;
  • R 6A can be selected from hydrogen, C ,_ 6 alkyl, -C(0)R 7A and -C(0)NR 8A R 9A ;
  • R 7A can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl.
  • R 8A and R 9A can be independently selected from hydrogen, alkyl, alkenyl. alkynyl. cycloalkyl. cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl.
  • R 8A and R 9A can be taken together to form an optionally substituted heterocyclyl; wherein when R I A is R 10A , then R I 0A and R 4A can be taken together and include L I A , where L 1 A connects R I 0A and R 4A to form an 1 1 - to 20-membered ring, or wherein when R I A is R I 0A . then R I 0A and R 5A can be taken together and include L 1 A .
  • R 1 A can be OR 6A .
  • R 1 A can be hydroxy.
  • R 6A when R 1 A is OR 6A , R 6A can be C
  • R 6A when R I A is OR 6A , R 6A can be -C(0)R 7A .
  • suitable R 7A groups include, but are not limited to, hydrogen, alky l. alkeny l, alkynyl. cycloalkyl, cycloalkenyl. cycloalkynyl, aryl, heteroaryl. heterocyclyl. aryl(Ci-(, alkyl).
  • R 6A when R I A is OR 6A , R 6A can be -C(0)NR 8A R 9A .
  • R 8A and R 9A can be independently various substituents. such as hydrogen, alkyl. alkenyl, alkynyl. cycloalkyl. cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C ] _6 alkyl), heteroaryl (Ci_ 6 alkyl) or heterocyclyl(C i -6 alkyl). In some embodiments.
  • R 8A and R 9A can be taken together to form an optionally substituted heterocyclyl.
  • suitable optionally substituted heterocyclyls that can be formed from R 8A and R 9A include 5 to 6 membered heterocyclyls.
  • R 6A can be hydrogen, C
  • R '* can be hydrogen, -C(0)R 7A and -C(0)NR SA R 9A .
  • R 6A can be -C(0)R 7A and -C(0)NR 8 V A .
  • R I A can be NH?.
  • R I A can be an optionally substituted mono-substituted amine.
  • An example of a suitable mono- substituted amine is a group having the formula of -NHR 1 Aa , wherein R 1 Ad can be selected from alkyl, alkenyl, alkynyl, cvcloalkyl, cvcloalkenvl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(Ci_6 alkyl), heteroaryl(C
  • R I Aa can be selected from alkyl.
  • R I Aa can be selected from alkyl. aryl, and aryl(Ci -6 alkyl).
  • R I Aa can be a mono-substituted amine having the formula -NHR 1 Aa , R I Aa can be a substituted or unsubstituted group.
  • R can be an optionally substituted di-substituted amine.
  • R can be a group having the formula of -NR I Bb R 1Cc , wherein R I Bb and R I Ct can be independently selected from alkyl, alkenyl, alkynyl. cycloalkyl, cvcloalkenvl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C
  • R I Bb and R I Ct can be independently selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C
  • R I Bb and R I Cc can be independently selected from alkyl, aryl, and aryl(Ci_6 alkyl).
  • R I Bb and R I Cc can be the same.
  • R I Bb and R I Cc can be different.
  • R I A is a di-substituted amine having the formula -NR I Bb R I Cc .
  • R 1 Bb and R I Cc can be substituted or unsubstituted groups.
  • R I A can be an optionally substituted heterocyclyl.
  • Various heterocyclyls can be used and can be connected either through a ring carbon or a ring heteroatom.
  • the heterocyclyl can be a 5 to 6 membered heterocyclyl.
  • the heterocyclyl can include 1 heteroatom.
  • the heterocyclyl can include 2 heteroatoms, wherein the heteroatoms can be the same or different.
  • R I A can be an optionally substituted heterocyclyl that contains at least one nitrogen in the ring and is an N-linked heterocyclyl.
  • R I A can be an unsubstituted heterocyclyl.
  • R I A can be a substituted heterocyclyl.
  • R I A can be an optionally substituted N-sulfonamido.
  • the groups attached to the sulfur can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C
  • R L UD can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl. cycloalkynyl. aryl, heteroaryl, heterocyclyl, aryl(Ci -6 alkyl). heteroaryl(C i-6 alkyl) and heterocyclyl(C i-(, alkyl).
  • R I DD can be selected from alkyl, alkenyl. cycioalkyl. aryl. heteroaryl. heterocyclyl.
  • R MD can be a substituted or unsubstituted group.
  • G I A can be .
  • R 2A can be hydrogen.
  • R 2A can be a Ci -6 alkyl. Examples of suitable Ci-6 alkyl include methyl, ethyl, n-propyl, isopropyl. n-butyl. isobutyl. tert-butyl. straight or branched pentyl and straight or branched hexyl.
  • R 'lA can be hydrogen.
  • R 3A can be a C] _6 alkyl.
  • R 2A and R 3A can be the same. In other embodiments, R 2A and R 3A can be different.
  • R 2A and R jA can both be hydrogen.
  • R 2A and R 3A can both be a C , alkyl.
  • R 2A and R ⁇ lA can both be methyl.
  • R 2A and R 3A can be taken together to form an optionally substituted C 3-6 cycioalkyl.
  • Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When R 2A and R lA are taken together, the cycioalkyl group can be unsubstituted.
  • the cycioalkyl group can be substituted with one or more substituents.
  • R 2A and R 3A can be taken together to form an optionally substituted Cs cycioalkyl.
  • R A and R' A can be taken together to form an unsubstituted C cycioalkyl.
  • R 2A and R 3A can be taken together to form a mono-substituted or di- substituted Cs cycioalkyl.
  • R 2A and R ,A can be taken together to form an optionally substituted 5 to 6 membered heterocyclyl.
  • heterocyclyls examples include, but are not limited to, optionally substituted nitrogen containing 5 to 6 membered hetcrocyclyls.
  • R 2A and R' A can be taken together to form an optionally substituted 5 to 6 membered N-linked heterocyclyl, for example, an optionally substituted piperdino or an optionally substituted pyrrolidine
  • R 4A can be an optionally substituted aryl.
  • R 4A can be an optionally substituted naphthyl.
  • R 4A can be an optionally substituted phenyl.
  • R 4A can be an unsubstituted phenyl.
  • R 4A can be a substituted phenyl.
  • One or more groups can be present on a substituted phenyl.
  • the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl.
  • the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di-substituted phenyl, 2,4-di-substituted phenyl and 2,3 -di-substituted phenyl.
  • the substituted phenyl can be substituted with 3 or more substituent.
  • R 4A can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 4A can be an optionally substituted C4- 6 cycloalkyl.
  • R 4A can be an unsubstituted cycloalkyl.
  • R 4A can be a substituted cycloalky l.
  • R 4A can be an optionally substituted heteroaryl.
  • R 4A can be an unsubstituted heteroary l.
  • R 4A can be a substituted heteroaryl. Examples of suitable heteroaryls are described herein.
  • R 4A can be an optionally substituted monocyclic heteroaryl.
  • R 4A can be an optionally substituted bicyclic heteroaryl, for example, an optionally substituted lH-pyrrolo[2,3-b]pyridine.
  • R 4A can be an optionally substituted heterocyclyl.
  • R ' can be an unsubstituted heterocyclyl.
  • R 4A can be a substituted heterocyclyl.
  • R 4A can be an optionally substituted monocyclic heterocyclyl.
  • R 4A can be an optionally substituted bicyclic heterocyclyl.
  • R 4A When R 4A is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same.
  • R 4A when multiple substituents are present on R 4A , at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R 4A are different. In some embodiments.
  • R 4A can be substituted with one or more substituents selected from halogen. Ci -6 alkyl. alkoxy, aryloxy. haloalkyl. haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl. an optionally substituted heterocyclyl, carbonyl.
  • R 4A when R 4A is a substituted aryl, the aryl can be substituted with one or more groups selected from C i -6 alkyi. alkoxy, aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy.
  • R 4A when R 4A is a substituted cycloalkyl, the cycloalkyl can be substituted with C i -6 alkyl, alkoxy, halogen and haloalkyl.
  • R 4A when R 4A is a substituted heterocyclyl, the heterocyclyl can be substituted with C(- alkyl, alkoxy, halogen, haloalkyl, aryl(Ci- alkyl) and C-carboxy.
  • the substituted heterocyclyl of R 4A can be substituted with a substituted or an unsubstituted benzyl.
  • the pyridazinone ring can be connected to R 4A via a substituted or unsubstituted alkylene.
  • Z 1 A can be 0. In other embodiments.
  • Z I A can be 1 . In still other embodiments.
  • Z I A can be 2.
  • Z 1A can be 3.
  • Z I A can be 4.
  • Z 2A can be 0.
  • Z 2A can be 1 .
  • Z 2A can be 2.
  • Z 2A can be 3.
  • Z ⁇ A can be 4.
  • Z I A can be 1. and Z 2A can be 0. In other embodiments, Z I A and Z 2A can be both 1.
  • Z I A and Z 2A can be both >1. In yet still other embodiments, at least one of Z I A and Z" can be 1. In some embodiments, at least one of Z I A and Z 2A can be 1 , and the other of Z I A and Z 2A can be > l .
  • G can be R 5A .
  • R 5A can be a variety of groups.
  • R " A can be an optionally substituted aryl.
  • R can be an optionally substituted naphthyl.
  • R iA can be an optionally substituted phenyl.
  • R can be an unsubstituted phenyl.
  • R iA can be a substituted phenyl.
  • One or more groups can be present on a substituted phenyl.
  • the substituted phenyl can be a mono- substituted pheny l, such as an ortho-substituted phenyl, a meta-substituted pheny l or a para- substituted phenyl.
  • the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di-substituted phenyl. 2.4-di-substituted phenyl and 2,3-di-substituted phenyl.
  • the substituted phenyl can be substituted with 3 or more substituents.
  • R ,A can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R A can be a substituted or an unsubstituted C 4-6 cycloalkyl.
  • R ' ⁇ can be an unsubstituted cycloalkyl.
  • R ⁇ A can be a substituted cycloalkyl.
  • R ?A can be an optionally substituted heteroaryl.
  • R iA can be an unsubstituted heteroaryl.
  • R can be a substituted heteroaryl.
  • R iA can be an optionally substituted monocyclic heteroaryl.
  • R " A can be an optionally substituted bicyclic heteroaryl.
  • R ?A can be an optionally substituted heterocyclyl. In some embodiments. R ?A can be an unsubstituted heterocyclyl. In other embodiments, R ?A can be a substituted heterocyclyl. In some embodiments, R ⁇ can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R ?A can be an optionally substituted bicyclic heterocyclyl.
  • R ⁇ When R ⁇ is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R ⁇ , at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R 3A are different.
  • R A can be substituted with one or more substituents selected from halogen, C
  • R ?A when R ?A is a substituted aryl, the aryl can be substituted with one or more groups selected from Ci_ 6 alkyl. alkoxy, halogen and haloalky l.
  • R ⁇ A when R ⁇ A is a substituted aryl, the aryl can be substituted with one or more groups selected from C i-6 alkyl, alkoxy. aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy.
  • w hen R 5A is a substituted cycloalkyl.
  • the cycloalkyl can be substituted with C] _6 alkyl. alkoxy.
  • R dA when R dA is a substituted heterocyclyl, the heterocyclyl can be substituted with C
  • the substituted heterocyclyl of R A can be substituted with a substituted or an unsubstituted benzyl.
  • R I A is not mono-substituted amine, such as -NH- alkyl. In other embodiments, R 1 A is not di-substituted amine. For example, in some embodiments, R I A is not -N(alkyl) 2 , including -N(CH 3 ) 2 . In some embodiments, R 6A is not C
  • the fused bicyclic nitrogen-containing ring system of Formula (II) can be connected to R 4A to form a cyclic compound, for example, a compound of Formula (Ih)
  • the fused bicy cord nitrogen-containing ring system of Formula ( ⁇ ) can be connected to R ' ⁇ to form a cyclic compound, such as a compound of Formula (Ij).
  • R 1 A is R 1 0A .
  • R ' can be NR ' .
  • R ' can be NH.
  • R ' can be an optionally substituted -CH 2 -.
  • R I 0A can be O (oxygen).
  • R , 0A can be S (sulfur).
  • L I A can be -L 2A -.
  • L 2A can be selected from an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted heteroalkylene and an optionally substituted heteroalkenylcne.
  • L " can be an optionally substituted alkylene, for example, an optionally substituted C4-7 alkylene.
  • L 2A can be an optionally substituted alkenylene. such as an optionally substituted C4-7 alkenylene.
  • L 2A can be an optionally substituted heteroalkylene.
  • optionally substituted heteroalkylenes include the following: an optionally substituted -(CH 2 ) 3 -0-. an optionally substituted -(CH 2 ) 4 -0-, an optionally substituted -(CH 2 ) 5 -0-. an optionally substituted -(CH 2 ) 3 -S-. an optionally substituted -(CH 2 ) 4 -S-, an optionally substituted -(CH 2 )s-S-. an optionally substituted - (CH 2 ) 3 -NH-, an optionally substituted -(CH 2 ) 4 -NH-, and an optionally substituted -(CH 2 )s-NH-. In yet still other embodiments.
  • L ⁇ can be an optionally substituted -(CH 2 ) 3 -0-. an optionally substituted -(CH 2 ) 4 -0-. or an optionally substituted -(CH 2 ) 5 -0-.
  • L 2A can be an optionally substituted C 3 oxygen-containing heteroalkenylene. an optionally substituted C 4 oxygen-containing hetei alkenylene. or an optionally substituted C 5 oxygen-containing heteroalkenylene.
  • L 1 A can be -L 3A -L 4A -L :iA -, wherein L 3A can be an optionally substituted Ci -6 alkylene; L can be an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted heterocyclyl. O (oxygen), S (sulfur), or NR I I A ; and L can be an optionally substituted C
  • L ',A can be an optionally substituted Ci -4 alkylene;
  • L 4A can be optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryi;
  • L ?A can be an optionally substituted C
  • L ,A can be an optionally substituted C
  • L 4A can be O (oxygen), S (sulfur), or NR 1 1 A ;
  • L ⁇ A can be an optionally substituted C alkylcne.
  • L ' A can be optionally substituted C 2-4 alkylenc;
  • L 4A can be optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl.
  • O oxygen
  • S sulfur
  • NR I I A NR I I A ;
  • L ?A can be optionally substituted C?- 4 alkylene.
  • W A can be -N (nitrogen)-. In other embodiments, including those disclosed herewith respect to Formula (II). W A can be -CH 2 -. In some embodiments, one or more of the carbon atoms of the fused-bicyclic nitrogen-containing ring system of Formula (II) can be substituted. For example, one or both of the carbon atoms adjacent to W A can be substituted carbon instead of -CH- and/or W A can be substituted carbon instead of -CH-.
  • a compound of Formula (II) can be a compound selected from Formula (lla).
  • Formula (lib) Formula (lie) and Formula (lid):
  • Examples of compounds of Formula (II) include the following:
  • a suitable beta-keto ester is shown in Scheme 1 , and examples of suitable conditions include mildly acidic or neutral conditions.
  • the 6-membered pyridazinone ring can be formed via a cyclization reaction with N.N-dimethylformamide-dimethyl acetal (DMF-DMA).
  • the benzyl group can be cleaved, and the ester group can be undergo hydrolysis to form a compound of Formula (I). Cleavage of the benzy l group can be accomplished using palladium on carbon (Pd/C). Hydrolysis of the ester can be achieved using NaOH.
  • the benzy l group can be cleaved prior to the hydrolysis of the ester group.
  • the ester group can be hydrolyzed to a carboxylic acid prior to cleavage of the benzyl group.
  • R ⁇ When R ⁇ is substituted, a variety of methods can be used to add one or more substituents to R ' ⁇
  • the optionally substituted heterocyclyl can be added via an addition-elimination reaction to a halogen substituted compound having the formula R ' ⁇ -NCb.
  • a halogen substituted R ? -N0 2 can undergo ipso-substitution using an optionally substituted heterocyclyl.
  • the resulting substituted nitro compound can be reduced to an amine using methods known to those skilled in the art (for example. Raney nickel, PtO? or Pd/C).
  • a compound of Formula (1) can then be obtained following the general reaction scheme shown in Scheme 1 .
  • a general scheme starting with an example of a nitro compound is provided in Scheme 2.
  • the phenyl ring can be further substituted with one or more substituents.
  • Another method for adding one or more substituents to form a substituted R 5 is using a boronic acid or boronic ester.
  • a boronic acid or boronic ester can be used in a Suzuki coupling type-reaction to add one or more substituents to R 3 .
  • Suitable conditions include using a palladium catalyst and a base (for example. Pd(PPh 3 )4 and K 2 C0 3 ).
  • a non-limiting example using a boronic acid or boronic ester to form a substituted Rs is shown in Scheme 3.
  • the phenyl ring can be further substituted with one or more substituents.
  • a compound of Formula (I) can be obtained via the general reaction scheme shown in Scheme 1.
  • X can be a halogen and R" can be an optionally substituted alkyl or an optionally substituted aryi.
  • a compound of Formula (T) can be obtained after the benzyl group is cleaved and the ester group undergoes hydrolysis.
  • Suitable coupling reagents can be used, including 2-( l H-Bcnzotriazole- l -yl)- l , l ,3,3- tetramethy luronium hexafluorophosphate (HBTU).
  • R 1 is a group other than a hydroxy or C i -6 alkoxy.
  • G and G ⁇ are as defined above. Additional information with respect to preparing compounds of Formula (I) is provided in U.S. Patent No. 4.345.934.
  • U.S. Publication No. U.S. 2009/281 107A1 U.S. Publication No. U.S. 2010/197651 Al.
  • a method for forming a compound of Formula (1) where G may be
  • R 1 may be an alkyl, such as methyl, is shown in Scheme 6.
  • the ester group can undergo hydrolysis to form a carboxylic acid.
  • the carboxylic acid can then be transformed using methods known to those skilled in the art to form the desired R 1 group.
  • an amide and the carboxylic acid group can undergo a coupling reaction to form a substituted amide group.
  • suitable amides include Weinreb amides, such as HNMe(OMe).
  • Suitable coupling reagents are known to those skilled in the art and include 2-(lH-Benzotriazole-l-yl)-l.l ,3.3-tetramethyiuronium hexafluorophosphate (HBTU).
  • HBTU 2-(lH-Benzotriazole-l-yl)-l.l ,3.3-tetramethyiuronium hexafluorophosphate
  • Example methods for forming a compound of Formula (1) where G 2 is an optionally substituted C , - 6 alkyl; -CH 2 OH; -CH(Y ')(0H), -C(0)Y' are shown in Scheme 7.
  • a 6-membered pyridazinone ring can be formed via a cyclization of the starting material with AyV-dimcthylacetamidc-dimethyl acetal or cinnamoyl chloride.
  • An example of using cinnamoyl chloride is provided in U.S. Publication No. 2012/0022251. which is hereby incorporated by reference for the limited purpose of using cinnamoyl chloride.
  • the 6-membered pyridazinone ring can be further modified to form a compound of Formula (I) where G 2 is an optionally substituted C
  • the nitrogen of the 6- membered pyridazinone ring may be alkylated using methods known to those skilled in the art.
  • G 2 is a C , _ 6 alkyl; -CH 2 OH; -CH(Y' )(OH). -C(0)Y' .
  • the exocyclic styrene alkene moiety may be oxidatively cleaved to afford an aldehyde, for example, via ozonolysis or using a sodium periodate - ruthenium trichloride mixture or the like.
  • the aldehyde may be reduced to afford an alcohol or reacted with a Grignard reagent under appropriate conditions.
  • G" is -CH 2 OH
  • the aldehyde may be reduce using sodium borohydride
  • G" -CH(CH 3 )OH
  • the aldehyde may be reacted with a Grignard reagent.
  • the alcohol may be oxidized to form a ketone at G " (for example, G 2 is C(O)Me) using appropriate conditions known to those skilled in the art, such as ozonolysis.
  • a method for forming a compound of Formula (I) where G ⁇ is-CN; or an optionally substituted aryl is shown in Scheme 8.
  • the ⁇ position of the ⁇ . ⁇ - unsaturated ketone in the 6-membered pyridazinone ring may be brominated using NBS (N- bromosuccinimide) under appropriate conditions to afford the vinyl bromide.
  • NBS N- bromosuccinimide
  • An example of using NBS is described in WO 2012/039414, which is hereby incorporated by reference for the limited purpose of using NBS.
  • the vinyl bromide may be treated with CuCN under appropriate conditions, for example as described in U.S. Patent No. 5,202,323 to afford a compound of Formula (I) where G 2 is -CN.
  • the vinyl bromide may be reacted with an aryl boronic acid (such as phenyl boronic acid) under appropriate conditions (for example, using a palladium catalyst) followed by further modification to afford a compound of Formula (I) where G ⁇ is an optionally substituted aryl.
  • an aryl boronic acid such as phenyl boronic acid
  • Example methods for forming a compound of Formula (I) that includes a macrocyclic ring formed from R I O -L' -R 4 are shown in Schemes 9 and 1 0.
  • the starting material may be reacted with allyltributyl tin in the presence of a metal catalyst, such a palladium, to afford the allyl intermediate.
  • the ester of the allyl intermediate may be hydrolyzed to afford an intermediate that includes a carboxylic acid moiety, which can be then reacted with an allyl amine via a coupling reaction to afford a diene intermediate.
  • Suitable coupling reagents can be used, including 2-(l H-Benzotriazole-l -yl)-l , 1.3,3- tetramethyluronium hexalluorophosphate (HBTU).
  • the diene intermediate can undergo a ring closing olefin metathesis macrocyclization using a suitable catalyst, for example, a Grubb " s type catalyst to afford the alkene compound.
  • a suitable catalyst for example, a Grubb " s type catalyst to afford the alkene compound.
  • suitable Grubb's type catalysts are described in in Tetrahedron Letters (2003), 44( 1 1 ):2401 -2404, which is incorporated by reference for the limited purpose of its description of Grubb's type catalysts.
  • the alkene may be hydrogenated, and the benzyl group may be cleaved, for example, using hydrogen (H 2 ) over Pd/C to afford to a compound of Formula (I).
  • the starting material may be reacted with an ally bromide that includes a protected amine to afford a protected amine intermediate.
  • the ester of the protected amine inlemiediate may be hydrolyzed to afford an intermediate that includes a carboxylic acid moiety and then the protecting group of the amine may be removed.
  • the carboxylic acid moiety can be reacted with the amine via an intramolecular macrolactamization coupling reaction, for example as described in Chemical Communications (2002), (12): 1280- 1281 , and WO 2009/004146, to afford the macrolactam intermediate.
  • the benzyl group of the macrolactam intermediate may be cleaved, for example, using TFA or BCI3 to afford to compounds of Formula (1).
  • a method for forming a compound of Formula (II) where R 1 A is a mono- substituted amine is shown in Scheme 1 1 .
  • the starting may be reacted with acetamidobenzenesulfonyl azide (ABSA) under appropriate conditions using methods and conditions known to those skilled in the art, for example, as described in WO 201 1 /120153. to afford the diazo intermediate.
  • the diazo intermediate may be reduced under appropriate conditions using methods and conditions known to those skilled in the art. for example using trimethy phosphine as described in WO 201 1 /120153 or tributyl phosphine as described in Chem. Pharm. Bull. (1988). 36: 1321 -1327.
  • the hydrazone intermediate may be alkylated under appropriate conditions using methods and conditions known to those skilled in the art to afford the alkyl hydrazine intermediate.
  • the alkyl hydrazone intermediate may be cyclized using a strong base (such as sodium hydride or LDA), for example as described in Chem. Pharm. Bull. ( 1989). 37:93-98. to afford the pyrimido[5.4-c]pyridazin-4(lH)-one intermediate.
  • the tert-butyl ester of the pyrimido[5.4- c]pyridazin-4(lH)-one intermediate may be cleaved using an acid, such as TFA, to afford an intermediate that includes a carboxylic acid moiety.
  • the carboxylic acid moiety can be reacted with methyl amine via a coupling reaction to afford the a compound of Formula (11).
  • Suitable coupling reagents can be used, including 2-( l H-Benzotriazole- l -yl)-l , 1.3,3- tetramethy luronium hexafluorophosphate (HBTU).
  • compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • composition refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • the term ''physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent'” is a type of excipient.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be administering intramuscular.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be administering intranasal.
  • an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein can be administering intradermal.
  • an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be administering orally.
  • one or more compounds described herein can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to assist in simulating nasal secretions.
  • compositions may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Some embodiments described herein relate to a method of ameliorating, treating and/or preventing an orthomyxovirus infection, which can include administering an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing).
  • a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing).
  • inventions described herein relate to a method of inhibiting an orthomyxovirus viral replication, which can include contacting a cell infected with the orthomyxovirus virus with an effective amount of a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing).
  • an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used to treat and/or ameliorate an influenza viral infection.
  • an effective amount of one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used to prevent an influenza viral infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing) can be used to inhibit the replication an influenza virus.
  • an effective amount of one or more compounds of Formulae (1) can be used to inhibit the replication an influenza virus.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein can be used to inhibit the influenza polymerase complex.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein e.g..
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be used for inhibiting and/or reducing the endonuclease activity of an influenza endonuclease that can include contacting the active site of the endonuclease with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing.
  • one or more compounds described herein inhibits and/or reduces the ability of the endonuclease to cleave the mRNA.
  • influenza viral infection can be an influenza A viral infection.
  • influenza viral infection can be an influenza B viral infection.
  • influenza viral infection can be an influenza C viral infection.
  • a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be used to treat and/or ameliorate one or more subtypes of influenza.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used to treat HlNl and/or H3N2.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be used to treat H2N2, H5N 1 and/or H7N9.
  • a compound described herein (a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be effective against more than 1 subtype of influenza.
  • a compound described herein (a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be effective against 2, 3, 4, and/or 5 or more subtypes of influenza.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate an upper respiratory viral infection attributed to (directly and/or indirectly) an influenza virus infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate a lower respiratory viral infection (directly and/or indirectly) an influenza virus infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (II) can be used treat and/or ameliorate a lower respiratory viral infection (directly and/or indirectly) an influenza virus infection.
  • a compound of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to an influenza virus infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate pneumonia due to an influenza virus infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate coup due to an influenza virus infection.
  • an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used lessen the severity of one or more symptoms of an influenza infection.
  • symptoms include, but are not limited to. the following: fever, chills, cough, sore throat, runny nose, stuffy nose, muscle aches, body aches, headache, fatigue, vomiting and/or diarrhea.
  • prevention mean a subject does not develop an infection because the subject has an immunity against the infection, or if a subject becomes infected, the severity of the disease is less compared to the severity of the disease if the subject has not been administered/received the compound.
  • forms of prevention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as an orthomyxovirus (e.g., an influenza virus).
  • treat do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject ' s overall feeling of well-being or appearance.
  • a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject is human.
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.
  • an effective amount of a compound of Formula (1). or a pharmaceutically acceptable salt thereof is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formula (1), or a pharmaceutically acceptable salt thereof.
  • an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof can be an amount that is effective to reduce viral load to lower than about 10E4 TCTD50/mL.
  • an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is an amount that is effective to achieve a reduction in viral titer in a nasal/pharyngcal swab or nasal wash sample of the subject in the range of about 1 .5-log to about a 2.5-log reduction or about a 3-log to about a 4-log reduction compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the viral load is measure before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after initiation of the treatment regime with the compound of Formula (1), or a pharmaceutically acceptable salt thereof (for example. 10 days after initiation of treatment).
  • a compound of Formula (1), or a pharmaceutically acceptable salt of the foregoing can result in one or more overall quality of life health, such as reduced illness duration, reduced illness severity, reduced time to return to normal health and normal activity, and reduced time to alleviation of one or more symptoms of orthomyxovirus infection, compared to a subject who is untreated.
  • a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing can result in a reduction in the length and/or severity of one or more symptoms associated with an orthomyxovirus infection compared to an untreated subject.
  • Symptoms of an orthomyxovirus infection include but not limited to cough, myalgia (muscle pain), nasal obstruction, sore throat, fatigue, headache and fever.
  • a compound of Formula (I), or a pharmaceutically acceptable salt of the thereof can result in a reduction in one or more secondary complications associated with an orthomyxovirus infection, including but not limited to otitis media (ear inflammation), sinusitis, bronchitis and pneumonia compared to an untreated subject.
  • a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing can result in at least a 1 , 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of an orthomyxovirus relative to pre-treatment levels in a subject, as determined after initiation of the treatment regime (for example, 10 days after initiation of treatment).
  • a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing can result in a reduction of the replication of an orthomyxovirus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in a reduction of orthomyxovirus replication in the range of 1 to 1 .5 log. 1 .5 log to 2 log. 2 log to 2.5 log, 2.5 to 3 log, or 3 to 3.5 log reduction of orthomyxovirus replication compared to the reduction of orthomyxovirus reduction achieved by oseltamivir (Tamiflu®). or may achieve the same reduction as that of oseltamivir (Tamiflu®) therapy in a shorter period of time, for example, in one day, two days, three days, or four days as compared to the reduction achieved after 5 days of oseltamivir (Tamiflu®) therapy.
  • infectious agents can develop resistance to one or more therapeutic agents.
  • resistance refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s).
  • the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain.
  • a compound of Formulae (I) and/or (11), or a pharmaceutically acceptable salt of the foregiong can be administered to a subject infected with an influenza virus that is resistant to one or more different anti-influenza agents (for example, amantadine, rimantadine and/or oseltamivir).
  • a compound of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing can be administered to a subject infected with an influenza virus that is resistant to a M2 protein inhibitor.
  • development of resistant influenza strains is delayed when subjects are treated with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, compared to the development of influenza strains resistant to other influenza drugs.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can decrease the percentage of subjects that experience complications from an influenza viral infection compared to the percentage of subjects that experience complication being treated with oseltamivir.
  • the percentage of subjects being treated with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, that experience complications can be 10%, 25%, 40%, 50%,. 60%, 70%,, 80% and 90%, less compared to subjects being treated with oseltamivir.
  • a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein can be used in combination with one or more additional agent(s).
  • a compound of Formula (1). or a pharmaceutically acceptable salt thereof can be used in combination with one or more agents currently used in a conventional standard of care for treating influenza.
  • the additional agent can be amantadine (adamantan-
  • additional agents include but are not limited to a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, peramivir (( 1 S,2S,3S,4R)-3-[( 1 S)- 1 -acetamido-2-ethylbutyl]-4-(diaminomethyiideneamino)-
  • 2- hydroxycyclopentane-l-carboxylic acid BioCryst Pharmaceuticals
  • laninamivir ((4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[( lR,2R)-3-hydiOxy-2-methoxypiOpyl]-5,6- dihydro-4H-pyran-2-carboxylic acid)
  • favipiravir T-705. 6-fluoro-3-hydroxy-2- pyrazinecarboxamide).
  • laninamivir octanoate ((3R,4S)-3-acetamido-4-guanidino-2-((l S,2S)- 2 -hydroxy- 1 -methoxy-3 -(octanoyloxy )propyl )-3 ,4-dihydro-2H-pyran-6-carboxylic acid) fludase (DAS 1 81 , NexBio), ADS-8902 (amantadine HCl/oseltamivir/ribavirin, Adamas Pharmaceuticals), an immuno-modulator (for example, a Type 1 interferon), beraprost (4- [2- hydroxy- 1 - [(E)-3-hydroxy-4-methyloct- 1 -en-6-ynyl] -2,3 ,3a,8b-tetrahydro- 1 H- cyclopenta[b] [l ]benzofuran-5-yl]butanoic acid), Neugene®,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein can be used in combination with oseltamivir.
  • Type 1 interferons are known to those skilled in the art. A non-limiting list of examples include: alpha-interferons, beta-interferons, delta-interferons, omega- interferons, tau-interferons, x-interferons. consensus interferons and asialo-interferons. Type 1 interferons can be pegylated. Examples of specific type 1 interferons include interferon alpha 1 A, interferon alpha I B. interferon alpha 2A.
  • interferon alpha 2B pegylated-interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX. Aradigm), pegylated-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON. Schering). recombinant interferon alpha 2b (INTRON A. Schering). pegylated interferon alpha 2b (PEG-INTRON. Schering. V1RAFERONPEG, Schering), interferon beta- la (REB1F, Serono, Inc. and Pfizer), consensus interferon alpha (1NFERGEN, Valeant Pharmaceutical).
  • a compound of Formulae (I) and/or (11), or a pharmaceutically acceptable salt of the foregoing can be administered with one or more additional agent(s) together in a single pharmaceutical composition.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition.
  • one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, with one or more additional agent(s) can vary.
  • a compound of Formulae ( ⁇ ) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be administered prior to all additional agents.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be administered prior to at least one additional agent.
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can he administered concomitantly with one or more additional agent(s).
  • a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing can be administered subsequent to the administration of at least one additional agent, hi some embodiments, a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered subsequent to the administration of all additional agents.
  • the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in an additive effect.
  • the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in a synergistic effect.
  • the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in a strongly synergistic effect.
  • the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) is not antagonistic.
  • the term "antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound).
  • the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
  • a potential advantage of utilizing a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the required amount(s) of the one or more additional agents, including pharmaceutically acceptable salts and prodrugs thereof, that is effective in treating a disease condition disclosed herein (for example, influenza), as compared to the amount required to achieve the same therapeutic result when one or more of the additional agents, including pharmaceutically acceptable salts and prodrugs thereof, are administered without a compound of Formulae (I) and/or ( ⁇ ). or a pharmaceutically acceptable salt of the foregoing.
  • a disease condition disclosed herein for example, influenza
  • the amount of an additional agent described above, including a pharmaceutically acceptable salt and prodrug thereof can be less when administered in combination with a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing, compared to the amount of additional agent, including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy.
  • Another potential advantage of utilizing a compound of Formulae ( ⁇ ) and/or (11), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereoi; is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
  • Additional advantages of utilizing a compound of Formulae (I) and/or ( ⁇ ). or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross resistance between a compound of Formulae (I) and/or ( ⁇ ).
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
  • the dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1 % and 500%. more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • dosages may be calculated as the free base.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how 7 to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest w ill vary w ith the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age. body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • Compound 317 was obtained following the procedure for obtaining compound 300 using (2-hydroxyphenyl)boronic acid with the modification that the boronic acid coupling product was alkylated using bromocyclohexane in DMF at RT using sodium iodide and potassium carbonate.
  • LCMS (ESI) m/z 407 [M+H] + .
  • Compound 631 was obtained by first following the procedure for obtaining compound 3e using (2-(piperidin- l -yl)phenyl)boronic acid and then following the procedure for obtaining compound 601 using methylamine.
  • LCMS (ESI) m/z 405 [M+H] .
  • Human lung carcinoma A549 cells (ATCC, Manassas, VA) were plated at a density of 5 x 10 4 cells/mL (5 x 10 J cells/well) in assay media (HanTs F12 media supplemented with 0.3% FBS, 1 % penicillin/streptomycin (all Mediatech. Manassas, VA) and 1 % DMSO (Sigma-Aldrich. St Louis. MO)) in black 96-well plates. Alternatively.
  • Madin-Darby canine kidney epithelial cells (MDCK. ATCC), were plated at a density of 1 x 10 5 cells/mL (1 x 10 4 cells/well) in assay media (DM EM supplemented with 0.3% FBS, 1 % penicillin/streptomycin and 1 % DMSO) in 96-well plates. After 24 hours, serially diluted test compounds were added to cells and incubated for an additional 24 hours. Cells were infected with 250 lU/well of Influenza strain A549 A/WSN/33 (H1 N1 ) (Virapur, San Diego CA) and incubated for 20 hours at 37°C. 5% CO?.
  • the cell culture supernatant was aspirated off and 50 ⁇ iL of 25 ⁇ 2 , -(4-Methylumbelliferyl)-a-D-N-acetylneuraminic acid (Sigma- Aldrich) dissolved in 33 mM MES, pH 6.5 (Emerald Biosystems. Bainbridge Island, WA) was added to the cells. After incubation for 45 mins at 30°C. reactions were stopped by addition of 1 50 ⁇ iL stop solution (100 mM glycine, pH 10.5. 25% ethanol, all Sigma- Aldrich). Fluorescence was measured with excitation and emission filters of 355 and 460 nm, respectively, on a Victor X3 multi-label plate reader (Perkin Elmer.
  • Cytotoxicity of uninfected parallel cultures was determined by addition of 100 ⁇ of CellTiter-GloODreagent (Promega, Madison, Wl), and incubation for 10 mins at T. Luminescence was measured on a Victor X3 multi-label plate reader.
  • EN PA FRET inhibition assay was performed using a 19 nucleotide synthetic oligoribonucleotide substrate: 5 , -FAM-AUUUUGUUUUUAAUAUUUC-BHQ-3 , (Integrated DNA Technologies. Inc.. Coralville. ⁇ ) (SEQ. ID. NO. 1 ). Upon RNA cleavage, the fluorescent FAM group is released from the BHQ quencher.
  • the PA sequence used to produce active enzyme is derived from any one of multiple influenza A virus strains (e.g...
  • ICso is defined as the concentration at which fluorescence is 50% that of the uninhibited control (DMSO).

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Abstract

Disclosed herein are pyridazinone compounds, pharmaceutical compositions that include one or more pyridazinone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with a pyridazinone compounds. Examples of an orthomyxovirus viral infection includes an influenza infection.

Description

PYRIDAZ1NONE COMPOUNDS AND USES THEREOF
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.
SEQUENCE LISTING
[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled ALIOS081 , created September 9, 2014. which is 4 kb bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.
BACKGROUND
Field
[0003] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are pyridazinone compounds, pharmaceutical compositions that include one or more pyridazinone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating an orthomyxovirus viral infection with one or more pyridazinone compounds.
Description
[0004] The viruses of the Orthomyxoviridae family are negative-sense, single- stranded RNA viruses. The Orthomyxoviridae family contains several genera including Influenzavirus A, Influenzavirus B, Influenzavirus C. Isavirus and Thogotovirus. Influenzaviruses can cause respiratory viral infections, including upper and lower respiratory tract viral infections. Respiratory viral infections are a leading cause of death of millions of people each year. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory system below the vocal cords, including the trachea, primary7 bronchi and lungs. SUMMARY
[0005] Some embodiments disclosed herein relate to a compound of Formula (T), or a pharmaceutically acceptable salt thereof. Other embodiments disclosed herein relate to a compound of Formula (11). or a pharmaceutically acceptable salt thereof.
[0006] Some embodiments disclosed herein relate to methods of ameliorating and/or treating an orthomyxovirus viral infection that can include administering to a subject suffering from the orthomyxovirus viral infection an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing. Other embodiments described herein relate to using one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, in the manufacture of a medicament for ameliorating and/or treating an orthomyxovirus viral infection. Still other embodiments described herein relate to compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, that can be used for ameliorating and/or treating an orthomyxovirus viral infection. Yet still other embodiments disclosed herein relate to methods of ameliorating and/or treating an orthomyxovirus viral infection that can include contacting a cell infected with the orthomyxovirus with an effective amount of one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing. Some embodiments disclosed herein relate to methods of preventing an orthomyxovirus infection that can include administering to a subject an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing. For example, the orthomyxovirus viral infection can be an influenza viral infection (such as influenza A, B and/or C).
[0007] Some embodiments disclosed herein relate to methods of inhibiting the replication of an orthomyxovirus that can include contacting a cell infected with the
-1- orthomyxovirus with an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (1) and/or (Π). or a pharmaceutically acceptable salt of the foregoing. For example, the orthomyxovirus viral infection can be an influenza viral infection (such as influenza A. B and/or C). Other embodiments disclosed herein relate to a method for inhibiting endonuclease activity of an influenza endonuclease that can include contacting the active site of the endonuclease with an effective amount of one or more compounds of Formulae (1) and/or (II). or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing. These and other embodiments are described in greater detail below7.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 show s example anti-influenza agents.
DETAILED DESCRIPTION
[0009] Influenza is a negative sense, single stranded RNA virus and a member of the Orthomyxoviridae family. There are currently three species of influenza; influenza A. influenza B and influenza C. Influenza A has a lipid membrane derived from the host cell, which contains the hemagglutinin, neuramididase and M2 proteins that project from the surface of the virus. Influenza A has been further classified based the hemagglutinin (H or HA) and the neuramididase (N). There are approximately 16 H antigens (HI to HI 6) and 9 N antigens (Nl to N9). Influenza A includes several subtypes, including H1 N1. H1 N2. H2N2. H3N1. H3N2, H3N8, H5N1 , H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2 and H10N7. The influenza virus polymerase is a heterotrimer composed of three subunits, polymerase acid (PA), polymerase basic 1 (PB 1 ) and polymerase basic 2 (PB2). This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells. The PA subunit contains the endonuclease active site. The endonuclease activity of the PA cleaves the cellular mRNA. which is then used by the PB 1 subunit as a primer for the viral mRNA synthesis.
-J- [0010] Influenza viruses can be transmitted from person to person via direct contact with infected secretions and/or contaminated surfaces or objections. Complications from an influenza viral infection include pneumonia, bronchitis, dehydration, and sinus and ear infections. Medications currently approved by the FDA against an influenza infection include a limited number of neuraminidase inhibitors and M2 protein inhibitors. Examples of approved neuraminidase inhibitors and M2 protein inhibitors include amantadine, rimantadine, Relenza® (zanamivir. GlaxoSmithKline) and Tamiflu® (oseltamivir. Genentech).
Definitions
[00111 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary7 skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0012] As used herein, any "R" group(s) such as, without limitation, R1 , R2, R', R4, and R6 represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstitutcd. If two "R" groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl. ary l, heteroaryl or heterocycle. For example, without limitation, if Ra and Rb of an NRa Rb group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
Figure imgf000006_0001
In addition, if two R" groups are described as being "taken together" with the atom(s) to which they are attached to form a ring as an alternative, the R groups may not be limited to the variables or substituents defined previously.
[0013] Whenever a group is described as being "'optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl. alkynyl. cycloalkyl. cycloalkenyl, aryl, heteroaryl. heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl )alkyl, hydroxy, alkoxy. acyl. cyano. halogen, thiocarbonyl, O-carbamyl, N-carbamyl. O-thiocarbamy l, N-thiocarbamyl. C-amido. N-amido, S-sulfonamido. N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato. isothiocyanato, nitro. azido, silyl, sulfenyl, sulfinyl. sulfonyl. haloalkyl. haloalkoxy. trihalomethanesulfonyl. trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
[0014| As used herein. "Ca to Ct," in which "a" and "b" are integers refer to the number of carbon atoms in an alkyl. alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroyclyl group. That is, the alkyl. alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl, ring(s) of the heteroaryl or ring(s) of the heterocyclyl can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "C ( to C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH -, CH CH2-, CH3CH2CH2-, (CH3)2CH-, CH CH2CH2CH2-. CH3CH2CH(CH3)- and (CH )3C-. If no "a" and "b" are designated with regard to an alkyl. alkenyl, alkynyl. cycloalky l cycloalkenyl, aryl. heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.
[0015] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g. , "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom. 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as "C |-C4 alkyl" or similar designations. By way of example only , "C| -C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl. butyl, isobutyl. tertiary butyl, penty l (straight and branched) and hexyl (straight and branched). The alkyl group may be substituted or unsubstituted.
[0016] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.
[0017| As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.
[0018| As used herein, "cycloalkyl" refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0019] As used herein, "cycloalkenyp refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl." as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
[0020] As used herein, "aryl" refers to a carbocyclic (all carbon) mono-cyclic or multi-cyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C i 4 aryl group, a C6-C |0 aryl group, or a C6 aryl group. Examples of aryl groups include, hut are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
[0021 ] As used herein, "heteroaryl" refers to a mono-cyclic or multi-cyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms. that is. an element other than carbon, including but not limited to. nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroary l group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s). 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryf" includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan. furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, thiazole, 1 ,2.3-thiadiazole. 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole. isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.
[0022] As used herein, "heterocyclyl'" or "heteroalicyclyl" refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 1 8-membered mono-cyclic, bicyclic. and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to. oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" groups include but are not limited to, 1 ,3-dioxin, 1 ,3- dioxane, 1 ,4-dioxane, 1 ,2-dioxolane, 1 ,3-dioxolane, 1 ,4-dioxolane, 1 ,3-oxathiane, 1 ,4- oxathiin, 1 ,3-oxathiolanc, 1 ,3-dithiole, 1 ,3-dithiolanc, 1 ,4-oxathiane, tctrahydro- l ,4-thiazinc, 2H- l ,2-oxazine, maleimide, succinimide. barbituric acid. thiobarbituric acid, dioxopiperazine. hydantoin, dihydrouracil, trioxane. hexahydro-1.3,5-triazine. imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline. thiazolidine, morpholine, oxirane, piperidine A -Oxide, piperidine. piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine. tetrahydropyran,
Figure imgf000010_0001
tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone. and their benzo-fused analogs (e.g., benzimidazolidinone. tetrahydroquinoline and 3,4-methylenedioxyphenyl).
[0023] As used herein, the term "alkylene" refers to a straight or a branched tethering fully saturated (no double or triple bonds) hydrocarbon group that connect molecular fragments via its terminal carbon atoms. Examples include but are not limited to methylene (-CH2-). ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-(CH2)4-) groups. A "lower alkylene group" refers to an alkylene group containing 1 to 6 carbons. A lower alkylene and alkylene group can be substituted by replacing one or more hydrogen of the lower alky lene group or alky lene group with a substituent(s) listed under the definition of "substituted."
[0024] As used herein, the term "alkenylene" refers to a straight or a branched tethering hydrocarbon group containing one or more double bonds that connect molecular fragments via its terminal carbon atoms. Examples include but are not limited to ethenylene (-CH=CH-). propenylene (-CH-CHCFE- or -CH2CH-CH-), and butenylene (- CH=CHCH2CH2-, -CH2CH=CHCH2- or - CH2CH2CH=CH-) groups. An alkenylene group may be substituted or unsubstituted.
[00251 As used herein, the term "heteroalkylene" refers to an alkylene containing one or more heteroatom groups or heteroatom containing groups in the carbon back bone (i.e., an alkylene group in which one or more carbon atoms is replaced with a heteroatom group or heteroatom containing group). In some embodiments, heteroalkyls may be substituted or unsubstituted. Heteroalkyls include, but are not limited to ether, thioether, amino-alkylene, and alkyiene-amino-alkylene moieties. Examples of heteroalkyls include, but are not limited to, -CH20-, -CH2CH2CH2CH20-, -CH2OCH2-, -CH2OCH2CH2-, - CH2CH2OCH2CH2-, -CH2OCH2CH2CH2-, -CH2OCH2CH2-, -(CH2)20(CH2)2-, -CH2S-, - CH2CH2CH2CH2S-, -CH2SCH2-. -CH2SCH2CH2-. -CH2CH2SCH2CH2-, -CH2SCH2CH2CH2-. -CH2SCH2CH2-. -(CH2)2S(CH2)2-, -CH2NH-. -CH2CH2CH2CH2NH-, -CH2NHCH2-. - CH2NHCH2CH2-. -CH2CH2NHCH2CH2-. -CH2NHCH2CH2CH2-, -CH2NHCH2CH2-, - (CH2)2NH(CH2)2-. and the like.
[0026] As used herein, the term "heteroalkenylene" refers to an alkenylene containing one or more heteroatoms in the carbon back bone (i.e., an alkenylene group in which one or more fully saturated carbon atoms (i.e. CH2) is replaced with a heteroatom group or a heteroatom containing group). In some embodiments, heteroalkenyls may be substituted or unsubstituted. Examples of heteroalkenyls include, but are not limited to, - CH=CHCH2OCH2CH2-, -CH=CHCH2OCH2CH2CH2-, -CH=CHCH2OCH2CH2-, CH2CH=CHCH20-, -CH2CH2CH=CHCH20-, -CH2CH2CH2CH=CHCH20-, (CH2)2CH=CH(CH2)20-, -CH=CHCH2S-, -CH=CHCH2SCH2-, -CH=CHCH2SCH2CH2-, - CH=CHCH2CH2SCH2CH2-, -CH=CHCH2SCH2CH2CH2-, -CH=CHCH2SCH2CH2-, - CH2CH=CHCH2S-. -CH2CH2CH=CHCH2S-. -CH2CH2CH2CH=CHCH2S-, (CH2)2CH=CH(CH2)2S-, -CH=CHCH2NH-, -CH=CHCH2NHCH2-,
Figure imgf000011_0001
CH=CHCH2NHCH2CH2-, -CH2CH=CHCH2NH-, -CH2CH2CH=CHCH2NH-.
CH2CH2CH2CH=CHCH2NH-, -(CH2)2CH=CH(CH2)2NH-. and the like.
[0027] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and/or aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
[0028] As used herein, "heteroaralkvl" and "heteroaryl(alkyr)'" refer to a heteroarvl group connected, as a substituent, via a lower alkylene group. The lower alkylene and/or heteroarvl group of heteroaralkvl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzo-fused analogs. [0029] A "(heteroalicyclyl)alkyl" and "(heterocyclyl ^lkyl" refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alky lene and/or heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methy l, (piperidin-4-yl)ethyl. (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1 ,3-thiazinan-4-yl)methyl.
[0030] As used herein, "alkoxy" refers to the formula -OR wherein R is alkyl. alkenyl. alkynyl, cycloalkyl, cycloalkenyl. aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyi or (heterocyclyl )alkyl is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy. n-propoxy. 1 -methyl ethoxy (isopropoxy), n-butoxy. iso-butoxy, sec-butoxy. tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.
[0031] As used herein, "acyl" refers to a hydrogen, alkyi, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
[0032] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl, 3 -hydroxy propyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
[0033] As used herein, "haloalky l" refers to an alky l group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalky l, di-haloalky l and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl. difluoromethyl, trifluoromethyl, l -chloi -2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0034] As used herein, "haloalkoxy" refers to an alkoxy group of the formula -O- alkyl in which one or more of the hydrogen atoms are replaced by a halogen (e.g.. mono- haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to. chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l -chloro-2- fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
[0035] A "sulfenyl" group refers to an "-SR" group in which R can be hydrogen, alkyl. alkenyl. alkynyl. cycloalkyl. cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. A sulfenyl may be substituted or unsubstituted. [0036] A "sulfmyl" group refers to an "-S(=0)-R" group in which R can be the same as defined with respect to sulfenyl. A sulfmyl may be substituted or unsubstituted.
[0037] A "sulfony l" group refers to an "SO2R" group in which R can be the same as defined with respect to sulfenyl. A sulfony l may be substituted or unsubstituted.
[0038] An "O-carboxy" group refers to a "RC(=0)0-" group in which R can be hydrogen, alkyl. alkenyl. alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl. aralkyl, (heteroaryl )alkyl or (heterocyclyl)alkyl. as defined herein. An O-carboxy may be substituted or unsubstituted.
[0039] The terms "ester" and "C-caiboxy" refer to a "-C(=0)OR" group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.
[0040] A "thiocarbonyl" group refers to a '"-C(=S)R" group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
[0041] A "trihalome hanesulfonyl" group refers to an "X3CSO2-" group wherein each X is a halogen.
[0042] A "trihalomethanesulfonamido" group refers to an "X3CS(0)2N(RA)-'" group wherein each X is a halogen, and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.
[0043] The term "amino" as used herein refers to a -NH? group.
[0044] As used herein, the term "hydroxy" refers to a -OH group.
[0045] A "cyano" group refers to a "-CN" group.
[0046] The term "azido" as used herein refers to a -N3 group.
[0047] An "isocyanato" group refers to a "-NCO" group.
[0048] A "thiocyanato" group refers to a "-CNS" group.
[0049] An "isothiocyanato" group refers to an " -NCS" group.
[0050] A "carbonyl" group refers to a C=0 group.
[0051 ] An "S-sulfonamido" group refers to a "-S02N(RARB)" group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.
[0052] An "N-sulfonamido" group refers to a "RSO?N(RA)-" group in which R and RA can be independently hydrogen, alkyl, alkeny l, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.
[0053] An " -carbamy Γ group refers to a "-OC(=0)N(RARB)" group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl. aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.
[0054] An "N-carbamyf group refers to an
Figure imgf000014_0001
group in which R and RA can be independently hydrogen, alkyl. alkenyl. alkynyl, cycloalkyl. cycloalkenyl. aryl, heteroaryl. heterocyclyl. aralkyl, (heteroaryl )alkyl or (heterocyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.
[0055] An "O-thiocarbamy ' group refers to a "-OC(=S)-N(RARB)11 group in which RA and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl )alkyl. An O-thiocarbamyl may be substituted or unsubstituted.
[0056] An "N-thiocarbamyl" group refers to an "ROC(=S)N(RA)-" group in which R and RA can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl. cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl. (heteroaryl )alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.
[0057] A "C-amido" group refers to a "-C(=0)N(RARB)" group in which RA and RB can be independently hydrogen, alkyl, alkenyl. alkynyl. cycloalkyl, cycloalkenyl, aryl. heteroaryl, heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substituted or unsubstituted.
[0058] An "N-amido" group refers to a
Figure imgf000014_0002
group in which R and RA can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl. aryl, heteroaryl. heterocyclyl, aralkyl. (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substituted or unsubstituted. [0059] The term "halogen atom" or "halogen" as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
[0060] Where the numbers of substituents is not specified (e.g. haloalkyl). there may be one or more substituents present. For example "haloalky l" may include one or more of the same or different halogens. As another example, "C i-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms.
[0061 ] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord w ith their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1 1 :942-944 (1972)).
[0062] The terms "protecting group" and "protecting groups" as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unw anted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way. that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl: alkylcarbonyls and alkoxycarbonyls (e.g.. t-butoxycarbonyl (BOC). acetyl and isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether and tetrahydropyranyl ether); substituted ethyl ether; a substituted benzyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tn-iso- propylsilyloxymethyi. [2-(trimethylsilyl)ethoxy]methyi and t-butyldiphenyisilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate and mesylate); acyclic ketal (e.g. dimethyl acetal and diisopropyl acetal); cyclic ketals (e.g., 1 ,3- dioxane and 1 ,3-dioxolane); acyclic acetal; cyclic acetal; acyclic hemiacetal; cyclic hemiacetal; dithioacetals (both cyclic and acyclic); dithioketals (both cyclic and acyclic) (e.g., S,S' -dimethyl, S,S*-diethyl, S,S*-diispropyl, 1 ,3-dithiane and 1 ,3-dithiolane); orthoesters (including cyclic orthoesters, such as cyclic orthoformatcs); carbamates (e.g., N- pheny lcarbamate) and triarylmethyl groups (e.g.. trityl. monomethoxytrityl (MMTr), 4,4'- dimethoxytrityl (DMTr), and 4.4',4"-trimethoxytrityl (TMTr); and those described herein).
[0063] "Leaving group" as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, 'leaving group" refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, "leaving groups" are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates, mesylates and halogens (e.g., 1, Br, and CI). Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331 ; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock ( 1981), pages 169- 171 ; and Organic Chemistry, 5lh ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.
[0064] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulionic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-gliicamine, tris(hydroxymethyl)methylamine, C |-C7 alkylamine, cyclohexylamine, triethanolamine, cthylcnediaminc, and salts with amino acids such as arginine and lysine.
[0065] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term "including' should be read to mean including, without limitation.' "including but not limited to.' or the like; the term 'comprising' as used herein is synonymous with including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having' should be interpreted as 'having at least;" the term "includes' should be interpreted as "includes but is not limited to;' the term "example" is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably,' 'preferred.' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "'comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Similarly, a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.
[00661 With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or "an'' does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
[0067] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
[0068] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
[0069] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as. for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound stmcture a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0070] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol. or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[00711 Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
Compounds
[0072] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,
wherein: G1 can be s
Figure imgf000019_0001
can be hydrogen, halogen. -CN. an optionally substituted C|-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, -CH2OH, -CH(Y' )(OH) or -C(0)Y' ; a3 can be selected from hydrogen, -C(0)Y2. -C(0)0-Y2. -(CH2)-0(CO)Y2. -(CH2)-0(CO)OY2, -(CHCH3)-0(CO)Y2. and -(CHCH3)- 0(CO)OY"; Y' and Y' can be independently an optionally substituted Ci-6 alkyl or an optionally substituted aryl; R1 can be selected from OR6, NH2, an optionally substituted mono-substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocyclyl, an optionally substituted N-sulfonamido and an optionally substituted alkoxyamine, or R' "; R^ can be hydrogen, C |_6 alkyl, an optionally substituted C 6 cycloalkyl. an optionally substituted ary l. an optionally substituted aryl(Ci_6 alkyl) or an optionally substituted C-amido: RJ can be hydrogen or C|_(l alkyl: or R2 and R3 can be taken together to form an optionally substituted C3-6 cycloalkyl. an optionally substituted 5 to 6 membered heterocyclyl or =0; R4 can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl. an optionally substituted heteroaryl and an optionally substituted heterocyclyl; or R can be A'RA4RLI4. wherein A can be CH or N; and RA4 and RB4 can be each independently an optionally substituted phenyl; R3 can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; R6 can be selected from hydrogen. C | -6 alkyl. -C(0)R7 and -C(0)NR8R9; R7 can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(Ct-6 alkyl), heteroaryl(Ci -6 alkyl) and heterocyclyl(C|- alkyl); R8 and R9 can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C |-6 alkyl), hctcroaryl(Ci -6 alkyl) and hcterocyclyl(CV6 alkyl); or R° and can be taken together to form an optionally substituted heterocyclyl; wherein when R1 is R10. then R10 and R4 can be taken together and include L 1. where L1 connects R10 and R4 to form an 1 1 - to 20-membered ring, or wherein when R1 is R 10, then R1 0 and R3 can be taken together and include L1 , where L 1 connects R1 and R3 to form an 1 1 - to 20-membered ring; wherein R 1 0 is optionally substituted -CH2-, optionally substituted -CH=CH-. O (oxygen). S (sulfur), or NR1 1 ; wherein R1 1 can be hydrogen or C i-6 alkyl; and Z1 and Z2 can be independently 0, 1 , 2, 3 or 4.
[00731 In some embodiments, GJ can be hydrogen. In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a prodrug in which GJ can be selected from -C(0)Y2, -C(0)0-Y\ -(CH2)-0(CO)Y2, -(CH2)-0(CO)OY2, - (CHCH3)-0(CO)Y2. and -(CHCH3)-0(CO)OY2.
[0074] A variety of substituents can be present on the 6-membered ring of Formula (I). For example, in some embodiments, G2 can be hydrogen. In other embodiments, G can be halogen. In still other embodiments, G" can be -CN. In yet still other embodiments, G" can be an optionally substituted aryl. In some embodiments, G" can be an optionally substituted heteroaryl. In other embodiments, G~ can be -CH?OH. In still other embodiments. G' can be -CH(Y )(OH). in yet still other embodiments, G~ can be - C(0)Y . In some embodiments. G' can be an optionally substituted C]_f, alkyl. In some embodiments, G~ can be an unsubstituted Ci-6 alkyl, such as methyl. When Y and Y~ are present in G~ and/or G~ , respectively, Y and Y" can be independently an optionally substituted Ci-6 alkyl or an optionally substituted aryl (such as an optionally substituted phenyl).
[0075] Various groups can be present at R1. In some embodiments, R1 can be OR6. For example, in some embodiments, R1 can be hydroxy. In other embodiments, when R1 is OR6. R6 can be C |-6 alkyl. In still other embodiments, when R1 is OR6, R6 can be - C(0)R7. Example of suitable R7 groups include, but are not limited to. hydrogen, alkyl, alkenyl, alkynyi, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C| _6 alkyl), heteroaryl(C i -6 alkyl) and heterocyclyl(C i -6 alkyl). In yet still other embodiments, when R1 is OR6, R6 can be -C(0)NR8R9. R8 and R9 can be independently various substituents, such as hydrogen, alkyl, alkenyl, alkynyi, cycloalkyl, cycloalkenyl, cycloalkynyl. aryl. heteroaryl. heterocyclyl, aryl(Ci-6 alkyl). heteroaryl(C| .6 alkyl) or heterocyclyl(C i-6 alkyl). In some embodiments, R' and R can be taken together to form an optionally substituted heterocycly l. Examples of suitable optionally substituted heterocyclyls that can be formed from R and R include 5 to 6 membered heterocyclyls. In some embodiments, R6 can be hydrogen, Ci-6 alkyl, an acy or C-amido. In some embodiments. R6 can be hydrogen. -C(0)R7 and -C(0)NR8R9. In other embodiments. R6 can be -C(0)R7 and - C(0)NR8R9.
[0076| In some embodiments, R1 can be H2. In other embodiments. R1 can be an optionally substituted mono-substituted amine. An example of a suitable mono- substituted amine is a group having the formula of -NHR , wherein R ' can be selected from alkyl, alkenyl, alkynyi, cycloalkyl, cycloalkenyl. cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C |.(, alkyl), heteroaryl(C 1 -6 alkyl) and heterocyclyl(C[- alkyl). In some embodiments, RI AA can be selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl. aryl(C | _6 alkyl), heteroaryl(C| _6 alkyl) and heterocyclyl(Ci_6 alkyl). In other embodiments, R1 AA can be selected from alkyl, aryl, and aryl(C|_6 alkyl). When R1 is a mono-substituted amine having the formula -NHRI AA. RI AA can be a substituted or unsubstituted group.
[0077] In other embodiments, R1 can be an optionally substituted di-substituted amine. For example. R1 can be a group having the formula of -NRI BBRI C C, wherein RI B and RI CC can be independently selected from alkyl, alkenyl, alkynyl. cycloalkyl. cycloalkenyl. cycloalkynyl. aryl. heteroaryl, heterocyclyl, aryl(Ci_6 alkyl). heteroaryl(Ci-6 alkyl) and heterocyclyl(C i.6 alkyl). In some embodiments, RI B and RI CC can be independently selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C [-6 alkyl), heteroaryl(C | .6 alkyl) and heterocyclyi(C | .6 alkyl). In other embodiments, RI BB and R C can be independently selected from alkyl, aryl, and aryl(C | .6 alkyl). In some embodiments, RI BB and RI CC can be the same. In other embodiments, RI BB and Rl c t can be different. When R1 is a di-substituted amine having the formula -NRI BBRl ct, R1 BB and RI CC can be substituted or unsubstituted groups.
[0078] In still other embodiments, R1 can be an optionally substituted heterocyclyl. Various heterocyclyls can be used and can be connected either through a ring carbon or a ring heteroatom. In some embodiments, the heterocyclyl can be a 5 to 6 membered heterocyclyl. In some embodiments, the heterocyclyl can include 1 heteroatom. In other embodiments, the heterocyclyl can include 2 heteroatoms. wherein the heteroatoms can be the same or different. In some embodiments, R1 can be an optionally substituted heterocyclyl that contains at least one nitrogen in the ring and is an N-linked heterocyclyl. In some embodiments. R1 can be an unsubstituted heterocyclyl. In some embodiments, R1 can be a substituted heterocyclyl.
[0079] In still other embodiments, R1 can be an optionally substituted N-sulfonamido. In some embodiments, when R1 is an optionally substituted N-sulfonamido, the groups attached to the sulfur can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C| _6 alkyl), heteroaryl(C 1 .6 alkyl) and heterocyclyl(C | _6 alkyl). An example of suitable structure for the optionally substituted N-sulfonamido is -NHS(0)2RI DD, wherein RI DD can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C |_6 alkyl), heteroaryl (C 1 -5 alkyl) and hctcrocyclyl(C| _6 alkyl). In some embodiments, RI DD can be selected from alkyl. alkenyl, cycloalkyl, aryl, heteroaryl. heterocyclyl, aryl(C]_(, alkyl), heteroaryl(C] _6 alkyl) and
Figure imgf000023_0001
alkyl). In other embodiments, RI UU can be selected from alkyl. aryl. and aryl(C] _6 alkyl). When R1 is a N-sulfonamido having the formula - NHS(0)2RI DO, RI DD can be a substituted or unsubstituted group.
[0080] In yet still other embodiments. R1 can be an optionally substituted alkoxyamine. Examples of an optionally substituted alkoxyamine include, but are not limited to, the following: -NH(C |.6 alkoxy) and -N(C i-6 alkyl)(C i-6 alkoxy), -NH(OCH3) and - NCH3(OCH3).
[0081 ] In some embodiments. G1 can be
Figure imgf000023_0002
. In some embodiments, R2 can be hydrogen. In other embodiments. R2 can be a C |- alkyl. Examples of suitable C | -6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight or branched pentyl and straight or branched hexyl. In still other embodimens, R2 can be an optionally substituted C3- cycloalkyl. In some embodiments, R2 can be an optionally substituted C5-6 cycloalkyl, such as an optionally substituted monocyclic C5-6 cycloalkyl or an optionally substituted fused, bicyclic C5- cycloalkyl. In yet still other embodimens, R" can be an optionally substituted aryl, such as an optionally substituted phenyl. In some embodimens. R can be an optionally substituted aryl(C i-6 alkyl), for example, an optionally substituted benzyl. In other embodimens. R" can be an optionally substituted C-amido. For example, R' can be C(=0)NH-(C i-6 alkyl). In some embodiments, R'1 can be hydrogen. In other embodiments, RJ can be a C i_6 alkyl.
[0082] In some embodiments, R2 and RJ can be the same. In other embodiments. R" and R can be different. In some embodiments, R' and R can both be hydrogen. In other embodiments, R2 and R"1 can both be a C |-6 alkyl. For example, R2 and R~' can both be methyl. In some embodimens, R~ can be C |-6 alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C| -6 alkyi) or an optionally substituted C-amido, and R ' can be hydrogen.
[0083] Alternatively, in some embodiments, R2 and R' can be taken together to form an optionally substituted C3-6 cycloalkyl. Suitable cycloalkyls include cyclopropyl. cyclobutyl, cyclopentyl and cyclohexyl. When R~ and R are taken together, the cycloalkyl group can be unsubstituted. In the alternative, the cycloalkyl group can be substituted with one or more substituents. In some embodiments. R' and R can be taken together to form an optionally substituted C5 cycloalkyl. In some embodiments. R2 and R1 can be taken together to form an unsubstituted C5 cycloalkyl. In other embodiments. R2 and R'1 can be taken together to form a mono-substituted or di-substituted C5 cycloalkyl. In some embodiments, R" and R can be taken together to form an optionally substituted 5 to 6 membered heterocyclyi. Examples of heterocyclyls that can be formed include, but are not limited to, optionally substituted nitrogen containing 5 to 6 membered heterocyclyls. In some embodiments, R2 and RJ can be taken together to form an optionally substituted 5 to 6 membered N-linked heterocyclyi, for example, an optionally substituted piperdino or an optionally substituted pyrrolidino. In some embodiments, R2 and R3 can be taken together to form =0, such that the carbon to which R2 and R' are attached together with R2 and R' form a carbonyl group.
[0084] Various groups can be R4. In some embodiments. R4 can be an optionally substituted ary l. In some embodiments, R4 can be an optionally substituted naphthyl. In other embodiments. R4 can be an optionally substituted phenyl. In some embodiments, R4 can be an unsubstituted phenyl. In other embodiments, R4 can be a substituted phenyl. One or more groups can be present on a substituted phenyl. For example, the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl. As another example, the substituted phenyl can be a di- substituted phenyl, such as a 2,5-di-substituted phenyl, 2,4-di-substituted phenyl and 2,3-di- substituted phenyl. In some embodiments, the substituted phenyl can be substituted with 3 or more substituent.
[0085] In other embodiments, R4 can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. For example, R4 can be an optionally substituted C -6 cycloalkyl. In some embodiments, R4 can be an unsubstituted cycloalkyl. In other embodiments, R4 can be a substituted cycloalkyl.
[0086] In still other embodiments, R4 can be an optionally substituted heteroaryl. In some embodiments. R4 can be an unsubstituted heteroaryl. In other embodiments, R4 can be a substituted heteroaryl. Examples of suitable heteroaryls are described herein. In some embodiments, R4 can be an optionally substituted monocyclic heteroaryl. In other embodiments, R4 can be an optionally substituted bicyclic heteroaryl, for example, an optionally substituted lH-pyrrolo[2,3-b]pyridine.
[0087] In yet still other embodiments, R4 can be an optionally substituted heterocyclyl. In some embodiments, R4 can be an unsubstituted heterocyclyl. In other embodiments, R4 can be a substituted heterocyclyl. In some embodiments, R4 can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R4 can be an optionally substituted bicyclic heterocyclyl.
[0088] When R4 is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R4, at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R4 are different. In some embodiments, R4 can be substituted with one or more substituents selected from halogen. Ci -6 alkyl. alkoxy, aryloxy. haloalkyl. haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl. an optionally substituted heterocyclyl, carbonyl. C- carboxy, -CH2-(mono-substituted amine) and CH2-(di-substituted amine). In some embodiments, when R4 is a substituted aryl, the aryl can be substituted with one or more groups selected from C i .6 alkyl, alkoxy, aryl (for example, phenyl), cyano. halogen, haloalkyl and haloalkoxy. In some embodiments, when R4 is a substituted cycloalkyl, the cycloalkyl can be substituted with C i-6 alkyl, alkoxy, halogen and haloalkyl. In some embodiments, when R4 is a substituted heterocyclyl, the heterocyclyl can be substituted with C | _6 alkyl, alkoxy, halogen, haloalkyl, ary!(C | .6 alkyl) and C-carboxy. In some embodiments, the substituted heterocyclyl of R4 can be substituted with a substituted or an unsubstituted benzyl. [0089] The pyridazinone ring can be connected to R4 via a substituted or unsubstituted alky lene. In some embodiments, Z1 can be 0. In other embodiments, Z1 can be 1. In still other embodiments, Z1 can be 2. In yet still other embodiments, Z1 can be 3. In some embodiments, Z1 can be 4. In some embodiments, Z2 can be 0. In other embodiments. Z" can be 1. In still other embodiments, Z" can be 2. In yet still other embodiments. Z can be 3. In some embodiments, r can be 4. In some embodiments, Z can be 1. and Z~ can be 0. In other embodiments, Z and Z" can be both 1. In still other embodiments. Z and Z~ can be both >1. In yet still other embodiments, at least one of Z and 7s can be 1. In some embodiments, at least one of Z and Z" can be 1 , and the other of Z and Z~ can be > 1.
[0090 j in some embodiments, R4 can be A*RA4RB4, wherein A1 can be CH or N; and RA4 and RB4 can be each independently an optionally substituted phenyl. For example, R4 can be CHRA4RB4 or NRA4RB4. As described herein, the phenyl groups can be the same or different, and can be substituted or unsubstituted.
[0091] In other embodiments. G can be R5. As with R4. R5 can be a variety of groups. In some embodiments, R? can be an optionally substituted aryl. In some embodiments, R^ can be an optionally substituted naphthyl. In other embodiments, R^ can be an optionally substituted phenyl. In some embodiments, R^ can be an unsubstituted phenyl. In other embodiments, R~ can be a substituted pheny l. One or more groups can be present on a substituted phenyl. For example, the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl. As another example, the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di- substituted phenyl. 2.4-di -substituted phenyl and 2.3-di-substituted phenyl. In some embodiments, the substituted phenyl can be substituted with 3 or more substituents.
[0092] In other embodiments, R? can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. For example, R^ can be a substituted or an unsubstituted C4 cycloalkyl. In some embodiments, R""1 can be an unsubstituted cycloalkyl. In other embodiments. R""1 can be a substituted cycloalkyl.
[0093] In still other embodiments, RJ can be an optionally substituted heteroaryl. In some embodiments, R^ can be an unsubstituted heteroaryl. In other embodiments. R""1 can be a substituted heteroaryl. In some embodiments, R^ can be an optionally substituted monocyclic heteroaryl. In other embodiments, R/ can be an optionally substituted bicyclic heteroaryl.
[0094] In yet still other embodiments, R"^ can be an optionally substituted heterocyclyl. In some embodiments. R? can be an unsubstituted heterocyclyl. In other embodiments, R^ can be a substituted heterocyclyl. In some embodiments, R5 can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R? can be an optionally substituted bicyclic heterocyclyl.
[0095] When R? is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R'\ at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on Rs are different. In some embodiments, R3 can be substituted with one or more substituents selected from halogen, C i -6 alkyl, alkoxy, aryloxy, haloalkyl, haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl. carbonyl, C- carboxy, -CH2-(mono-substituted amine) and CH2-(di-substituted amine). In some embodiments, when R? is a substituted aryl, the aryl can be substituted with one or more groups selected from Ci_6 alkyl. alkoxy, halogen and haloalky l. In other embodiments, when R? is a substituted ary l. the aryl can be substituted with one or more groups selected from Ci-6 alkyl, alkoxy. aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy. In some embodiments, when R5 is a substituted cycloalkyl, the cycloalkyl can be substituted with C i-6 alkyl, alkoxy, halogen and haloalkyl. In some embodiments, when R? is a substituted heterocyclyl, the heterocyclyl can be substituted with C i-6 alkyl. alkoxy. halogen, haloalkyl. aryl(C i-6 alkyl) and C-carboxy. In some embodiments, the substituted heterocyclyl of R^ can be substituted with a substituted or an unsubstituted benzyl.
[0096] In some embodiments, R1 is not mono-substituted amine, such as -NH- alkyl. In other embodiments, R1 is not di-substituted amine. For example, in some embodiments, R1 is not -N(alkyl)2, including -N(CH3)2. In some embodiments, R6 is not C | -6 alkyl. In still other embodiments, R1 is not an optionally substituted heterocyclyl. In other embodiments, R1 is not an optionally substituted N -linked heterocyclyl. [0097] In some embodiments, the pyridazinone ring can be connected to R4 to form a cyclic compound, for example, a compound of Formula (Ih) In other embodiments, the pyridazinone ring can be connected to to form a cyclic compound, such as a compound of Formula (Ij). In some embodiments, when R1 is R10, then R10 and R4 can be taken together and include L1, where L1 connects R10 and R4 to form an 1 1 - to 20-membered ring, or wherein when R1 is R10. then R10 and R^ can be taken together and include L1, where L 1 connects R1 and R5 to form an 1 1 - to 20-membered ring; wherein R10 can be an optionally substituted -CH2-, an optionally substituted -CH=CH-, O (oxygen). S (sulfur). o NR1 1 ; and wherein R can be hydrogen or C i-6 alkyl. In some embodiments, R can be NR" . For example, R10 can be NH. In other embodiments, R1 0 can be an optionally substituted -CH2-. In still other embodiments, R10 can be O (oxygen). In yet still other embodiments, R10 can be S (sulfur).
[0098] With respect to L1, in some embodiments, L1 can be -L2-. In some embodiments, when L1 is -L2-, L2 can be selected from an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted heteroalkylene and an optionally substituted heteroalkenylene. In some embodiments, L2 can be an optionally substituted alkylene, for example, an optionally substituted C4-7 alkylene. In other embodiments, L can be an optionally substituted alkenylene. such as an optionally substituted C4-7 alkenylene. In still other embodiments, Lr can be an optionally substituted heteroalkylene. Examples of suitable optionally substituted heteroalkylenes include the following: an optionally substituted -(CH2)3-0- an optionally substituted -(CH2)4-0- an optionally substituted -(CH2)5-0-, an optionally substituted -(CH2)3-S-, an optionally substituted -(CH2)4-S-, an optionally substituted -(CH2)5-S-, an optionally substituted -(CH2) -NH-, an optionally substituted -(CH2)4-NH-. and an optionally substituted -(CH2)5-NH-. In yet still other embodiments, L" can be an optionally substituted heteroalkenylene, such as an optionally substituted -(CH2)(CH=CH)(CH2)-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)-0-, an optionally substituted -(CH2)(CH=CH)(CH2)2-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)2-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)-S-, an optionally substituted -(CH2)(CF1=CFI)(CH2)2-S-, an optionally substituted -(CH2)2(CH=CH)(CH2)2-S an optionally substituted -(CH2)2(CH=CH)(CH2)-NH- an optionally substituted -(CH2)(CH=CH)(CH2)2-NH- and an optionally substituted -(CH2)2(CH=CH)(CH )2-NH-. In some embodiments, L2 can be an optionally substituted -(CH2)3-0-, an optionally substituted -(CH2)4-0-, or an optionally substituted -(CH2)5-0-. In other embodiments, L" can be an optionally substituted C3 oxygen-containing heteroalkenylene, an optionally substituted C4 oxygen-containing heteroalkenylene. or an optionally substituted Q oxygen-containing heteroalkenylene.
[0099] In other embodiments, L1 can be -L '-L4-! -, wherein L3 can be an optionally substituted Ci-6 alkylene; L4 can be an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyi, O (oxygen), S (sulfur), or NR1 1 ; and can be an optionally substituted C i-6 alkylene or an optionally substituted heteroalkylene. In some embodiments, L can be an optionally substituted C i- alkylene; L4 can be optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and can be an optionally substituted C| _4 alkylene. In other embodiments, LJ can be an optionally substituted C |- alkylene; L4 can be O (oxygen), S (sulfur), or NR1 1 ; and L? can be an optionally substituted C alkylene. In still other embodiments, L3 can be optionally substituted C2-4 alkylene; L4 can be optionally substituted cycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocyclyi, O (oxygen), S (sulfur), or NR1 1 ; and L? can be optionally substituted C2-4 alkylene.
[0100] In some embodiments, a compound of Formula (I) can be a compound selected from Formula (la). Formula (lb), Formula (Ic), Formula (Id), Formula (Ie). Formula (If) and Formula (Ig).
Figure imgf000030_0001
wherein G 1. R1 , R2, R3. R4, R and z1 are as defined above with respect to Formula (1). n various embodiments, for Formula (Ic). the phenyl ring can be substituted or unsubstituted; for Formula (Id), Rl a can be an optionally substituted N-linked heterocyclyl; for Formula (It), R6 is not hydrogen; and for Formula (If), R1 is not OR6. In some embodiments, R6 is not hydrogen and/or not a C|- alky 1 for Formulae (If) and/or (Ig).
[0101 ] Examples of compounds of Formula (I) include the following:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
-34-
Figure imgf000037_0001
er examples of compounds of Formula (1) include the following:
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
-38-
Figure imgf000041_0001
-39-
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
wherein: GI A can be selected f
Figure imgf000044_0002
rom and R5A; RI A can be selected from OR6A. NHi- an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted mono-substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocyclyl and an optionally substituted N-sulfonamido, or RI 0A; WA can be - CH- or -N-; R2A can be hydrogen or C i-6 alkyl; R3A can be hydrogen or C i-6 alkyl; or R2A and R"'A can be taken together to form an optionally substituted C3-6 cycloalkyl or an optionally substituted 5 to 6 membered heterocyclyl; R4A can be selected from an optionally substituted aryl. an optionally substituted cycloalkyl. an optionally substituted cycloalkenyl, an optionally substituted heteroaryi and an optionally substituted heterocyclyl; R' A can be selected from an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryi and an optionally substituted heterocyclyl; R6A can be selected from hydrogen, C ,_6 alkyl, -C(0)R7A and -C(0)NR8AR9A; R7A can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C| .6 alkyl). heteroaryl(C|-6 alkyl) and heteiOcyclyl(C|-6 alkyl); R8A and R9A can be independently selected from hydrogen, alkyl, alkenyl. alkynyl. cycloalkyl. cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C ]_(, alkyl), heteroary^C , alkyl) and heterocyclyl(C i-6 alkyl); or R8A and R9A can be taken together to form an optionally substituted heterocyclyl; wherein when RI A is R10A, then RI 0A and R4A can be taken together and include LI A, where L1 A connects RI 0A and R4A to form an 1 1 - to 20-membered ring, or wherein when RI A is RI 0A. then RI 0A and R5A can be taken together and include L1 A. where LI A connects RI A and R,A to form an 1 1- to 20-membered ring; wherein RI 0A is optionally substituted -CH2-, optionally substituted -CH=CH-, O (oxygen), S (sulfur), or NRI I A; wherein Rn A can be hydrogen or C i- alkyl; and ZI A and Z2A can be independently 0. 1, 2, 3 or 4.
[0106] Various groups can be present at RI A. In some embodiments, R1 A can be OR6A. For example, in some embodiments, R1 A can be hydroxy. In other embodiments, when R1 A is OR6A, R6A can be C | _6 alkyl. In still other embodiments, when RI A is OR6A, R6A can be -C(0)R7A. Example of suitable R7A groups include, but are not limited to, hydrogen, alky l. alkeny l, alkynyl. cycloalkyl, cycloalkenyl. cycloalkynyl, aryl, heteroaryl. heterocyclyl. aryl(Ci-(, alkyl). heteroaryl(C|-6 alkyl) and heterocyclyl(Ci-6 alkyl). In yet still other embodiments, when RI A is OR6A, R6A can be -C(0)NR8AR9A. R8A and R9A can be independently various substituents. such as hydrogen, alkyl. alkenyl, alkynyl. cycloalkyl. cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C ] _6 alkyl), heteroaryl (Ci_6 alkyl) or heterocyclyl(C i-6 alkyl). In some embodiments. R8A and R9A can be taken together to form an optionally substituted heterocyclyl. Examples of suitable optionally substituted heterocyclyls that can be formed from R8A and R9A include 5 to 6 membered heterocyclyls. In some embodiments, R6A can be hydrogen, C |-6 alkyl, an acyl or C-amido. In some embodiments, R '* can be hydrogen, -C(0)R7A and -C(0)NRSAR9A. In other embodiments, R6A can be -C(0)R7A and -C(0)NR8 VA.
[0107] In some embodiments, RI A can be NH?. In other embodiments, RI A can be an optionally substituted mono-substituted amine. An example of a suitable mono- substituted amine is a group having the formula of -NHR1 Aa, wherein R1 Ad can be selected from alkyl, alkenyl, alkynyl, cvcloalkyl, cvcloalkenvl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(Ci_6 alkyl), heteroaryl(C|-6 alkyl) and heterocyclyl(C| _6 alkyl). In some embodiments, RI Aa can be selected from alkyl. alkenyl. cycloalkyl, aryl, heteroaryl. heterocyclyl, aryl(C ]_(, alkyl), heteroaryl(C] _6 alkyl) and heterocyclyl(C|_6 alkyl). In other embodiments, RI Aa can be selected from alkyl. aryl, and aryl(Ci-6 alkyl). When RI A is a mono-substituted amine having the formula -NHR 1 Aa, RI Aa can be a substituted or unsubstituted group.
1 A
[0108] In other embodiments, R can be an optionally substituted di-substituted amine. For example, R can be a group having the formula of -NRI BbR1Cc, wherein RI Bb and RI Ct can be independently selected from alkyl, alkenyl, alkynyl. cycloalkyl, cvcloalkenvl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C | -6 alkyl), heteroaryl(C i -6 alkyl) and heterocyclvi(C I .(, alkyl). In some embodiments. RI Bb and RI Ct can be independently selected from alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C|- alkyl), heteroaryl(C i -6 alkyl) and heterocyclyl(Ci- alkyl). In other embodiments, RI Bb and RI Cc can be independently selected from alkyl, aryl, and aryl(Ci_6 alkyl). In some embodiments, RI Bb and RI Cc can be the same. In other embodiments, RI Bb and RI Cc can be different. When RI A is a di-substituted amine having the formula -NRI BbRI Cc. R1 Bb and RI Cc can be substituted or unsubstituted groups.
[0109] In still other embodiments. RI A can be an optionally substituted heterocyclyl. Various heterocyclyls can be used and can be connected either through a ring carbon or a ring heteroatom. In some embodiments, the heterocyclyl can be a 5 to 6 membered heterocyclyl. In some embodiments, the heterocyclyl can include 1 heteroatom. In other embodiments, the heterocyclyl can include 2 heteroatoms, wherein the heteroatoms can be the same or different. In some embodiments, RI A can be an optionally substituted heterocyclyl that contains at least one nitrogen in the ring and is an N-linked heterocyclyl. In some embodiments, RI A can be an unsubstituted heterocyclyl. In some embodiments, RI A can be a substituted heterocyclyl.
[0110] In still other embodiments, RI A can be an optionally substituted N-sulfonamido. In some embodiments, when R1 A is an optionally substituted N-sulfonamido, the groups attached to the sulfur can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(C| -6 alkyl), heteroaryl(Ci_6 alkyl) and heterocyclyl(Ci_6 alkyl). An example of suitable structure for the optionally substituted N-sulfonamido is -NHS(0)2R1 Dd. wherein RL UD can be selected from hydrogen, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl. cycloalkynyl. aryl, heteroaryl, heterocyclyl, aryl(Ci-6 alkyl). heteroaryl(C i-6 alkyl) and heterocyclyl(C i-(, alkyl). In some embodiments, RI DD can be selected from alkyl, alkenyl. cycioalkyl. aryl. heteroaryl. heterocyclyl. aryl(C ] .6 alkyl). heteroaryl(C ] -6 alkyl) and heterocyclyl(C i.(, alkyl). In other embodiments, R")cI can be selected from alkyl. aryl, and aryl(C i-6 alkyl). When RI A is a N-sulfonamido having the formula - NHS(0)2RL L)D, RMD can be a substituted or unsubstituted group.
[01 1 1 ] In some embodiments, GI A can be
Figure imgf000047_0001
. In some embodiments. R2A can be hydrogen. In other embodiments. R2A can be a Ci-6 alkyl. Examples of suitable Ci-6 alkyl include methyl, ethyl, n-propyl, isopropyl. n-butyl. isobutyl. tert-butyl. straight or branched pentyl and straight or branched hexyl. In some embodiments. R'lA can be hydrogen. In other embodiments, R3A can be a C] _6 alkyl. In some embodiments. R2A and R3A can be the same. In other embodiments, R2A and R3A can be different. In some embodiments. R2A and RjA can both be hydrogen. In other embodiments, R2A and R3A can both be a C , alkyl. For example, R2A and R~lA can both be methyl. Alternatively, in some embodiments, R2A and R3A can be taken together to form an optionally substituted C3-6 cycioalkyl. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When R2A and RlA are taken together, the cycioalkyl group can be unsubstituted. In the alternative, the cycioalkyl group can be substituted with one or more substituents. In some embodiments, R2A and R3A can be taken together to form an optionally substituted Cs cycioalkyl. In some embodiments, R A and R'A can be taken together to form an unsubstituted C cycioalkyl. In other embodiments, R2A and R3A can be taken together to form a mono-substituted or di- substituted Cs cycioalkyl. In some embodiments, R2A and R ,A can be taken together to form an optionally substituted 5 to 6 membered heterocyclyl. Examples of heterocyclyls that can be formed include, but are not limited to, optionally substituted nitrogen containing 5 to 6 membered hetcrocyclyls. In some embodiments, R2A and R'A can be taken together to form an optionally substituted 5 to 6 membered N-linked heterocyclyl, for example, an optionally substituted piperdino or an optionally substituted pyrrolidine
[01 12] Various groups can be R4A. In some embodiments, R4A can be an optionally substituted aryl. In some embodiments, R4A can be an optionally substituted naphthyl. In other embodiments, R4A can be an optionally substituted phenyl. In some embodiments, R4A can be an unsubstituted phenyl. In other embodiments. R4A can be a substituted phenyl. One or more groups can be present on a substituted phenyl. For example, the substituted phenyl can be a mono-substituted phenyl, such as an ortho-substituted phenyl, a meta-substituted phenyl or a para-substituted phenyl. As another example, the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di-substituted phenyl, 2,4-di-substituted phenyl and 2,3 -di-substituted phenyl. In some embodiments, the substituted phenyl can be substituted with 3 or more substituent.
[0113] In other embodiments, R4A can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. For example, R4A can be an optionally substituted C4- 6 cycloalkyl. In some embodiments, R4A can be an unsubstituted cycloalkyl. In other embodiments, R4A can be a substituted cycloalky l.
[0114] In still other embodiments, R4A can be an optionally substituted heteroaryl. In some embodiments, R4A can be an unsubstituted heteroary l. In other embodiments. R4A can be a substituted heteroaryl. Examples of suitable heteroaryls are described herein. In some embodiments. R4A can be an optionally substituted monocyclic heteroaryl. In other embodiments, R4A can be an optionally substituted bicyclic heteroaryl, for example, an optionally substituted lH-pyrrolo[2,3-b]pyridine.
[0115] In yet still other embodiments, R4A can be an optionally substituted heterocyclyl. In some embodiments, R ' can be an unsubstituted heterocyclyl. In other embodiments, R4A can be a substituted heterocyclyl. In some embodiments, R4A can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R4A can be an optionally substituted bicyclic heterocyclyl. [0116] When R4A is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R4A, at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R4A are different. In some embodiments. R4A can be substituted with one or more substituents selected from halogen. Ci-6 alkyl. alkoxy, aryloxy. haloalkyl. haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl. an optionally substituted heterocyclyl, carbonyl. C- carboxy, -CH2-(mono-substituted amine) and CH2-(di-substituted amine). In some embodiments, when R4A is a substituted aryl, the aryl can be substituted with one or more groups selected from C i -6 alkyi. alkoxy, aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy. In some embodiments, when R4A is a substituted cycloalkyl, the cycloalkyl can be substituted with C i-6 alkyl, alkoxy, halogen and haloalkyl. In some embodiments, when R4A is a substituted heterocyclyl, the heterocyclyl can be substituted with C(- alkyl, alkoxy, halogen, haloalkyl, aryl(Ci- alkyl) and C-carboxy. In some embodiments, the substituted heterocyclyl of R4A can be substituted with a substituted or an unsubstituted benzyl.
[0117] The pyridazinone ring can be connected to R4A via a substituted or unsubstituted alkylene. In some embodiments. Z1 A can be 0. In other embodiments. ZI A can be 1 . In still other embodiments. ZI A can be 2. In yet still other embodiments, Z1A can be 3. In some embodiments, ZI A can be 4. In some embodiments, Z2A can be 0. In other embodiments, Z2A can be 1 . In still other embodiments, Z2A can be 2. In yet still other embodiments, Z2A can be 3. In some embodiments. Z~A can be 4. In some embodiments. ZI A can be 1. and Z2A can be 0. In other embodiments, ZI A and Z2A can be both 1. In still other embodiments, ZI A and Z2A can be both >1. In yet still other embodiments, at least one of ZI A and Z" can be 1. In some embodiments, at least one of ZI A and Z2A can be 1 , and the other of ZI A and Z2A can be > l .
[0118] In other embodiments, G can be R5A. As with R4A, R5A can be a variety of groups. In some embodiments, R" A can be an optionally substituted aryl. In some embodiments, R can be an optionally substituted naphthyl. In other embodiments, RiA can be an optionally substituted phenyl. In some embodiments, R can be an unsubstituted phenyl. In other embodiments, RiA can be a substituted phenyl. One or more groups can be present on a substituted phenyl. For example, the substituted phenyl can be a mono- substituted pheny l, such as an ortho-substituted phenyl, a meta-substituted pheny l or a para- substituted phenyl. As another example, the substituted phenyl can be a di-substituted phenyl, such as a 2,5-di-substituted phenyl. 2.4-di-substituted phenyl and 2,3-di-substituted phenyl. In some embodiments, the substituted phenyl can be substituted with 3 or more substituents.
[0119] In other embodiments, R,A can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. For example, R A can be a substituted or an unsubstituted C4-6 cycloalkyl. In some embodiments, R'^ can be an unsubstituted cycloalkyl. In other embodiments, R~ A can be a substituted cycloalkyl.
[0120] In still other embodiments, R?A can be an optionally substituted heteroaryl. In some embodiments, RiA can be an unsubstituted heteroaryl. In other embodiments, R can be a substituted heteroaryl. In some embodiments, RiA can be an optionally substituted monocyclic heteroaryl. In other embodiments, R" A can be an optionally substituted bicyclic heteroaryl.
[0121 ] In yet still other embodiments, R?A can be an optionally substituted heterocyclyl. In some embodiments. R?A can be an unsubstituted heterocyclyl. In other embodiments, R?A can be a substituted heterocyclyl. In some embodiments, R^ can be an optionally substituted monocyclic heterocyclyl. In other embodiments, R?A can be an optionally substituted bicyclic heterocyclyl.
[0122] When R^ is substituted, one or more groups can be present. When two or more of the substituents are present, two or more of the substituents can be the same. In some embodiments, when multiple substituents are present on R^, at least one of the substituents is different from the remaining substituents. In some embodiments, all of the substituents present on R3A are different. In some embodiments, R A can be substituted with one or more substituents selected from halogen, C | -6 alkyl, alkoxy, aryloxy, haloalkyl, haloalkoxy, hydroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl. carbonyl, C- carboxy, -CH2-(mono-substituted amine) and CH -(di-substituted amine). In some embodiments, when R?A is a substituted aryl, the aryl can be substituted with one or more groups selected from Ci_6 alkyl. alkoxy, halogen and haloalky l. Tn other embodiments, when R^A is a substituted aryl, the aryl can be substituted with one or more groups selected from C i-6 alkyl, alkoxy. aryl (for example, phenyl), cyano, halogen, haloalkyl and haloalkoxy. In some embodiments, w hen R5A is a substituted cycloalkyl. the cycloalkyl can be substituted with C] _6 alkyl. alkoxy. halogen and haloalkyl. In some embodiments, when RdA is a substituted heterocyclyl, the heterocyclyl can be substituted with C |-6 alkyl. alkoxy. halogen, haloalkyl. aryl(C i-6 alkyl) and C -carboxy. In some embodiments, the substituted heterocyclyl of R A can be substituted with a substituted or an unsubstituted benzyl.
[0123| In some embodiments, RI A is not mono-substituted amine, such as -NH- alkyl. In other embodiments, R1 A is not di-substituted amine. For example, in some embodiments, RI A is not -N(alkyl)2, including -N(CH3)2. In some embodiments, R6A is not C| _(, alkyl. In still other embodiments, RI A is not an optionally substituted heterocyclyl. In other embodiments, R1 A is not an optionally substituted N-linked heterocyclyl.
[0124] In some embodiments, the fused bicyclic nitrogen-containing ring system of Formula (II) can be connected to R4A to form a cyclic compound, for example, a compound of Formula (Ih) In other embodiments, the fused bicy clic nitrogen-containing ring system of Formula (Π) can be connected to R'^ to form a cyclic compound, such as a compound of Formula (Ij). In some embodiments, when R1 A is R 1 0A. then R10A and R4A can be taken together and include LI A, where Li A connects RI 0A and R4A to form an 1 1 - to 20- membered ring, or wherein w hen RI A is RI 0A, then RI 0A and R5A can be taken together and include L , w here L ' connects R and R" to form an 1 1 - to 20-membered ring; wherein RI 0A can be an optionally substituted -CH2-, an optionally substituted -CH=CH-. O (oxygen). S (sulfur), or NR1 I A; and wherein RM A can be hydrogen or C i-6 alkyl. In some embodiments, R ' can be NR ' . For example, R ' can be NH. In other embodiments, R ' can be an optionally substituted -CH2-. In still other embodiments, RI 0A can be O (oxygen). In yet still other embodiments. R, 0A can be S (sulfur).
[0125] With respect to LI A, in some embodiments, LI A can be -L2A-. In some embodiments, when LI A is -L2A-, L2A can be selected from an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted heteroalkylene and an optionally substituted heteroalkenylcne. In some embodiments. L" can be an optionally substituted alkylene, for example, an optionally substituted C4-7 alkylene. In other embodiments, L2A can be an optionally substituted alkenylene. such as an optionally substituted C4-7 alkenylene. In still other embodiments. L2A can be an optionally substituted heteroalkylene. Examples of suitable optionally substituted heteroalkylenes include the following: an optionally substituted -(CH2)3-0-. an optionally substituted -(CH2)4-0-, an optionally substituted -(CH2)5-0-. an optionally substituted -(CH2)3-S-. an optionally substituted -(CH2)4-S-, an optionally substituted -(CH2)s-S-. an optionally substituted - (CH2)3-NH-, an optionally substituted -(CH2)4-NH-, and an optionally substituted -(CH2)s-NH-. In yet still other embodiments. L2A can be an optionally substituted heteroalkenylene, such as an optionally substituted -(CH2)(CH=CH)(CH2)-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)-0-, an optionally substituted -(CH2)(CH=CH)(CH2)2-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)2-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)-S- an optionally substituted -(CH2)(CH=CH)(CH2)2-S-, an optionally substituted -(CI I2)?(CI I=CI I)(CI I2)2-S an optionally substituted -(CH2)2(CH=CH)(CH2)-NH- an optionally substituted -(CH2)(CH=CH)(CH2)2-NH- and an optionally substituted -(CH2)2(CH=CH)(CH2)2-NH-. In some embodiments, L~ can be an optionally substituted -(CH2)3-0-. an optionally substituted -(CH2)4-0-. or an optionally substituted -(CH2)5-0-. In other embodiments, L2A can be an optionally substituted C3 oxygen-containing heteroalkenylene. an optionally substituted C4 oxygen-containing hetei alkenylene. or an optionally substituted C5 oxygen-containing heteroalkenylene.
[0126] In other embodiments, L1 A can be -L3A-L4A-L:iA-, wherein L3A can be an optionally substituted Ci-6 alkylene; L can be an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted heterocyclyl. O (oxygen), S (sulfur), or NRI I A; and L can be an optionally substituted C | -6 alkylene or an optionally substituted heteroalkylene. In some embodiments, L',A can be an optionally substituted Ci -4 alkylene; L4A can be optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryi; and L?A can be an optionally substituted C| _4 alkylene. In other embodiments, L ,A can be an optionally substituted C|-4 alkylene; L4A can be O (oxygen), S (sulfur), or NR1 1 A; and L~ A can be an optionally substituted C alkylcne. In still other embodiments, L 'A can be optionally substituted C2-4 alkylenc; L4A can be optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl. O (oxygen). S (sulfur), or NRI I A; and L?A can be optionally substituted C?-4 alkylene.
[0127] In some embodiments, including those disclosed herewith respect to Formula (II), WA can be -N (nitrogen)-. In other embodiments, including those disclosed herewith respect to Formula (II). WA can be -CH2-. In some embodiments, one or more of the carbon atoms of the fused-bicyclic nitrogen-containing ring system of Formula (II) can be substituted. For example, one or both of the carbon atoms adjacent to WA can be substituted carbon instead of -CH- and/or WA can be substituted carbon instead of -CH-.
[0128] In some embodiments, a compound of Formula (II) can be a compound selected from Formula (lla). Formula (lib). Formula (lie) and Formula (lid):
Figure imgf000053_0001
[0129] Examples of compounds of Formula (II) include the following:
Figure imgf000054_0001
of the foregoing.
Synthesis
[0130] Compounds of Formulae (I) and (II), and those described herein may be prepared in various ways. Some compounds of Formulae (I) and (11) can be obtained commercially and/or prepared utilizing known synthetic procedures. General synthetic routes to the compounds of Formulae (I) and (II). and some examples of starting materials used to synthesize the compounds of Formulae (I) and (IT) are shown and described herein. The routes shown and described herein are il lustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein: all such modifications and alternate routes are within the scope of the claims. Scheme 1
Figure imgf000055_0001
Figure imgf000055_0002
[0131] One method for forming a compound of Formula (I) where G is R/ is shown in Scheme 1. An amine having the formula of R'-NFF can be converted to a diazonium salt having the formula R3-N2 +X\ wlierein X" is an inorganic or organic anion, using methods known to those skilled in the art (for example, NaN02, HC1). When R3 is an optionally substituted phenyl group, the R'^-NFF can be an optionally substituted aniline. The diazonium salt can undergo a diazonium coupling reaction with a beta-keto ester using methods and conditions known to those skilled in the art. An example of a suitable beta-keto ester is shown in Scheme 1 , and examples of suitable conditions include mildly acidic or neutral conditions. The 6-membered pyridazinone ring can be formed via a cyclization reaction with N.N-dimethylformamide-dimethyl acetal (DMF-DMA). The benzyl group can be cleaved, and the ester group can be undergo hydrolysis to form a compound of Formula (I). Cleavage of the benzy l group can be accomplished using palladium on carbon (Pd/C). Hydrolysis of the ester can be achieved using NaOH. In some instances, the benzy l group can be cleaved prior to the hydrolysis of the ester group. In other instances, the ester group can be hydrolyzed to a carboxylic acid prior to cleavage of the benzyl group.
[0132] When R^ is substituted, a variety of methods can be used to add one or more substituents to R'\ For example, when R^ is substituted with an optionally substituted heterocyclyl. the optionally substituted heterocyclyl can be added via an addition-elimination reaction to a halogen substituted compound having the formula R'^-NCb. In some embodiments, a halogen substituted R?-N02 can undergo ipso-substitution using an optionally substituted heterocyclyl. The resulting substituted nitro compound can be reduced to an amine using methods known to those skilled in the art (for example. Raney nickel, PtO? or Pd/C). A compound of Formula (1) can then be obtained following the general reaction scheme shown in Scheme 1 . A general scheme starting with an example of a nitro compound is provided in Scheme 2. In Scheme 2. the phenyl ring can be further substituted with one or more substituents.
Scheme 2
Figure imgf000056_0001
X = halogen and Het = optionally substituted heterocyclyl
[0133] Another method for adding one or more substituents to form a substituted R5 is using a boronic acid or boronic ester. In some embodiments, a boronic acid or boronic ester can be used in a Suzuki coupling type-reaction to add one or more substituents to R3. Suitable conditions include using a palladium catalyst and a base (for example. Pd(PPh3)4 and K2C03). A non-limiting example using a boronic acid or boronic ester to form a substituted Rs is shown in Scheme 3. In Scheme 3, the phenyl ring can be further substituted with one or more substituents. A compound of Formula (I) can be obtained via the general reaction scheme shown in Scheme 1. In Scheme 3, X can be a halogen and R" can be an optionally substituted alkyl or an optionally substituted aryi.
Figure imgf000057_0001
Scheme 4
Figure imgf000057_0002
(T)
A method for forming a compound of Formula (I) where G1 is
Figure imgf000057_0003
js shown jn Scheme 4. As illustrated in Scheme 4, the nitrogen can be alkylated. A compound of Formula (T) can be obtained after the benzyl group is cleaved and the ester group undergoes hydrolysis.
[0135] Various methods can be used to form a group other than a hy droxy or Ci-6 alkoxy at R1. The ester group can undergo hydrolysis to form a carboxylic acid. The carboxylic acid can then be transformed using methods known to those skilled in the art to form the desired R group. For example, an optionally substituted amine and the carboxylic acid group can undergo a coupling reaction to form an optionally substituted amide group. Suitable coupling reagents can be used, including 2-( l H-Bcnzotriazole- l -yl)- l , l ,3,3- tetramethy luronium hexafluorophosphate (HBTU). After formation of the R1 group, the benzyl group can be cleaved using methods known to those skilled in the art, including those described herein, and a compound of Formula (I) can be obtained. Scheme 5 shows a general reaction scheme for obtaining compounds of Formula (I) w here R1 is a group other than a hydroxy or C i-6 alkoxy. and G and G~ are as defined above. Additional information with respect to preparing compounds of Formula (I) is provided in U.S. Patent No. 4.345.934. U.S. Publication No. U.S. 2009/281 107A1 , U.S. Publication No. U.S. 2010/197651 Al. PCT Publication No. WO 201 1/120153. Miyamoto et al., ( hem. Pharm. Bull , ( 1989) 37:93 and Miyamoto et al.. Chem. Pharm. Bull , (1988) 36: 1321.
Scheme 5
Figure imgf000058_0001
cheme 6
Figure imgf000059_0001
A method for forming a compound of Formula (1) where G may be
Figure imgf000059_0002
and R1 may be an alkyl, such as methyl, is shown in Scheme 6. As illustrated in Scheme 6. the ester group can undergo hydrolysis to form a carboxylic acid. The carboxylic acid can then be transformed using methods known to those skilled in the art to form the desired R1 group. For example, an amide and the carboxylic acid group can undergo a coupling reaction to form a substituted amide group. Examples of suitable amides include Weinreb amides, such as HNMe(OMe). Suitable coupling reagents are known to those skilled in the art and include 2-(lH-Benzotriazole-l-yl)-l.l ,3.3-tetramethyiuronium hexafluorophosphate (HBTU). The compound including the substituted amide
reacted with a suitable Grignard reagent to form Formula (Γ). where G I may T b_e
Figure imgf000059_0003
and R1 may be an alkyl (for example, methyl). Additional information with respect to preparing compounds of Formula (I) is provided in Imada et ai., J. Med. Chem. , 2006, 49( 13): 3809-3825. and Clark et al.. Bioorg. Med.Chem. Lett. , 2004. 14( 12): 3299-3302.
Scheme 7
Figure imgf000060_0001
(I); G2 = -CH2OH
[0137] Example methods for forming a compound of Formula (1) where G2 is an optionally substituted C , -6 alkyl; -CH2OH; -CH(Y ')(0H), -C(0)Y' are shown in Scheme 7. For instance, a 6-membered pyridazinone ring can be formed via a cyclization of the starting material with AyV-dimcthylacetamidc-dimethyl acetal or cinnamoyl chloride. An example of using cinnamoyl chloride is provided in U.S. Publication No. 2012/0022251. which is hereby incorporated by reference for the limited purpose of using cinnamoyl chloride. After cyclization, the 6-membered pyridazinone ring can be further modified to form a compound of Formula (I) where G2 is an optionally substituted C | -6 alkyl. The nitrogen of the 6- membered pyridazinone ring may be alkylated using methods known to those skilled in the art. To form compounds where G2 is a C , _6 alkyl; -CH2OH; -CH(Y' )(OH). -C(0)Y' . the exocyclic styrene alkene moiety may be oxidatively cleaved to afford an aldehyde, for example, via ozonolysis or using a sodium periodate - ruthenium trichloride mixture or the like. The aldehyde may be reduced to afford an alcohol or reacted with a Grignard reagent under appropriate conditions. For example, where G" is -CH2OH, the aldehyde may be reduce using sodium borohydride; and where G" = -CH(CH3)OH, the aldehyde may be reacted with a Grignard reagent. The alcohol may be oxidized to form a ketone at G" (for example, G2 is C(O)Me) using appropriate conditions known to those skilled in the art, such as ozonolysis.
Scheme 8
Figure imgf000061_0001
[0138] A method for forming a compound of Formula (I) where G~ is-CN; or an optionally substituted aryl is shown in Scheme 8. For example, the β position of the α.β- unsaturated ketone in the 6-membered pyridazinone ring may be brominated using NBS (N- bromosuccinimide) under appropriate conditions to afford the vinyl bromide. An example of using NBS is described in WO 2012/039414, which is hereby incorporated by reference for the limited purpose of using NBS. The vinyl bromide may be treated with CuCN under appropriate conditions, for example as described in U.S. Patent No. 5,202,323 to afford a compound of Formula (I) where G2 is -CN. The vinyl bromide may be reacted with an aryl boronic acid (such as phenyl boronic acid) under appropriate conditions (for example, using a palladium catalyst) followed by further modification to afford a compound of Formula (I) where G~ is an optionally substituted aryl.
Scheme 9
Figure imgf000062_0001
[0139] Example methods for forming a compound of Formula (I) that includes a macrocyclic ring formed from RI O-L' -R4 are shown in Schemes 9 and 1 0. In Scheme 9, the starting material may be reacted with allyltributyl tin in the presence of a metal catalyst, such a palladium, to afford the allyl intermediate. The ester of the allyl intermediate may be hydrolyzed to afford an intermediate that includes a carboxylic acid moiety, which can be then reacted with an allyl amine via a coupling reaction to afford a diene intermediate. Suitable coupling reagents can be used, including 2-(l H-Benzotriazole-l -yl)-l , 1.3,3- tetramethyluronium hexalluorophosphate (HBTU). The diene intermediate can undergo a ring closing olefin metathesis macrocyclization using a suitable catalyst, for example, a Grubb"s type catalyst to afford the alkene compound. Examples of suitable Grubb's type catalysts are described in in Tetrahedron Letters (2003), 44( 1 1 ):2401 -2404, which is incorporated by reference for the limited purpose of its description of Grubb's type catalysts. The alkene may be hydrogenated, and the benzyl group may be cleaved, for example, using hydrogen (H2) over Pd/C to afford to a compound of Formula (I).
Scheme 10
Figure imgf000063_0001
[0140| In Scheme 10, the starting material may be reacted with an ally bromide that includes a protected amine to afford a protected amine intermediate. The ester of the protected amine inlemiediate may be hydrolyzed to afford an intermediate that includes a carboxylic acid moiety and then the protecting group of the amine may be removed. The carboxylic acid moiety can be reacted with the amine via an intramolecular macrolactamization coupling reaction, for example as described in Chemical Communications (2002), (12): 1280- 1281 , and WO 2009/004146, to afford the macrolactam intermediate. The benzyl group of the macrolactam intermediate may be cleaved, for example, using TFA or BCI3 to afford to compounds of Formula (1).
Scheme 1 1
Figure imgf000064_0001
[0141 ] A method for forming a compound of Formula (II) where R1 A is a mono- substituted amine is shown in Scheme 1 1 . For example, the starting may be reacted with acetamidobenzenesulfonyl azide (ABSA) under appropriate conditions using methods and conditions known to those skilled in the art, for example, as described in WO 201 1 /120153. to afford the diazo intermediate. The diazo intermediate may be reduced under appropriate conditions using methods and conditions known to those skilled in the art. for example using trimethy phosphine as described in WO 201 1 /120153 or tributyl phosphine as described in Chem. Pharm. Bull. (1988). 36: 1321 -1327. to afford the hydrazone intermediate. The hydrazone intermediate may be alkylated under appropriate conditions using methods and conditions known to those skilled in the art to afford the alkyl hydrazine intermediate. The alkyl hydrazone intermediate may be cyclized using a strong base (such as sodium hydride or LDA), for example as described in Chem. Pharm. Bull. ( 1989). 37:93-98. to afford the pyrimido[5.4-c]pyridazin-4(lH)-one intermediate. The tert-butyl ester of the pyrimido[5.4- c]pyridazin-4(lH)-one intermediate may be cleaved using an acid, such as TFA, to afford an intermediate that includes a carboxylic acid moiety. The carboxylic acid moiety can be reacted with methyl amine via a coupling reaction to afford the a compound of Formula (11). Suitable coupling reagents can be used, including 2-( l H-Benzotriazole- l -yl)-l , 1.3,3- tetramethy luronium hexafluorophosphate (HBTU).
Pharmaceutical Compositions
[0142] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0143| The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0144] The term ''physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
[0145] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0146] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
[01 7] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent'" is a type of excipient.
[0148] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
[0149] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
[0150] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be administering intramuscular. In other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be administering intranasal. In still other embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be administering intradermal. In yet still other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be administering orally.
[01511 When administered orally, one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to assist in simulating nasal secretions.
[0152] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0153] The compositions may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
Methods of Use:
[0154] Some embodiments described herein relate to a method of ameliorating, treating and/or preventing an orthomyxovirus infection, which can include administering an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing).
[0155| Other embodiments described herein relate to a method of inhibiting an orthomyxovirus viral replication, which can include contacting a cell infected with the orthomyxovirus virus with an effective amount of a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing).
[0156] In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used to treat and/or ameliorate an influenza viral infection. In other embodiments, an effective amount of one or more compounds of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used to prevent an influenza viral infection.
[0157] In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing) can be used to inhibit the replication an influenza virus. In some embodiments, an effective amount of one or more compounds of Formulae (1). or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used to inhibit the influenza polymerase complex. In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used for inhibiting and/or reducing the endonuclease activity of an influenza endonuclease that can include contacting the active site of the endonuclease with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, one or more compounds described herein inhibits and/or reduces the ability of the endonuclease to cleave the mRNA.
[0158] In some embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza A viral infection. In other embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza B viral infection. In still other embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza C viral infection. In some embodiments, a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be used to treat and/or ameliorate one or more subtypes of influenza. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat HlNl and/or H3N2. In addition or in the alternative, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be used to treat H2N2, H5N 1 and/or H7N9. In some embodiments, a compound described herein (a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be effective against more than 1 subtype of influenza. For example, a compound described herein (a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be effective against 2, 3, 4, and/or 5 or more subtypes of influenza. [0159] In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate an upper respiratory viral infection attributed to (directly and/or indirectly) an influenza virus infection. In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate a lower respiratory viral infection (directly and/or indirectly) an influenza virus infection. In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate one or more symptoms of an influenza virus infection (such as those described herein). In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to an influenza virus infection. In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II). or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate pneumonia due to an influenza virus infection. In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used treat and/or ameliorate coup due to an influenza virus infection.
[0160] In some embodiments, an effective amount of one or more compounds of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing) can be used lessen the severity of one or more symptoms of an influenza infection. Examples of symptoms include, but are not limited to. the following: fever, chills, cough, sore throat, runny nose, stuffy nose, muscle aches, body aches, headache, fatigue, vomiting and/or diarrhea.
[01611 As used herein, the terms "prevent" and "preventing," mean a subject does not develop an infection because the subject has an immunity against the infection, or if a subject becomes infected, the severity of the disease is less compared to the severity of the disease if the subject has not been administered/received the compound. Examples of forms of prevention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as an orthomyxovirus (e.g., an influenza virus).
[0162] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.
[0163] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
[0164] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.
[0165| Various indicators for determining the effectiveness of a method for treating an orthomyxovirus viral infection are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.
[0166] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to a lower level, for example, from about 10E4 TCID50/mL(TClD = tissue culture infectious dose) to about 10E3 TCID50/mL, or to about 100 TCID50/mL, or to about 10 TClD50/mL. In some embodiments, an effective amount of a compound of Formula (1). or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formula (1), or a pharmaceutically acceptable salt thereof. For example, wherein the viral load is measure before administration of the compound of Formula (1), or a pharmaceutically acceptable salt thereof, and again after initiation of the treatment regime with the compound of Formula (1), or a pharmaceutically acceptable salt thereof (for example, 10 days after initiation of treatment). In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be an amount that is effective to reduce viral load to lower than about 10E4 TCTD50/mL. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a reduction in viral titer in a nasal/pharyngcal swab or nasal wash sample of the subject in the range of about 1 .5-log to about a 2.5-log reduction or about a 3-log to about a 4-log reduction compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, wherein the viral load is measure before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after initiation of the treatment regime with the compound of Formula (1), or a pharmaceutically acceptable salt thereof (for example. 10 days after initiation of treatment).
[0167| In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt of the foregoing, can result in one or more overall quality of life health, such as reduced illness duration, reduced illness severity, reduced time to return to normal health and normal activity, and reduced time to alleviation of one or more symptoms of orthomyxovirus infection, compared to a subject who is untreated. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in a reduction in the length and/or severity of one or more symptoms associated with an orthomyxovirus infection compared to an untreated subject. Symptoms of an orthomyxovirus infection are described herein and include but not limited to cough, myalgia (muscle pain), nasal obstruction, sore throat, fatigue, headache and fever. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the thereof, can result in a reduction in one or more secondary complications associated with an orthomyxovirus infection, including but not limited to otitis media (ear inflammation), sinusitis, bronchitis and pneumonia compared to an untreated subject.
[0168] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in at least a 1 , 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of an orthomyxovirus relative to pre-treatment levels in a subject, as determined after initiation of the treatment regime (for example, 10 days after initiation of treatment). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in a reduction of the replication of an orthomyxovirus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of orthomyxovirus replication in the range of 1 to 1 .5 log. 1 .5 log to 2 log. 2 log to 2.5 log, 2.5 to 3 log, or 3 to 3.5 log reduction of orthomyxovirus replication compared to the reduction of orthomyxovirus reduction achieved by oseltamivir (Tamiflu®). or may achieve the same reduction as that of oseltamivir (Tamiflu®) therapy in a shorter period of time, for example, in one day, two days, three days, or four days as compared to the reduction achieved after 5 days of oseltamivir (Tamiflu®) therapy.
[0169] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term "resistance" as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formulae (I) and/or (11), or a pharmaceutically acceptable salt of the foregiong, can be administered to a subject infected with an influenza virus that is resistant to one or more different anti-influenza agents (for example, amantadine, rimantadine and/or oseltamivir). In some embodiments, a compound of Formulae (I) and/or (IT), or a pharmaceutically acceptable salt of the foregoing, can be administered to a subject infected with an influenza virus that is resistant to a M2 protein inhibitor. In some embodiments, development of resistant influenza strains is delayed when subjects are treated with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, compared to the development of influenza strains resistant to other influenza drugs.
[0170] In some embodiments, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can decrease the percentage of subjects that experience complications from an influenza viral infection compared to the percentage of subjects that experience complication being treated with oseltamivir. For example, the percentage of subjects being treated with a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, that experience complications can be 10%, 25%, 40%, 50%,. 60%, 70%,, 80% and 90%, less compared to subjects being treated with oseltamivir.
[0171 ] In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, can be used in combination with one or more additional agent(s). In some embodiments, a compound of Formula (1). or a pharmaceutically acceptable salt thereof, can be used in combination with one or more agents currently used in a conventional standard of care for treating influenza. For example, the additional agent can be amantadine (adamantan-
1 - amine, Symmetrel), rimantadine (Flumadine), zanamivir (Relenza) and oseltamivir (Tamiflu). For the treatment of influenza, additional agents include but are not limited to a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, peramivir (( 1 S,2S,3S,4R)-3-[( 1 S)- 1 -acetamido-2-ethylbutyl]-4-(diaminomethyiideneamino)-
2- hydroxycyclopentane-l-carboxylic acid, BioCryst Pharmaceuticals), laninamivir ((4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[( lR,2R)-3-hydiOxy-2-methoxypiOpyl]-5,6- dihydro-4H-pyran-2-carboxylic acid), favipiravir (T-705. 6-fluoro-3-hydroxy-2- pyrazinecarboxamide). laninamivir octanoate ((3R,4S)-3-acetamido-4-guanidino-2-((l S,2S)- 2 -hydroxy- 1 -methoxy-3 -(octanoyloxy )propyl )-3 ,4-dihydro-2H-pyran-6-carboxylic acid) fludase (DAS 1 81 , NexBio), ADS-8902 (amantadine HCl/oseltamivir/ribavirin, Adamas Pharmaceuticals), an immuno-modulator (for example, a Type 1 interferon), beraprost (4- [2- hydroxy- 1 - [(E)-3-hydroxy-4-methyloct- 1 -en-6-ynyl] -2,3 ,3a,8b-tetrahydro- 1 H- cyclopenta[b] [l ]benzofuran-5-yl]butanoic acid), Neugene®, ribavirin, (R)-3-((5-fluoro-2-(5- fluoro- l H-pyrrolo[2,3-bJpyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpcntanoic acid (CAS Reg. No. 1422050-75-6), (2S,3S)-3-((5-fluoro-2-(5-fluoro- l H-pyrrolo[2.3-b]pyridin-3- yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid (CAS Reg. No. 1259366-34- 1 , VX-787). FluMist Quadrivalent® (Medlmmune). Fluarix® Quadrivalent (GlaxoSmithKline), Fluzone® Quadrivalent (Sanofi Pasteur), Flucelvax® (Novartis) and FluBlok® (Protein Sciences). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, can be used in combination with oseltamivir. [0172] Type 1 interferons are known to those skilled in the art. A non-limiting list of examples include: alpha-interferons, beta-interferons, delta-interferons, omega- interferons, tau-interferons, x-interferons. consensus interferons and asialo-interferons. Type 1 interferons can be pegylated. Examples of specific type 1 interferons include interferon alpha 1 A, interferon alpha I B. interferon alpha 2A. interferon alpha 2B. pegylated-interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX. Aradigm), pegylated-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON. Schering). recombinant interferon alpha 2b (INTRON A. Schering). pegylated interferon alpha 2b (PEG-INTRON. Schering. V1RAFERONPEG, Schering), interferon beta- la (REB1F, Serono, Inc. and Pfizer), consensus interferon alpha (1NFERGEN, Valeant Pharmaceutical).
[0173] In some embodiments, a compound of Formulae (I) and/or (11), or a pharmaceutically acceptable salt of the foregoing, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
[0174] The order of administration of a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, with one or more additional agent(s) can vary. In some embodiments, a compound of Formulae (Γ) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered prior to all additional agents. In other embodiments, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can he administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered subsequent to the administration of at least one additional agent, hi some embodiments, a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, can be administered subsequent to the administration of all additional agents.
[0175] In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in an additive effect. In some embodiments, the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in a synergistic effect. In some embodiments, the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) can result in a strongly synergistic effect. In some embodiments, the combination of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) is not antagonistic.
[0176] As used herein, the term "antagonistic" means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound). As used herein, the term "synergistic effect" means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term "additive effect" means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
[0177] A potential advantage of utilizing a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the required amount(s) of the one or more additional agents, including pharmaceutically acceptable salts and prodrugs thereof, that is effective in treating a disease condition disclosed herein (for example, influenza), as compared to the amount required to achieve the same therapeutic result when one or more of the additional agents, including pharmaceutically acceptable salts and prodrugs thereof, are administered without a compound of Formulae (I) and/or (Π). or a pharmaceutically acceptable salt of the foregoing. For example, the amount of an additional agent described above, including a pharmaceutically acceptable salt and prodrug thereof, can be less when administered in combination with a compound of Formulae (1) and/or (11), or a pharmaceutically acceptable salt of the foregoing, compared to the amount of additional agent, including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formulae (Γ) and/or (11), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereoi; is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
[0178] Additional advantages of utilizing a compound of Formulae (I) and/or (Π). or a pharmaceutically acceptable salt of the foregoing, in combination with one or more of the additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross resistance between a compound of Formulae (I) and/or (Π). or a pharmaceutically acceptable salt of the foregoing, and the one or more additional agent(s) described above (including pharmaceutically acceptable salts and prodrugs thereoi); different routes for elimination of a compound of Formulae (1) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and the one or more additional agent(s) described above (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxicities between a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and the one or more additional agent(s) described above (including pharmaceutically acceptable salts and prodrugs thereoi); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formulae (I) and/or (II), or a pharmaceutically acceptable salt of the foregoing, and the one or more additional agent(s) described above, including pharmaceutically acceptable salts and prodrugs thereof.
[0179] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
[01801 The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0181 ] In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1 % and 500%. more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly- discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0182] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
[0183] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0184] It should be noted that the attending physician would know how7 to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest w ill vary w ith the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age. body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
[0185] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
EXAMPLES
[0186] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
EXAMPLE 1
Figure imgf000081_0001
[0187] To a stirred solution of NaH (21.8 g. 912 mmol, 3.0 eq.) in THF (300 mL) was added BnOH (32.8 g, 304.0 mmol, 1 .0 eq.) under a N2 atmosphere at 0°C. After addition, the mixture was stirred for 30 min. Compound A (63.5 g. 304.0 mmol, 1 .0 eq.) was added portionvvise. and the mixture was allowed to warm to ambient temperature and stirred for 12 h. The product was followed by TLC using petroleum ether (PE):EtOAc = 5: 1 . The mixture was poured into 2M HCl solution to adjust to ~pH 6. The solution was exacted w ith EtOAc (200 mL x 3). The combined organic phases were dried over N 2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 30: 1 to 5 : 1) to give B as a colorless oil (46 g, 88.5 %). 'HNM (CDCT3) δ 7.39-7.29 (m, 5H), 4.59 (s, 2H), 4.17-4.24 (q, 2H), 4.14 (s, 2H), 3.53 (s, 2H), 1.31 - 1.22 (t, 3H). [0188] To a stirred solution of B ( 10.0 g. 42.3 mmol, 1 .0 eq.) in CH3CN (20 mL) under a N2 atmosphere at 0°C, was added TosN3 (8.35 g, 42.3 mmol, 1 .0 eq.) and TEA (12.84 g, 127.1 mmol, 3.0 eq.). The mixture was stirred at 0 °C for 2 h. The mixture was warmed to room temperature (RT) and stirred for 6 h. The progress of the reaction was followed by TLC (PErEtOAc = 5: 1 ). After complete conversion was observed, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (PErEtOAc = 30: 1 to 5: 1 ) to give C as a colorless oil (4.5 g, 40.5%). 'HNMR (CDC13) δ 7.39-7.26 (m. 5H), 4.64 (s, 2H). 4.60 (s, 2H). 4.29-4.24 (q, 2H). 1 .32-1 .28 (t, 3H).
[0189] To a solution of C (4.04 g, 15.4 mmol, 1 .0 eq.) in THF (5 mL) was added P(CH3)j/THF solution ( 16.9 mL, 16.9 niM, 1.1 eq.) at RT. The mixture was stirred for 15 min (indicated by LLC, PE:EtOAc =2: 1) and then quenched with water (2.8 mL). The mixture was stirred for 15 min and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (PE:EtOAc = 5: 1 to 2: 1) to give D as a yellow solid (4.0 g, 98.2%). 'HNMR (CDC13) δ 7.39-7.24 (m. 5H), 4.66-4.66 (s, 1H), 4.66- 4.61 (s, 2H), 4.53-4.53 (s, 1H), 4.31 -4.24 (m, 2 H), 1.35- 1.29 (m, 3H).
[0190] To a stirred solution of D (20.0 g, 75.7 mmol, 1.0 eq.) in THF (100 mL) was added NaHC0 (19.1 g, 227.3 mmol, 3.0 eq.) and (Boc)20 (22.84 g, 1 13.6 mmol, 1.5 eq.). The mixture was heated to reflux for 6 h and monitored by TLC (PE:EtOAc =2: 1 ). After complete conversion was observed, the solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with water (80 mL x 2). The organic layer was separated, dried over Na2S04 and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EtOAc = 8: 1 ) to give E as a white solid ( 1 5 g. 54.30%). 'HNMR (CDC13) δ 1 1 .59 (s. 1 H). 7.40-7.26 (m, 5H), 4.71 -4.61 (m. 2H), 4.39 (s. 2H), 4.71 - 4.27 (q. 2H), 1.70-1.48 (m, 9H). 1.38-1.24 (t, 3H).
[0191] To a solution of E (4.2 g, 1 1.5 mmol, 1 eq.) in THF (100 mL) at RT, was added DMF-DMA (6.15 g, 51.7 mmol, 4.5 eq.). The mixture was stirred at RT for 16 h. After complete conversion w7as observed as indicated by TLC, the reaction w7as treated with water (5—6 mL) and stirred for 30 min. The solvent was evaporated under reduced pressure at 40-50°C. The residue was crystallized from EtOAc to give the pure product as a white solid, (0.5 g). The mother liquor was concentrated and purified by column chromatography on silica gel (DCM:MeOH = 50: 1 to 10: 1 ) to give F as a solid (2.4 g, 75.95%). ' i INMR (CD3OD) δ 8.22 (s, 1 H), 7.48-7.46 (m, 2H), 7.41 -7.34 (m. 3H), 5.20 (s, 2H), 4.41 -4.36 (q, 2H). 1 .39- 1 .35 (t. 3H). LCMS (ESI) m/z [M+H]+ = 275.2 (calc. = 274. 1 ). Retention Time =1 .097 min.
EXAMPLE 2
5-hydroxy-4-oxo-l-(3-(trifluoromethyl)phenyl)-l,4-dihvdropyridazine-3-carboxylic acid
Figure imgf000083_0001
Figure imgf000083_0002
[0192] A mixture of 2a (3.2 g. 20 mmol) and 6 M HC1 aqueous solution (20 mL. 120 mmol) was stirred at 0 °C. To the mixture was added a solution of NaN02 (1 .66 g, 24 mmol) in H20 (5 mL) dropwise. After addition, the mixture was stirred for 1 5 min. The resulting aqueous solution was added to a suspension of l a (4.7 g. 20 mmol) and NaOAc (9.84 g. 120 mmol) in EtOH (40 mL) at 0°C. After complete conversion, the mixture was poured into water and extracted with AcOEt (30 mL x 3). The combined organic phases were washed with a sat. NaHCC aqueous solution and brine, dried over MgS04, and concentrated under reduced pressure. Crude 3a (5.6 g) can be used without further purification. Ή NMR (400 MHz, CDC13) δ 14.79 (s, 0.5H), 12.94 (s, 0.5H), 7.70-7.30 (m, 9H), 4.76 (s, 1 H), 4.73 (s, 1 H), 4.70(s. 1 H), 4.67 (s, 1 H), 4.39 (t, J = 7.2 Hz. l H), 4.32 (t, J = 7.2 Hz, l H), 1 .43-1 .37 (m, 3H).
[0193] A solution of 3a (4.8 g, 12 mmol) in DMF-DMA (33 mL) was heated to reflux for 2.5 h. After complete conversion, the reaction was cooled to RT. The precipitate was collected by suction-filtration. The filter cake was washed with a small amount of EtOAc and dried over in vacuum to give pure 4a as a w hite solid (3.5 g. 69.7 %). Ή NMR (400 MHz, DMSO-t/6) δ 8.89 (s, 1 H), 8.16 (s, 1 H). 8.1 1 (d, J = 7.6 Hz, 1 H), 7.89-7.82 (m. 2H). 7.49-7.39 (m, 5H), 5.52 (s. 2H), 4.33 (q, J = 7.2 Hz, 2H). 1 .29 (t, J = 7.2 Hz, 3H).
[0194] A suspension of 4a (41 8 mg, 1.0 mmol) and Pd/C (50 mg) in EtOH/THF ( 1 : 1. 10 mL) was stirred at RT under ¾ atmosphere (15 psi.) for 30 min. After complete conversion, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The crude product was crystallized in EtOAc to give pure 5a as a white solid (300 mg. 91.4 %). Ή NMR (400 MHz, CD3OD) δ 8.72 (s. 1H), 8.15 (s. 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.84-7.78 (m, 2H), 4.44 (q, J = 7.2 Hz. 2H), 1.41 (t, J = 7.2 Hz. 3H).
[0195] To a solution of 5a (328 mg, 1.0 mmol) in MeOH (5 mL) was added 1 N NaOH aqueous solution (3 mL, 3.0 mmol). The mixture was stirred at RT for 3 h. After complete conversion, MeOH was removed via vacuum. The aqueous phase was acidified with 1 N hydrochloride to pi I = 4. A white solid was precipitated from the mixture. The solid was collected by filtration, washed with water and dried over in vacuum to provide compound 1 as a white solid (120 mg, 40.0 %). LCMS (ESI) m/z = 300.8 [M+H] + .
EXAMPLE 3
l -(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-5-hvdroxy-4-oxo-l ,4-dihvdropyridazine-
3-carboxylic acid (2)
Figure imgf000085_0001
[0196] To a solution of 2b (1 g. 3.87 mmol) in HN03 (2 mL) and H3P04 (3 mL) was added a solution of NaN02 (400 mg. 5.85 mmol) in H20 (20 mL) at 0 HC dropwise. The mixture was stirred for 0.5 h at the same temperature. The resulting aqueous solution was then added to a suspension of l b ( 1.38 g, 5.85 mmol) and AcOK ( 10 g, 102 mmol) in RtOH (80 mL) at 0"C. The reaction wras warmed to RT and stirred for 3 h. The mixture was basified to pH = 9 with sat. aq. NaHC03 solution. The mixture was extracted with EtOAc (60 mL x 3). The combined organic phases were dried over Na2S04, filtered and concentrated via vacuum. The residue was purified by column chromatography on silica gel (10% EA in PE) to give pure 3b as a white solid ( 1.0 g, 35%). Ή NMR (400 MHz, CD3C1) S 8.16 (s. 1H), 7.62 (d, J = 8.8 Hz, 1H), 743-7.39 (m, 5H), 6.99 (d, J = 8.8 Hz, 1H), 4.74 (s, 2H), 4.68 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.06 (s, 3H), 3.26 (q, J = 7.2 Hz, 4H), 1.38 (t, J = 7.2 Hz, 3H), 1 .15 (t, J = 7.2 Hz, 6H).
[0197] A mixture of 3b (1 .0 g, 1.98 mmol) in DMF-DMA (50 mL) was stirred for 3 h at RT. After complete conversion, the solvent was removed under reduced pressure, and the residue was crystallized with EtOAc to give pure 4b as a yellow solid (0.5 g, 50.4 %). Ή NMR (400 MHz, CD C1) 0 7.87 (s. 1 1 1), 7.85 (d, J = 8.4 I Iz, 111), 7.71 (s, 1 1 1), 7.42-7.32 (m, 5H), 7.07 (d. J = 8.4 Hz, 1 H), 5.31 (s, 2H). 3.97 (s, 3H). 3.78 (s, 3H). 3.23 (q, J = 7.2 Hz, 4H). 1 .16 (t. J = 7.2 Hz. 6H).
[0198] To a solution of 4b (0.5 g, 1 .0 mmol) in EtOH (5 mL) and water (5 mL) was added 2 N NaOH (0.8 mL. 16 mmol) at 0 °C. The mixture was stirred at the same temperature for 3 h. EtOH was removed under reduced pressure, and the aqueous phase was acidified to pH = 4 with 2 N HC1 solution. The precipitate was collected by suction- filtration. The filter cake was washed with water and dried in vacuum to give 5b as a white solid (0.3 g, 61.6%). Ή NMR (400 MHz, CD3C1) δ 8.05 (s, 1H), 7.87-7.85 (m, 2H), 7.40- 7.36 (m, 5H), 7.09 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H), 3.78 (s, 3H), 3.21 (q, ./ = 7.2 Hz. 4H), 1.16 (t, .7 = 7.2 Hz, 6H).
10199] A mixture of 5b (0.3 g. 0.62 mmol) and Pd(OH)2 (0.2 g) in MeOH (20 mL) was stirred for 4 h under ¾ atmosphere (30 psi). After complete conversion, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 2 as a white solid (100 mg, 41 .0%). LCMS (ESI) m/∑= 398.0 [M+H] +.
EXAMPLE 4
l-(4-tert-butylphenyl)-5-hvdroxy-4-oxo-l ,4-dihvdropyridazine-3-carboxylic acid (3)
Figure imgf000087_0001
4c 5c
[0200] A solution of 2c (1.0 g, 9.7 mmol) in HBF (6 mL, 50 % in water) was cooled with an ice brine bath. To the solution was added a solution of NaN02 (0.8 g, 1 1 .4 mmol) in H O (10 mL) dropwisc at 0 "C. The reaction was stirred to keep the bath temperature between -5°C and 5°C for 1 h. The in situ formed diazonium solution was added to a mixture of compound l c (2.3 g. 9.7 mmol) and NaOAc (1 .23 g, 15 mmol) in EtOH (50 mL) at 0°C. After addition, the mixture was stirred at 0°C for 4 h. The resulting suspension was filtered. The filtrate was concentrated to provide the crude product, which was then purified by column chromatography on silica gel (PE'.EtOAc = 20: 1 to 10: 1 ) to give pure 3c as a colorless oil (600 mg, 23 %). Ή NMR (400 MHz. CDC13) δ 7.43-7.18 (m. 9H). 4.74 (s. 2H). 4.68 (s, 2H). 4.37 (t, J = 7.2, 1H). 4.27 (t, J = 7.2, 1H). 1.40-1.21 (m, 12H).
[0201] A mixture of 3c (0.6 g, 1.52 mmol) in DMF-DMA (50 mL) was stirred at RT for 3 h. After complete conversion, the mixture was concentrated under reduced pressure. The residue was treated with EtOAc ( 1 mL) and PE ( 10 mL). The solution was stirred for 10 min. The precipitate was collected by suction- filtration. The filter cake was washed with PE and dried in vacuum to give pure 4c as a yellowish solid (0.3 g, 49 %). LCMS (ESI) m/z = 407.2 [M+I I] ' .
[0202] To a solution of 4c (0.3 g, 0.74 mmol) in EtOH (5 mL) and water (5 mL), was added 2 N NaOH (0.8 mL. 1 .6 mmol) at 0°C. The mixture was stirred for 3 h. After complete conversion, the mixture was concentrated under reduced pressure to remove the EtOH. The aqueous phase was acidified to pH = 4 with 2 N HC1 aq. solution. The mixture was extracted with EtOAc (3 mL x 3). The combined organic phases were dried over with Na2S04, filtered and concentrated to give crude 5c as a white solid (0.2 g, 71 .0 %). wliich was used without further purification. Ή NM (400 MHz, CDC 13) δ 8.19 (s. 1H), 7.52-7.50 (m, 2H), 7.45-7.36 (m, 7H), 5.39 (s, 2H). 1.34 (s, 9H).
[0203] A mixture of 5c (0.2 g, 0.53 mmol) and Pd(OH)2 (0.2 g) in MeOH (20 mL) was stirred for 4 h under a H2 atmosphere ( 15 psi). After the reaction was completed, the mixture was filtered through a pad of celite and concentrated to give the crude product. The crude product was purified by prep-HPLC to give compound 3 as a white solid (100 mg, 65.7 %). LCMS (ESI) m z = 289.1 [M+H] +.
[0204] Compound 4 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 4-lluoroaniline. LCMS (ESI) m/z = 249 [M-H] and 251 [M+H]+.
[0205] Compound 5 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 3-methoxyaniline. LCMS (ESI) m/z = 261 [M-I I] and 263 [M+H]+.
[0206] Compound 6 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 3-phenoxyaniline. LCMS (ESI) m/z = 323 [M-H] and 324 [M+H]+.
[0207] Compound 7 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-(trifluoromethyi)aniline. LCMS (ESI) m/z = 301 [M+H]+ and 323 [M+Na]+.
[0208] Compound 8 was obtained following one of the procedures for obtaining compounds 1 . 2 or 3 using 2-isopropylaniline. LCMS (ESI) m/z = 275 [M+H]+.
[0209] Compound 9 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-phenoxyaniline. LCMS (ESI) m/z = 325 [M+H]+. [0210] Compound 10 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2,3-dihydro- l H-inden-5-amine. LCMS (ESI) m/z = 273 [M+H]+.
[0211 ] Compound 11 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-(pipcridin- l -yl)anilinc. LCMS (ESI) /z = 316 [M+H|+.
[0212] Compound 12 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2,6-dimethylaniline. LCMS (ESI) m/z = 261 [M+H]+ and 283 [M+Na]+.
[0213] Compound 13 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 4-methoxy-[l J '-biphenyl]-3-amine. LCMS (ESI) m/z = 339 [M+H]+.
[0214] Compound 14 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 2-(difluoromethoxy)aniline. LCMS (ESI) m/z = 299 [M+H]+.
[0215] Compound 15 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-methylquinolin-8-amine. LCMS (ESI) m/z = 298 [M+H]+.
[0216] Compound 16 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-(tert-butyl)aniline. LCMS (ESI) m/z = 289 [Μ+ΗΓ.
[0217] Compound 17 was obtained following one of the procedures for obtaining compounds 1, 2 or 3 using N-(3-aminophenyl)methanesulfonamide. LCMS (ESI) m/z = 348 [M+Na]+ and 673 [2M+Na]+.
[0218] Compound 18 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using [L l'-biphenyl]-2-amine. LCMS (ESI) m/z = 309 [M+H]+ and 331
[0219] Compound 19 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-((cyclohexyl(meth\ )amino)methyl)anilinc. LCMS (ESI) m/z = 358 [M+H]+.
[0220] Compound 20 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 3.5-bis(trifluoromethyl)aniline. LCMS (ESI) m/'z = 369 [M+H]+ and 391 [M+Na]+.
[0221 ] Compound 21 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 2-(trifIuoromethoxy)aniline. LCMS (ESI) m/z = 317 [M+H]+. [0222] Compound 22 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 3-amino-N-butylbenzenesulfonamide. LCMS (ESI) m/z = 368 [M+HJ+.
[0223] Compound 23 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-ethoxyaniline. LCMS (ESI) m/z = 211 [M+H]+, 299 [M+Na]+ and 575 [2M+Na]+.
[0224] Compound 24 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 2-(phenylsulfonyl)aniline. LCMS (ESI) m/z = 373 [M+H]+ and 767 [2M+Na]+.
[0225] Compound 25 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 4-butoxyaniline. LCMS (ESI) m/z = 305 [M+H]+.
[0226] Compound 26 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 3,5-dimethoxyaniline. LCMS (ESI) m/z = 293 [M+H]+.
[0227] Compound 27 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 4-(trifluoromethyi)aniline. LCMS (ESI) m/z = 301 [M+H]+.
[0228] Compound 28 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 4-(piperidin- l -yl)aniline. LCMS (ESI) m/'z = 316 [M+H]+.
[0229] Compound 29 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-(2-aminophenyl)ethanol. LCMS (ESI) m/'z = 277 [M+H] _.
[0230] Compound 30 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 3-(trifluoromethoxy)aniline. LCMS (ESI) m/z = 31 7 [M+H]+.
[0231] Compound 31 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 4-(methylsulfonyl)aniline. LCMS (ESI) m/z = 31 1 [M+H]+.
[0232] Compound 32 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2.3-dihydrobenzo[b] [1.4]dioxin-6-amine. LCMS (ESI) m/'z = 291 [M+H]+.
[0233] Compound 33 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using l H-indazol-6-amine. LCMS (ESI) m/z = 273 [M+H]+.
[0234] Compound 34 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2'-ethyl-[l,r-biphenyl]-2-amine. LCMS (ESI) m/z = 337 [M+H]+. [0235] Compound 35 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using [l , l ':2', l "-terphenyl]-2-amine. LCMS (ESI) m/z = 385 [M+I I] h.
[0236] Compound 36 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 2'-amino-[ l , l '-biphenyl]-4-carbonitrile. LCMS (ESI) m/z = 334 [M+H]+ and 356 [M+Na]+.
[0237] Compound 37 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 4'-isobutyl-[l .r-biphenyl]-2-amine. LCMS (ESI) m/z = 365 [M+H]+.
[0238] Compound 38 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2'-methyl-[l,r-biphenyl]-2-amine. LCMS (ESI) m/z = 323 [M+H]+.
[0239] Compound 39 was obtained following one of the procedures for obtaining compounds 1, 2 or 3 using 2,-isopropyl-[l , l'-biphenyi]-2-amine. LCMS (ESI) m/z = 351 [M+H]+.
[0240] Compound 40 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2'-(trifluoromethoxy)-[Lr-biphenyi]-2-amine. LCMS (ESI) m/z = 393 [M+H]+.
[0241 ] Compound 41 was obtained following one of the procedures for obtaining compounds 1 , 2 or 3 using 2-morpholinoanilinc. LCMS (ESI) m/z = 31 8 [M+HJ 1 .
[0242] Compound 42 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using l H-indazol-5-amine. LCMS (ESI) m/z = 273 [M+H]+.
[0243] Compound 43 was obtained following one of the procedures for obtaining compounds 1. 2 or 3 using 4-phenoxyaniline. LCMS (ESI) m/z = 325 [M+H]+.
[0244] Compound 44 was obtained following the procedure for obtaining compound 24 except hydrolysis of the ethyl ester was not performed. LCMS (ESI) m/z = 401 [M+H]+.
Figure imgf000092_0001
-90-
Figure imgf000093_0001
-91-
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
-94-
Figure imgf000097_0001
EXAMPLE 5
5-hvdroxY-4-oxo-l-(2-(pyrrolidin-l-yl)phenyl)-l,4-dihydropyridazine-3-carboxylic acid
Figure imgf000097_0002
200
[0245] A solution of Id ( 10.0 g, 70.9 mmol) in pyrrolidine (30 mL) was stirred at RT for 1 h. The solvent was evaporated under reduced pressure to give crude 2d as a colorless oil ( 10.0 g, 73.5 %). The residue was used without further purification.
[0246] A mixture of 2d (10.0 g. 52.0 mmol) and Pd/C ( 1.0 g) in MeOH (20 mL) was stirred under ¾ atmosphere (15 psi) for 4 h. After complete conversion, the mixture was filtered through a pad of celite. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (clution PE: EtOAc = 50: 1 to 20: 1 ) to give pure 3d as a colorless oil (8.0 g, 95.2 %). Ή NMR (400 MHz, CDC13) δ 6.94 (d. J = 8.0 Hz, 1 H), 6.88-6.81 (m, 1 H), 6.71 -6.66 (m. 2H). 3.79 (s, 2H), 3.01 -2.98 (m. 4H). 1 .88-1 .85 (m, 4H).
[0247] To a stirred solution of 3d (743 mg, 4.59 mmol) in HC1 (4.6 mL. 27.54 mmol) at 0 °C was added NaN02 (380 mg. 5.5 mmol) in H20 ( 10 mL). The solution was stirred at 0 °C for 40 min. The resulting aqueous solution was added to a suspension of 4d ( 1.08 g, 4.59 mmol) and NaOAc (2.26 g, 27.54 mmol) in EtOH (1 0 mL) at 0°C. After addition, the solution was stirred at 0 °C for 30 min and then warmed to RT. The reaction was kept on stirring for another 4 h. After complete conversion, the mixture was treated with EtOAc (30 mL). The organic phase was separated, washed with water and brine, and dried over with Na2S0 . The solvent was removed under the reduced pressure. The residue, 5d, (4.0 g. 87.2 %) was used without further purification.
[0248] A solution of 5d (0.8 g, 1.96 mmol) in DMF-DMA (10 mL) was stirred at RT for 4 h. The solution was concentrated in vacuum, and the residue was crystallized in EtOAc to give pure 6d as a yellowish solid (400 mg, 48.69 %). Ή NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H), 7.42-7.31 (m, 6H), 7.21 (d. J = 7.6 Hz, 1 H). 6.94 (d. J = 8.4 Hz, 1 H), 6.85-6.81 (m, 1 H), 5.23 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.81 -2.78 (m, 4H), 1 .74- 1 .70 (m, 4H). 1 .35 (t. J= 7.2 Hz. 3H).
[0249] To a stirred solution of 6d (0.4 g. 0.95 mmol) in EtOH ( 10 mL) was added 2 N NaOH solution (1 .4 mL. 2.86 mmol) dropwise. After addition, the mixture was stirred at RT for 1 h. After complete conversion, the EtOH was removed via vacuum. The resulting aqueous phase was acidified with 1 N HC1 solution to pH = 2. The precipitate was collected by suction-filtration. The filter cake was wrashed with water and dried in vacuu to give pure 7d as a white solid (250 mg, 67.3 %).
[0250] A mixture of 7d (250 mg, 0.64 mmol) and Pd/C (50 mg) in MeOH (10 mL) was stirred under ¾ atmosphere (15 psi) for 15 min. After complete conversion, the mixture was filtered through a pad of celite. The filtrate was concentrated via vacuum. The residue was crystallized in EtOH ( 10 mL) to give compound 200 as a yellowish solid (50 mg, 25.91 %). LCMS (ESI) m/z = 302.0 [M+I I]
[0251 ] Compound 201 was obtained following the procedure for obtaining compound 200 using l -chloro-2-nitro-4-(trifluoromethyl)benzene and pyrrolidine. LCMS (ESI) w/z = 370 [M+H]+.
[0252] Compound 202 was obtained following the procedure for obtaining compound 200 using l -fluoro-2-nitrobenzene and 4-methylpiperidine. LCMS (ESI) m/z =
330 [M+H]+.
[0253] Compound 203 was obtained following the procedure for obtaining Compound 200 using l -fluoro-2-nitrobenzene and 2-benzylpyrrolidine. LCMS (ESI) m/z = 392 [M+H]+.
[0254] Compound 204 was obtained following the procedure for obtaining compound 200 using l-fluoro-2-nitrobenzene and 1 -methylpiperazme. LCMS (ESI) m/z =
331 [M+H]+.
[0255] Compound 205 was obtained following the procedure for obtaining compound 200 using l -fluoro-2 -nitrobenzene and 1-ethylpiperazine. LCMS (ESI) m/z = 345 [M+H]+.
[0256] Compound 206 was obtained following the procedure for obtaining compound 200 using l -fluoro-2-nitrobenzene and 4,4-dimethylpiperidinc. LCMS (ESI) m/z = 344 [M+H]+.
[0257] Compound 207 was obtained following the procedure for obtaining compound 200 using 4-isopropylpiperidine. LCMS (ESI) m/z = 358 [M+H]+.
[0258] Compound 208 was obtained following the procedure for obtaining compound 200 using 4-(tert-butyl)piperidine hydrochloride. LCMS (ESI) m/z = 372 [M+H]+.
[0259] Compound 209 was obtained following the procedure for obtaining compound 200 using 3,3-dimethylpiperidine hydrochloride. LCMS (ESI) m/z = 344 [M+H]+.
[0260] Compound 210 was obtained following the procedure for obtaining compound 200 using 3-methylpiperidine hydrochloride. LCMS (ESI) m/z = 330 [M+H]+.
[0261] Compound 211 was obtained following the procedure for obtaining compound 200 using 3-phenyipiperidine. LCMS (ESI) m/z = 392 [M+H] ~.
Figure imgf000100_0001
-98-
Figure imgf000101_0001
EXAMPLE 6
l-(2\5'-dimethylbiphenyl-2^1 -5-hvdroxy-4-oxo-l,4-dihydropyridazine-3-carboxylic acid (300)
Figure imgf000101_0002
[0262] Compound 3e was prepared in accordance with the following reaction scheme as detailed below.
Figure imgf000101_0003
3e
[0263] A mixture of 2-bromobenzenamine (3.4 g, 20 mmol) and 6 M HCI aqueous solution (20 mL, 120 mmol) was stirred at 0 °C. Lo the mixture was added a solution of NaN02 ( 1 .66 g, 24 mmol) in H20 (5 mL) dropwise. After addition, the mixture was stirred for 15 min. The resulting aqueous solution was added to a suspension of le (4.7 g, 20 mmol) and NaOAc (9.84 g, 120 mmol) in EtOH (40 mL) at 0 °C dropwise. Water (about 15 mL) was added to dissolve the NaOAc. After complete conversion, the mixture was poured into water and extracted with AcOEt (50 mL x 3). The combined organic phases were washed with sat. aq. NaHC03 solution and brine, dried over MgS04. and concentrated under reduced pressure. Crude 2e (6.3 g. 75.2%) was used without further purification. LCMS (ESI) m/z = 418.8. 420.9 [M+H]+.
[0264] A solution of 2e (3.3 g, 8 mmol) in DMT-DMA (22 mL) was heated to reflux for 2.5 h. After complete conversion, the reaction was cooled to RT. The precipitate was collected by suction-filtration, and the filter cake was washed with a small amount of EtOAc/PE ( 1 : 1 , 6 mL) and dried over in vacuum to give pure 3e as a white solid (3.0 g, 87.4 %). LCMS (ESI) m/z = 429, 431 [M+H]+.
[0265| To a suspension of 3e (500 mg, 1.16 mmol), 2,5-dimethylphenylboronic acid (210.3 mg, 1.40 mmol) and K2C03 (322 mg, 2.33 mmol) in dioxane (10 mL) was added Pd(PPh3)4 (135 mg, 0.0168 mmol). The mixture was degassed for 5 min, and then refilled with N2. The reaction was stirred at 100°C under N2 atmosphere for 2 h and then cooled to RT. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EA =5: 1 to 2: 1 ) to give pure 4e as a white solid (389 mg. 73.3 %). Ή NMR (400 MHz. CDC13) δ 7.53-7.41 (m. 3H). 7.27-7.14 (m, 7H), 7.01 (s, 2H). 6.84 (s. 1 H). 4.64-4.51 (m, 2H), 4.33 (q, J = 7.2 Hz. 2H). 2.23 (s. 3H), 1 .81 (s. 3H), 1 .31 (t. J = 7.2 Hz. 3H).
[0266] A mixture of 4e (389 mg. 0.85 mmol) and Pd/C (50 mg) in EtOH (20 mL) was stirred under a H2 atmosphere (15 psi) for 30 min. The solution was filtered through a pad of celite. The filtrate was concentrated to give the crude product as a white solid (249 mg, 80.5 %). which was used without further purification. LCMS (ESI) /// z 365.0 [M+H]
+
[0267] To a solution of 5c (249 mg, 0.68 mmol) in THE (3 mL) was added IN NaOH solution ( 1.36 mL, 1.36 mmol). The mixture was stirred at RT for 2 h. After complete conversion, THF was removed under reduced pressure, and the aqueous phase was acidified with 1 N HC1 to pH = 4. The precipitate was collected by suction-filtration. The filter cake was washed with water and dried in vacuum to give compound 300 as a white solid (130 mg, 56.9 %). LCMS (ESI) m/z = 336.9 [M+H] +.
[0268] Compound 301 was obtained following the procedure for obtaining compound 300 using (3,5-dimethylphenyl)boronic acid. LCMS (ESI) m/z = 337 [M+H]+.
[0269] Compound 302 was obtained following the procedure for obtaining compound 300 using (4-(tert-butyl)phenyl)boronic acid. LCMS (ESI) m/z = 365 [M+H]+.
[0270] Compound 303 was obtained following the procedure for obtaining compound 300 using p-tolylboronic acid. LCMS (ESI) m/z = 323 [M+H]+.
[0271 ] Compound 304 was obtained following the procedure for obtaining compound 300 using tert- butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate. Ή NMR (CD3OD): δ 1.45 (s, 9H). LCMS (ESI) m/z = 3 16 [M-Boc+H]+.
[0272] Compound 305 was obtained following the procedure for obtaining compound 300 using (4-fluoro-2-methylphenyl)boronic acid. LCMS (ESI) m/z = 341 [M+H]+.
[0273] Compound 306 was obtained following the procedure for obtaining compound 300 using (4-fluorophenyl)boronic acid. LCMS (ESI) m/z = 327 [M+H]".
[0274] Compound 307 was obtained following the procedure for obtaining compound 300 using (4-(trifluoromethyl)phcnyl)boronic acid. LCMS (ESI) m/z = 377 [M+H]+ and 399 [M+Na]+.
[0275] Compound 308 was obtained following one of the procedures for obtaining compound 300 using 2-(cyclohex-l -en-l -yl)-4,4.5,5-tetramethyl-1.3,2- dioxaborolane. LCMS (ESI) m/z = 315 [M+H]+.
[0276] Compound 309 was obtained following the procedure for obtaining compound 300 using (2,3-dimethylphenyl)boronic acid. LCMS (ESI) m/z = 337 [M+H]+.
[0277] Compound 310 was obtained following the procedure for obtaining compound 300 using (2-isopropoxyphenyl)boronic acid. LCMS (ESI) m/z = 367 [M+H]+.
[0278] Compound 311 was obtained following the procedure for obtaining compound 300 using (2-phenoxyphenyl)boronic acid. LCMS (ESI) m/z = 401 [M+H]+. [0279] Compound 312 was obtained following the procedure for obtaining compound 304 with the addition of a TFA/CI I2CI2 step to cleave the Boc group. LCMS (ESI) w/z = 316 [M+H]+.
[0280] Compound 313 was obtained following the procedure for obtaining compound 300 using (l H-indol-6-yl)boronic acid. LCMS (ESI) /// z 348 [M+H]+.
[0281 ] Compound 314 was obtained following the procedure for obtaining compound 300 using 2-isopropoxy-5-methylphenyl)boronic acid. LCMS (ESI) m/z = 381 [M+H]+.
[0282] Compound 315 was obtained following the procedure for obtaining compound 300 using (2-mefhoxyphenyl)boronic acid. LCMS (ESI) m/z = 339 [M+H]+.
[0283] Compound 316 was obtained following the procedure for obtaining compound 300 using dibenzo[b,d]furan-4-ylboronic acid. LCMS (ESI) m/z = 399 [M+H]+.
[0284] Compound 317 was obtained following the procedure for obtaining compound 300 using (2-hydroxyphenyl)boronic acid with the modification that the boronic acid coupling product was alkylated using bromocyclohexane in DMF at RT using sodium iodide and potassium carbonate. LCMS (ESI) m/z = 407 [M+H]+.
[0285] Compound 318 was obtained following the procedure for obtaining compound 300 using (3-methoxyphenyl)boronic acid. LCMS (ESI) m/z = 339 [M+H]+.
[0286] Compound 319 was obtained following the procedure for obtaining compound 300 using (2-hydroxyphcnyl)boronic acid with the modification that the boronic acid coupling product was alkylated using bromocyclopentane in DMF at RT using sodium iodide and postassium carbonate. LCMS (ESI) m/z = 393 [M+H]+.
[0287] Compound 320 was obtained following the procedure for obtaining compound 300 using (l H-indol-5-yl)boronic acid. LCMS (ESI) m/z = 348 [M+H]+.
[0288] Compound 321 was obtained following the procedure for obtaining compound 300 using 4-(4.4,5.5 etramethyl-l ,3.2-dioxaborolan-2-yl)-lH-indazole. LCMS (ESI) ^ = 362 [M+H]+.
[0289] Compound 322 was obtained following the procedure for obtaining compound 300 using (2-chloro-5-methoxyphenyl)boronic acid. LCMS (ESI) m/z = 373 [M+H]+. [0290] Compound 323 was obtained following the procedure for obtaining compound 300 using (3-chloro-5-methoxyphenyl)boronic acid. LCMS (ESI) m/z = 373 [M+H]+.
[0291 ] Compound 324 was obtained following the procedure for obtaining compound 300 using (l -methyl-lH-indol-6-yl)boronic acid with the modification that the ester/ether precursor was treated with methy l iodide and potassium carbonate in DMF prior to debenzylation and ester hydrolysis. LCMS (ESI) m/z = 362 [M+H]+.
[0292] Compound 325 was obtained following the procedure for obtaining compound 300 using (2-isobutoxyphenyl)boronic acid. LCMS (ESI) m/z = 381 [M+H]+.
[0293] Compound 326 was obtained following the procedure for obtaining compound 300 using (3-ethoxy-5-methylphenyl)boronic acid. LCMS (ESI) m/z = 367 [M+H]+.
Figure imgf000105_0001
Figure imgf000106_0001
-104-
Figure imgf000107_0001
-105-
Figure imgf000108_0001
EXAMPLE 7
l-(2-(trifluoromethyl)phenethyl -l,4-dihYdro-5-hvdroxy-4-oxopyridazine-3-carboxylic acid (400)
Figure imgf000108_0002
Figure imgf000108_0003
408 400
[0294] Potassium carbonate (0.20 g, 1 .5 mmol) was added to a solution of compound F (80 mg. 2.9 mmol) and trifluoromethylphenethyl bromide (0.15 mL. 8.8 mmol). in DMF (1 mL). The reaction was heated at 55 °C for 30 min. The mixture was diluted with EtOAc (50 mL) and washed H20 (3x), brine (lx), dried (Na2S04), and concentrated. The crude mixture was chromatographed (S1O2, EtOAc:hexane) to provide If (80 mg, 62%).
[0295] Compound If (80 mg, 1.8 mmol) was hydrogenated over 10% Pd/C (4 mg) in THF/EtOH (1 mL, 50% v/v) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated. The crude product was recrystallized from hexane/CLLCL to provide compound 408 (51 mg, 61 %). LCMS (DUIS) m/z = 357 [M+I I] +.
[0296] Sodium hydroxide (1 .0 mL, 2.0 M in LLO) was added to a solution of compound 408 (48 mg. l .1 mmol) in EtOH (5 mL). The reaction was stirred at RT for 4 h. The mixture was concentrated and then acidified with 1 M HCl to give a precipitate which was collected by filtration to give compound 400 as a white solid (3.7 mg. 10%). LCMS (ESI) m/z = 329 [M+H]+ and 392 [M+CH3CN+Na]+.
[0297] Compound 401 was obtained following the procedure for obtaining compound 400 using (2-bromoethyl)benzene. LCMS (ESI) m/z = 261 [M+H]+.
[0298] Compound 402 was obtained following the procedure for obtaining compound 400 using (3-bromopropyl)benzene. LCMS (ESI) m/z = 275 [M+H] , 287 [M+Na]+ and 338 [M+C¾CN+Na]+.
[0299] Compound 403 was obtained following the procedure for obtaining compound 400 using 3-(bromomethyl)-l , l '-biphenyl. LCMS (ESI) m/z = 323 [M+H]+. 345 [M+Nal+ and 667 [2M+ Na]+.
[0300] Compound 404 was obtained following the procedure for obtaining compound 400 using tert-butyl 3-(2-bromoethyl)- lH-indole- l -carboxylate. LCMS (ESI) m/z = 400 [M+H]+, 422 [M+Na]+ and 344 [M+H-C4H8]+.
[0301] Compound 405 was obtained following the procedure for obtaining compound 400 using l -(l -(bromomethyl)cyclopentyl)-3-(tritluoromethyi)benzene, with the modifications that step 1 of the reaction was heated at 85 °C for 24 h and step 3 was not performed. LCMS (ESI) m/z = 409 [M-HJ- and 455 LM+HC02J".
[0302] Compound 406 was obtained following the procedure for obtaining compound 400 using l -(l -(bromomethyl)cyclopentyl)-3-(trifluoromethyl)benzene, with the modification that step 1 of the reaction was heated at 85 °C for 24 h. LCMS (ESI) m/z = 381 [M-H]" and 763 [2M-H]\
[0303] Compound 407 was obtained following the procedure for obtaining compound 404 with the modification that compound 404 was treated with trifluoroacetic acid in dichloromethane. LCMS (ESI) m/z = 300 [M+H]+ and 322 [M+Na]+. [0304] Compound 408 was obtained following the procedure for obtaining compound 400 using l -(2-bromoethyl)-2-(tritluoromethyl)benzene with the modification that step 3 was not performed. LCMS (ESI) m/z = 357 [M+H]+.
[0305] Compound 409 was obtained following the procedure for obtaining compound 400 using benzyl bromide. LCMS (ESI) m/∑= 247 [M+H]+.
[0306] Compound 410 was obtained following the procedure for obtaining compound 400 using (l -(bromomethyl)cyclopentyl)benzene with the modification that step 1 of the reaction was heated at 85 °C for 24 h. LCMS (ESI) m/z = 315 [M+Hf.
[0307] Compound 411 was obtained following the procedure for obtaining compound 410 with the modification that step 3 was not performed. LCMS (ESI) m/z = 343 [M+H]+.
[0308] Compound 412 was obtained following the procedure for obtaining compound 400 using l -(2-bromoethyl)-3-(trifluoromethyl)benzene. LCMS (ESI) m/z = 327 [M-H]".
[0309] Compound 413 was obtained following the procedure for obtaining compound 400 using l -(2-bromoethyl)-2-methoxybenzene. LCMS (ESI) m/z = 289 [M-H]".
[0310] Compound 414 was obtained following the procedure for obtaining compound 400 using l -(2-bromoethyl)-3-methoxybenzene. LCMS (ESI) m/z = 289 [M-H]".
[0311 ] Compound 415 was obtained following the procedure for obtaining compound 400 using l -(2-biOmoethyl)-4-methoxybenzene. LCMS (ESI) m/z' = 289 [M-H ]".
[0312] Compound 416 was obtained following the procedure for obtaining compound 400 using l -(l -bi mo-2-methylpropan-2-yl)-4-methylbenzene with the modification that step 1 of the reaction was heated at 95 °C for 96 h. LCMS (ESI) m/z = 301 [M-H]".
[0313] Compound 417 was obtained following the procedure for obtaining compound 400 using 4-(2-bromoethyl)-l ,2-dimethoxybenzene. LCMS (ESI) m/z = 319 [M- H]\
[0314] Compound 418 was obtained following the procedure for obtaining compound 400 using 2-bromo-3,4-dihydronaphthalen-l(2H)-one with the modifications that step 1 of the reaction was performed at T for 1 h and step 2 was stopped after 1 h. LCMS (ESI) w/z = 301 | M+H]+.
[0315] Compound 419 was obtained following the procedure for obtaining compound 400 using l -( l -(bromomethyl)cyclopentyl)-3,5-bis(trifluoromethyl)benzene with the modification that step 1 of the reaction was heated at 85 °C for 24 h. LCMS (ESI) m/z = 449 [M-H]".
[0316] Compound 420 was obtained following the procedure for obtaining compound 419 with the modification that step 3 wras not performed. LCMS (ESI) m/z = 477 [M-H]" and 523 [M-HC02]\
[0317] Compound 421 was obtained following the procedure for obtaining compound 400 using (2-bromoethyl)cyclohexane. LCMS (ESI) m/z = 267 [M+H]+.
[0318] Compound 422 was obtained following the procedure for obtaining compound 400 using (l-(lH-pyrrolo[2,3-b]pyridin- l -yl)cyclopentyl)methanol with the modification that the alkylation was carried out under Mitsunobu conditions (PhjP; DEAD; THF; RT to 85 °C for 12 h). LCMS (ESI) m/z = 353 [M-H]".
[0319] Compound 423 was obtained following the procedure for obtaining compound 400 using l -(2-bromoethyl)naphthalene. LCMS (ESI) m/z = 31 1 [M+H]+.
[0320] Compound 424 was obtained following the procedure for obtaining compound 400 using l -(l -(bromomethyl)cyclopropyl)-3-(trifluoromethyl)benzenc. LCMS (ESI) m/2 = 353 [M-H]".
[0321 ] Compound 425 was obtained following the procedure for obtaining compound 400 using ( l -(3-methyl-l H-pyri lo[2.3-b]pyridin-l -yl)cyclopenty l)methanol with the modification that the alkylation was carried out under Mitsunobu conditions (Ph3P; DIAD; THF; RT to 80 °C for 8 h). LCMS (ESI) m/z = 367 [M-H]".
[0322] Compound 426 was obtained following the procedure for obtaining compound 400 using l -(l -(bromomethyl)cyclopropyl)-4-chlorobenzene. LCMS (ESI) m/z = 321 [M+H]+.
[0323] Compound 427 was obtained following the procedure for obtaining compound 400 using 2-(2-bromoethyl)naphthalene. LCMS (ESI) m/z = 31 1 [M+H]+. Table 4 - Compounds of Formula (I)
Structure
Figure imgf000112_0001
Figure imgf000113_0001
-111-
Figure imgf000114_0001
-112-
Figure imgf000115_0001
[0324] Diisopropylethylamine (52 μΕ, 0.30 mmol) was added to a solution of lg (28 mg, 0.059 mmol), trifluorobutamine hydrochloride (30 mg, 0.18 mmol) and HBTU (33 mg, 0.89 mmol) in DMF (0.3 mL). The mixture was stirred at RT for 1 .5 h. The reaction was diluted with EtOAc (20 mL) and washed successively with I N HCl, water (3x) and brine. The reaction was purified by chromatography (10 g column, elution gradient 50% ethyl acetate/hexane - 100% ethyl acetate to provide 2g (27 mg, 78%).
[0325] Compound 2g was deprotected by treatment with an atmospheric pressure (balloon) of H2(g) over 10% Pd/C (3 mg) in ethanol (10 mL) for 1 .5 h. The mixture was filtered to remove the eatalyst and concentrated to provide pure compound 500 (22.4 mg). LCMS (ESI) m/z = 492 [M+H] +.
Figure imgf000116_0001
[0326] To a stirred solution of 3g (182 mg, 0.50 mmol). HATU (380 mg, 1.0 mmol) and DIPEA (516 mg. 4.0 mmol) in DMF (20 mL) was added MeNLL.HCT (134 mg, 2.0 mmol). The mixture was stirred at RT for 4 h. After complete conversion, the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give compound 501 as a white solid (50 mg. 26.5 %). LCMS (ESI) m/z = 378.1 [M+H]
[0327] Compound 502 was obtained following the procedure for obtaining compound 500 using 3,3-difluoropyrrolidine. LCMS (ESI) m/z = 470 [M-H]" and 941 [2M-
[0328] Compound 503 was obtained following the procedure for obtaining compound 500 using l -(trifluoromethyl)cyclopentanamine. LCMS (ESI) m/z = 516 [M-H]" and 1033 [2M-H]".
[0329] Compound 504 was obtained following the procedure for obtaining compound 500 using dimethylamine. LCMS (ESI) m/z = 408 [M-H]" and 454 [M- HC02]". [0330] Compound 505 was obtained following the procedure for obtaining compound 500 using 2,2,2-trifluoroethanamine. LCMS (ESI) m/∑ = 462 [Μ-Π]".
[0331 ] Compound 506 was obtained following the procedure for obtaining compound 500 using methanamine and 1 - C 1 - ^,5- bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-5-hydroxy-4-oxo-l ,4-dihydropyrid carboxylic acid. LCMS (ESI) m/∑ = 462 [M-H]\
[0332] Compound 507 was obtained following the procedure for obtaining Compound 500 using cyclopropanamine. LCMS (ESI) m/∑ = 420 [M-H]\
[0333] Compound 508 was obtained following the procedure for obtaining compound 500 using cyclopropanamine and 1 -(( l-(3,5- bis(trifluoromethyl)pl enyl)cyclopentyr)methyl)-5-hydroxy-4-oxo-l ,4-dihydropyridazine-3 carboxylic acid. LCMS (ESI) m/∑ = 488 [M-H]" and 977 [2M-H]\
[0334] Compound 509 was obtained following the procedure for obtaining compound 500 using phenylmethanamine. LCMS (ESI) m/∑ = 470 [M-H]".
[0335] Compound 510 was obtained following the procedure for obtaining compound 500 using cyclopropylmethyl amine. LCMS (ESI) m/∑= 436 [M-H]".
[0336] Compound 511 was obtained following the procedure for obtaining compound 500 using methanamine. LCMS (ESI) m/∑ = 394 [M-H]" and 789 [2M-H]".
[0337] Compound 512 was obtained following the procedure for obtaining compound 500 using methanesulfonamide with the modification that a mixed anhydride was first prepared using ethyl chloroformate in place of HBTU and methanesulfonamide was subsequently added in a separate step. LCMS (ESI) m/∑ = 459 [M-H]".
[0338] Compound 513 was obtained following the procedure for obtaining compound 500 using compound 406 and 3,4-dichlorobenzylamine with the modification that trifluoroacetic acid at 55 °C was used in place of Pd/C/H2 to remove the O-benzy group. LCMS (ESI) m/z = 540 [M+H]+.
[0339] Compound 514 was obtained following the procedure for obtaining compound 500 using cyclopentanamine. LCMS (ESI) m/∑ = 448 [M-H]".
[0340] Compound 515 was obtained following the procedure for obtaining compound 500 using cyclobutanamine. LCMS (ESI) m/∑ = 434 [M-H]". [0341] Compound 516 was obtained following the procedure for obtaining compound 500 using cyclohexanamine. LCMS (ESI) m/z = 462 [M-I I]".
[0342] Compound 517 was obtained following the procedure for obtaining compound 500 using aniline. LCMS (ESI) m/z = 456 [M-H]\
[0343] Compound 518 was obtained following the procedure for obtaining compound 500 using compound 35 and methanamine. LCMS (ESI) m/z = 398 [M+H]+.
[0344] Compound 519 was obtained following the procedure for obtaining compound 500 using compound 39 and methanamine. LCMS (ESI) m/z = 364 [M+H]+.
[0345] Compound 520 was obtained following the procedure for obtaining compound 500 using compound 40 and methanamine. LCMS (ESI) m/z = 406 [M+H]+.
[0346] compound 521 was obtained following the procedure for obtaining compound 500 using compound 313 and methanamine. LCMS (ESI) m/z = 361 [M+H]+.
[0347] Compound 522 was obtained following the procedure for obtaining compound 500 using compound 3 14 and methanamine. LCMS (ESI) m/z = 394 [M+H]+.
[0348] Compound 523 was obtained following the procedure for obtaining compound 500 using compound 406 and 4-chlorobenzylamine with the modification that trilluoroacetic acid at 55 °C was used in place of Pd/C/LL to remove the O-benzyl group. LCMS (ESI) m/z = 504 [M+H]+.
[0349] Compound 524 was obtained following the procedure for obtaining compound 500 using compound 406 and 4-methylbenzylaminc. LCMS (ESI) m/z = 484 [M+H]+.
[0350] Compound 525 was obtained following the procedure for obtaining compound 500 using compound 406 and 4-methoxybenzyl amine. LCMS (ESI) m/z = 500 [M-H]\
Table 5 - Compounds of Formula (I)
Figure imgf000119_0001
Figure imgf000120_0001
-118-
Figure imgf000121_0001
-119- EXAMPLE 9A
l,4-dihvdro-5-hvdroxy-N-methyl-l -(2-(4-methylpiperazin-l -yl)phenyl)-4- -3-carboxamide (600)
Figure imgf000122_0001
1 h 2h
[0351] To a solution of 30% methylamine in EtOH (20 mL), was added one portion of l h (200 mg, 0.47 mmol). The mixture was stirred at RT for 3 h. After complete conversion, the solvent was removed under reduced pressure. The residue containing 2h was used without further purification.
[0352] A mixture of 2h ( 100 mg, 0.23 mmol) and Pd (OH) 2 (30 mg) in MeOH (20 mL) was stirred at 20 °C for 4 h under H2 atmosphere (15 psi). After the reaction was completed, the mixture was filtered through a pad of celite and concentrated to give a crude product, which was then purification by crystallization in EtOH to give compound 600 as a yellowish solid (50 mg. 63.2 %). LCMS (ESI) /;/ z 344.2 [M+H]+.
EXAMPLE 9B
l,4-dihvdro-l-(2,3-dihvdrobenzo|b| |l,4|dioxin-6-Yl)-5-hvdroxy-N-methyl-4- oxopyridazine-3-carboxamide (601 )
Figure imgf000122_0002
3h 4h 601
[0353] A suspension of 3h (200 mg. 0.49 mmol) and 10% Pd/C (50 mg) in EtOH/DMF (1 : 1 , 1 0 mL) was stirred at RT under H2 atmosphere (1.0 atm.) for 30 min. After complete conversion, the mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was crystallized in PE:EtOAc ( 1 :3) to give the pure 4h as a yellowish solid ( 130 mg, 83.4 %). [0354] To a solution of 30% methylamine in EtOH (10 mL), was added one portion of 4h (130 mg, 0.41 mmol). The mixture was stirred at RT for 12 h. After complete conversion, the solvent was removed under reduced pressure. The residue was re-dissolved by EtOH ( 10 mL) and concentrated in the vacuum to provide compound 601 as a yellowish solid ( 100 mg, 80.4%). LCMS (ESI) m/z = 303.9 [M+H]+.
[0355] Compound 602 was obtained following the procedure for obtaining compound 601 using ammonia and the compound lg. LCMS (ESI) m/z = 380 [M-H]" and 761 [2M-H]".
[0356] Compound 603 was obtained following the procedure for obtaining compound 601 using methylamine and compound 24. LCMS (ESI) /;/ - 386 [M+H]+.
[0357] Compound 604 was obtained following the procedure for obtaining compound 600 using methylamine and compound 413. LCMS (ESI) m/z = 304 [M+H]+.
[0358] Compound 605 was obtained following the procedure for obtaining compound 601 using benzylamine and compound 24. LCMS (ESI) m/z = 462 [M+H]+.
[0359] Compound 606 was obtained following the procedure for obtaining compound 601 using methylamine and compound 421. LCMS (ESI) m/z = 280 [M+H]+.
[0360] Compound 607 was obtained following the procedure for obtaining compound 600 using methylamine and compound 416. LCMS (ESI) m/z = 314 [M-H]".
[0361] Compound 608 was obtained following the procedure for obtaining compound 600 using methylamine and compound 412. LCMS (ESI) m/z = 340 [M-H]".
[0362] Compound 609 was obtained following the procedure for obtaining compound 600 using methylamine and compound 422. LCMS (ESI) m/z = 366 [M-H]".
[0363] Compound 610 was obtained following the procedure for obtaining compound 601 using methylamine and compound 319. LCMS (ESI) m/z = 406 [M+H]+.
[0364] Compound 611 was obtained following the procedure for obtaining compound 601 using methylamine and compound 318. LCMS (ESI) m/z = 352 [M+H]+.
[0365] Compound 612 was obtained following the procedure for obtaining compound 601 using methylamine and compound 322. LCMS (ESI) m/z = 386 [M+H]+.
[0366] Compound 613 was obtained following the procedure for obtaining compound 601 using methylamine and compound 320. LCMS (ESI) m/z = 361 [M+H]+. [0367] Compound 614 was obtained following the procedure for obtaining compound 601 using methylamine and compound 423. LCMS (ESI) /z = 324 [M+I I] 1 .
[0368] Compound 615 was obtained following the procedure for obtaining compound 601 using methylamine and compound 205. LCMS (ESI) m/z = 358 [M+H]+.
[0369] Compound 616 was obtained following the procedure for obtaining compound 601 using methylamine and compound 209. LCMS (ESI) m/z = 357 [M+H]+.
[0370] Compound 617 was obtained following the procedure for obtaining compound 601 using methylamine and compound 24. LCMS (ESI) m/z = 372 [M+H]+.
[0371 ] Compound 618 was obtained following the procedure for obtaining compound 601 using methylamine and compound 313 with the modification that the ester/ether precursor was treated with methyl iodide and potassium carbonate in DMF prior to debenzylation and amide formation. LCMS (ESI) m/z = 375 [M+H]+.
[0372] Compound 619 was obtained following the procedure for obtaining compound 601 using methylamine and compound 316 or following the procedure for obtaining compound 300 using (5a,9a-dihydrodibenzo[b,d]furan-2-yi)boronic acid. LCMS (ESLWs = 450 [M+H]+.
[0373] Compound 620 was obtained following the procedure for obtaining compound 601 using methylamine and compound 320 with the modification that the ester/ether precursor was treated with methyl iodide and potassium carbonate in DMF prior to debenzylation and amide formation. LCMS (ESI) m/z = 375 [M+H]+.
[0374] Compound 621 was obtained following the procedure for obtaining compound 600 using methylamine and compound 424. LCMS (ESI) m/z = 366 [M-H]\
[0375] Compound 622 was obtained following the procedure for obtaining compound 600 using methylamine and compound 425. LCMS (ESI) m/z = 380 [M-H]\
[0376] Compound 623 was obtained following the procedure for obtaining compound 600 using 2-methylbenzyl amine and compound 406. LCMS (ESI) in :: 380 [M- H]\
[0377] Compound 624 was obtained following the procedure for obtaining compound 600 using 2-mef oxybenzy! amine and compound 406. LCMS (ESI) m/z = 500 [M-H]\ [0378] Compound 625 was obtained following the procedure for obtaining compound 600 using benzo[d] [l ,3]dioxol-5-ylmethanamine and compound 406. LCMS (ESI) w/z = 514 [M-H]".
[0379] Compound 626 was obtained following the procedure for obtaining compound 601 using ammonia and compound 424. LCMS (ESI) m/∑ = 352 [M-H]\
[0380] Compound 627 was obtained following the procedure for obtaining compound 601 using methylamine and compound 410. LCMS (ESI) m/z = 328 [M+H]+.
[0381 ] Compound 628 was obtained by first following the procedure for obtaining compound 6d using 1 ,2.3,4-tetrahydroquinoline and then following the procedure for obtaining compound 601 using methylamine. LCMS (ESI) m/z = 377 [M+H]+.
[0382] Compound 629 was obtained following the procedure for obtaining compound 601 using methylamine and compound 323. LCMS (ESI) m/z = 386 [M+H]+.
[0383] Compound 630 was obtained following the procedure for obtaining compound 601 using methylamine and compound 325. LCMS (ESI) m/∑= 394 [M+H]+.
[0384] Compound 631 was obtained by first following the procedure for obtaining compound 3e using (2-(piperidin- l -yl)phenyl)boronic acid and then following the procedure for obtaining compound 601 using methylamine. LCMS (ESI) m/z = 405 [M+H] .
[0385] Compound 632 was obtained by first following the procedure for obtaining compound 6d using indoline and then following the procedure for obtaining compound 601 using methylamine. LCMS (ESI) m/z = 363 [M+HJ+.
[0386] Compound 633 was obtained following the procedure for obtaining compound 601 using methylamine and compound 326. LCMS (ESI) m/z = 380 [M+H]+.
[0387] Compound 634 was obtained following the procedure for obtaining compound 601 using methylamine and compound 426. LCMS (ESI) m/z = 334 [M+H]+.
[0388] Compound 635 was obtained following the procedure for obtaining compound 601 using methylamine and compound 427. LCMS (ESI) mJz = 324 [M+H]+.
[0389] Compound 636 was obtained following the procedure for obtaining compound 614 with the modification that compound 614 was treated with acetic anhydride and diisopropyl ethyl amine in dichloromethane at RT for 2 h. LCMS (ESI) m/z = 366 [M+H]+.
Figure imgf000126_0001
-124-
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
-127- EXAMPLE 10
Compounds of Formulae (I) and (II)
[0390] The foregoing syntheses are exemplary and can be used as a starting point to prepare additional compounds of Formulae (1) and (II). Examples of additional compounds of Formulae (I) and (II) are shown in Tables 7-9. These compounds can be prepared in various ways, including those synthetic schemes shown and described herein.
Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
Table 7
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
-130-
Figure imgf000133_0001
Figure imgf000134_0001
-132-
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
-135-
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
-138-
Figure imgf000141_0001
Figure imgf000142_0001
-140-
Figure imgf000143_0001
Figure imgf000144_0001
-142-
Figure imgf000145_0001
-143-
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
-146-
Figure imgf000149_0001
Figure imgf000150_0001
-148-
Figure imgf000151_0001
-149-
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
-154-
Figure imgf000157_0001
Figure imgf000158_0001
-156-
Figure imgf000159_0001
-157-
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
-162-
Figure imgf000165_0001
-163-
Figure imgf000166_0001
-164-
Figure imgf000167_0001
Figure imgf000168_0001
-166-
Figure imgf000169_0001
-167-
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
-176-
Figure imgf000179_0001
-177-
Figure imgf000180_0001
Figure imgf000181_0001
-179-
Figure imgf000182_0001
-180-
Figure imgf000183_0001
-181-
Figure imgf000184_0001
-182-
Figure imgf000185_0001
Figure imgf000186_0001
-184-
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
-190-
Figure imgf000193_0001
-191-
Figure imgf000194_0001
-192-
Figure imgf000195_0001
-193-
Figure imgf000196_0001
-194-
Figure imgf000197_0001
-195-
Figure imgf000198_0001
-196-
Figure imgf000199_0001
-197-
Figure imgf000200_0001
-198-
Figure imgf000201_0001
-199-
Figure imgf000202_0001
-200- Table 9 - Compounds of Formula (11)
Figure imgf000203_0001
EXAMPLE 11
Influenza Antiviral Assay
[0391 ] Human lung carcinoma A549 cells (ATCC, Manassas, VA) were plated at a density of 5 x 104 cells/mL (5 x 10J cells/well) in assay media (HanTs F12 media supplemented with 0.3% FBS, 1 % penicillin/streptomycin (all Mediatech. Manassas, VA) and 1 % DMSO (Sigma-Aldrich. St Louis. MO)) in black 96-well plates. Alternatively.
Madin-Darby canine kidney epithelial cells (MDCK. ATCC), were plated at a density of 1 x 105 cells/mL (1 x 104 cells/well) in assay media (DM EM supplemented with 0.3% FBS, 1 % penicillin/streptomycin and 1 % DMSO) in 96-well plates. After 24 hours, serially diluted test compounds were added to cells and incubated for an additional 24 hours. Cells were infected with 250 lU/well of Influenza strain A549 A/WSN/33 (H1 N1 ) (Virapur, San Diego CA) and incubated for 20 hours at 37°C. 5% CO?. The cell culture supernatant was aspirated off and 50 ^iL of 25 μΜ 2,-(4-Methylumbelliferyl)-a-D-N-acetylneuraminic acid (Sigma- Aldrich) dissolved in 33 mM MES, pH 6.5 (Emerald Biosystems. Bainbridge Island, WA) was added to the cells. After incubation for 45 mins at 30°C. reactions were stopped by addition of 1 50 ^iL stop solution (100 mM glycine, pH 10.5. 25% ethanol, all Sigma- Aldrich). Fluorescence was measured with excitation and emission filters of 355 and 460 nm, respectively, on a Victor X3 multi-label plate reader (Perkin Elmer. Waltham, MA). Cytotoxicity of uninfected parallel cultures was determined by addition of 100 μΕ of CellTiter-GloODreagent (Promega, Madison, Wl), and incubation for 10 mins at T. Luminescence was measured on a Victor X3 multi-label plate reader.
[0392] Compounds of Formulae (1) and (11) are active in the assay as noted in Tables 10-17, where 'A' indicates an ECJO < 20 μΜ, Έ' indicates an EC o of >20 μΜ and < 100 μΜ and 'C indicates an EC50 > 100 μΜ.
Table 10 - Activity of compounds
Figure imgf000204_0001
Figure imgf000204_0002
Figure imgf000204_0003
Table 1 1 - Activity of compounds
Figure imgf000204_0006
Figure imgf000204_0004
Figure imgf000204_0005
Table 12 - Activity of compounds No. % Inhibition 319 A
314 C 320 C
Table 13 - Activity of compound Iss
No. % Inhibition
406 A
407 C
408 B
409 C
410 A
Figure imgf000205_0001
41 1 A
Table 14 - Activity of compounds
Figure imgf000205_0005
Figure imgf000205_0002
Table 15 - Activity of compoun
Figure imgf000205_0003
Figure imgf000205_0004
Figure imgf000205_0006
No. % Inhibition No. % Inhibition No. % Inhibition
668 C 679 A 690 C
669 C 680 A 691 A
670 c 681 A 692 A
671 A 682 A 693 A
672 A 683 C 694 A
673 C 684 A 695 A
674 A 685 A 696 C
675 C 686 A 697 c
676 A 687 A 698 A
677 A 688 A 699 A
678 A 689 C
Table 16- Potency of compounds
Figure imgf000206_0001
Figure imgf000206_0002
Figure imgf000206_0003
No. % Inhibition No. % Inhibition No. % Inhibition
787 A 792 A 797 A
788 A 793 A 798 C
789 A 794 A 799 A
790 A 795 A
791 A 796 C
Table 17- Potency of compounds
Figure imgf000207_0003
Figure imgf000207_0001
Figure imgf000207_0002
EXAMPLE 12
EN PA FRET Inhibition Assay
[0393] EN PA FRET inhibition assay was performed using a 19 nucleotide synthetic oligoribonucleotide substrate: 5,-FAM-AUUUUGUUUUUAAUAUUUC-BHQ-3, (Integrated DNA Technologies. Inc.. Coralville. ΙΛ) (SEQ. ID. NO. 1 ). Upon RNA cleavage, the fluorescent FAM group is released from the BHQ quencher. The PA sequence used to produce active enzyme is derived from any one of multiple influenza A virus strains (e.g.. A/goose/Nanchang/3- 120/01 (H3N2), A/Victoria/3/1975 (H3N2), A/Brisbane/ 10/2007 (H3N2), A/WSN/33 (H1N1 ), A/CA/4/2009 (H1N1 ), A/CA/5/2009 (H1N1 ). A/Shanghai/1/2013 (H7N9), A/Guizhou/ 1/2009 (H5N1 )). The full length recombinant protein was expressed from a baculovirus vector in insect cells. Full length EN PA was used in this assay at an effective concentration of 1 to 10 Nm. together with 50 Nm FRET probe with a final volume of 20 ml cleavage buffer (20 Mm Tris Ph8, 100 Mm NaCl. 5% Glycerol, 10 Mm β-ΜΕ, 0.01% Tween-20, 2 Mm MnC ).
[0394] Compounds described herein were added to a 384-well black polypropylene plate. Fluorescence was measured in a continuous mode up to 30 minutes with a Wallac 1420 Victor3 V multilabel counter (PerkinElmer Life Sciences, Shelton, CT) (excitation 485 nm; emission 535 nm). Measured ICso is defined as the concentration at which fluorescence is 50% that of the uninhibited control (DMSO). IC50 was calculated by fitting the data to the sigmoidal equation Y= % Min + (% Max - % Min) / ( 1 + X / 1C50). where Y corresponds to the percent relative enzyme activity. Max is the maximum enzyme activity in the presence of DMSO. Min is the inhibited activity at saturating concentration of compound, and X corresponds to the compound concentration. The ICso values were derived from the mean of a minimum of two independent experiments.
[0395] Compounds of Formulae (1) and (IT) are potent in the assay as noted in Tables 18-25, where Ά" indicates an IC50 < 100 nM, 'B' indicates an IC50 of >100 nM and < 1000 nM and "C" indicates an IC50 > 1000 nM
Table 18 - Potency of compounds
Figure imgf000208_0001
Figure imgf000208_0002
Figure imgf000208_0003
Figure imgf000208_0004
8 C 18 B 28 C 38 B
9 B 19 B 29 B 39 B
10 D 20 B 30 C 40 B
11 B 21 A 31 B 41 B
12 B 22 B 32 B 42 B
13 B 23 B 33 B 43 B
14 C 24 A 34 B 44 C
15 B 25 C 35 A
16 B 26 B 36 B
17 B 27 B 37 B
Table 19 - Potency of compounds
Figure imgf000209_0001
Figure imgf000209_0002
Table 20 - Potency of compounds
Figure imgf000209_0003
Figure imgf000209_0004
Table 21 - Potency of compounds
Figure imgf000209_0010
Figure imgf000209_0005
Figure imgf000209_0006
Table 22 - Potency of compounds
Figure imgf000209_0007
Figure imgf000209_0008
Figure imgf000209_0009
Figure imgf000209_0011
No. Potency No. Potency No. Potency No. Potency
508 B 513 B 518 B 523 B
509 B 514 B 519 B 524 B
510 B 515 B 520 C 525 B
51 1 B 516 B 521 C
512 B 517 B 522 B
Table 23 - Potency of compounds
Figure imgf000210_0001
Figure imgf000210_0002
Table 24 - Potency of compounds
Figure imgf000210_0003
Figure imgf000210_0004
Figure imgf000210_0005
No. Potency No. Potency No. Potency
766 A 783 A 794 A
768 A 784 B 795 B
771 B 785 A 796 B
772 B 786 A 797 B
773 A 787 A 798 B
774 A 788 A 799 A
775 A 789 A
776 A 790 A
777 A 791 B
778 A 792 A
782 A 793 B
Table 25 - Potency of com ounds
Figure imgf000211_0001
Figure imgf000211_0002
No. Potency No. Potency No. Potency
883 A 889 A 895 A
884 A 890 A 896 A
885 B 891 A 897 A
886 A 892 A 898 A
887 A 893 A 899 A
888 A 894 A
[0396] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:
1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
G1 is selected from
Figure imgf000213_0001
the group consisting of and R°;
G2 is hydrogen, halogen, -CN, an optionally substituted C i-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryi, -CH2OH, - CH(Y')(0H) or -C(0)Y',;
G3 is selected from the group consisting of hydrogen, -C(0)Y2, -C(0)0-Y2, -(CH2)-0(CO)Y2, -(CH2)-0(CO)OY2, -(CHCHV)-0(CO)Y2, and
-(CHCH3)-0(CO)OY2;
Y1 and Y2 are independently an optionally substituted C |- alkyl or an optionally substituted aryl;
R1 is selected from the group consisting of OR6, NI I2, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted mono- substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocyclyl. an optionally substituted N-sulfonamido and an optionally substituted alkoxyamine, or R10;
R2 is hydrogen, C]_6 alkyl, an optionally substituted C3-6 cycloalkyl. an optionally substituted aryl, an optionally substituted aryl(C i-6 alkyl) or an optionally substituted C -ami do;
R3 is hydrogen or C 1 -6 alkyl;
or R2 and R3 are taken together to form an optionally substituted C3-6 cycloalkyl, an optionally substituted 5 to 6 membered heterocyclyl or =0; R is selected from the group consisting of an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroary l and an optionally substituted heterocyclyl;
or R4 is A'R RB4, wherein A1 is CH or N; and RA4 and RB4 are each independently an optionally substituted pheny l;
R^ is selected from the group consisting of an optionally substituted aryl, an optionally substituted cycloalkyl. an optionally substituted cycloalkenyl. an optionally substituted heteroary l and an optionally substituted heterocyclyl;
R6 is selected from the group consisting of hydrogen. C, _6 alkyl, -C(0)R ' and -C(0)NR8R9;
R7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynvl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C[-6 alkyl), heteroaryl(C I - alkyl) and heterocyclyl(C| .6 alkyl);
8 d 9
R an R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C| .6 alkyl), heteroaryl(C| .6 alkyl) and heterocyclyl(C i ., alkyl);
or R8 and R9 are taken together to form an optionally substituted heterocyclyl;
wherein when R1 is R10, then R10 and R4 are taken together and include L1 , where L1 connects R1 W and R4 to form an 1 1 - to 20-membered ring, or wherein when R1 is R10, then R10 and R^ are taken together and include L1, where L1 connects R1 and R^ to form an 1 1 - to 20-membered ring; wherein R10 is optionally substituted -CH2-, optionally substituted - CH=CH-, O (oxygen). S (sulfur), or NR1 1 :
wherein R1 1 is hydrogen or Ci-6 alkyl; and
Z and Z" are independently 0. 1. 2, 3 or 4.
2. The compound of Claim 1 ,
wherein:
G2 is hydrogen or C|-6 alkyl; selected from the group consisting of hydrogen, -C(0) Y2, -C(0)0-Y
(CH2)-0(CO)Y2, -(CH2)-0(CO)OY2, -(CHCH3)-0(CO)Y2, and -(CHCH )- 0(CO)OY2;
Y2 is C alkyl;
R1 is selected from the group consisting of OR6, NH2, mono-substituted amine, di-substituted amine, heterocyclyl and N-sulfonamido, said mono-substituted amine, an di-substituted amine, heterocyclyl and N-sulfonamido are each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyh cycloalkynyl, aryh heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl )alkyl. hydroxy, alkoxy. acyl. cyano. halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulflnyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino;
R2 is hydrogen or C |-6 alkyl;
R3 is hydrogen or C |-6 alkyl;
or R- and RJ are taken together to form an optionally substituted C3-6 cycloalkyl or an optionally substituted 5 to 6 membered heterocyclyl;
3. The compound of Claim 1 ,
wherein:
Figure imgf000215_0001
; and
R" and R are taken together to form an optionally substituted piperidino or an optionally substituted pyrrolidine
4. The compound of Claim 1 , having the structure of Formula (Ih) or Formula a pharmaceutically acceptable salt thereof:
Figure imgf000216_0001
wherein:
L' is -ΐΛ, or ΐΑΐΛΐ ;
L" is selected from the group consisting of an optionally substituted alkylcne, an optionally substituted alkenylene. an optionally substituted heteroalkylene and an optionally substituted heteroalkenylene;
L3 is an optionally substituted C i-6 alkylene;
L4 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl. O (oxygen). S (sulfur). or NR1 ' ; and
L? is an optionally substituted C i-6 alkylene or an optionally substituted heteroalkylene.
5. The compound of Claim 4, wherein L2 is an optionally substituted alkylene.
6. The compound of Claim 5, wherein L2 is an optionally substituted C4.7 alkylene.
7. The compound of Claim 4. wherein L2 is an optionally substituted alkenylene.
8. The compound of Claim 7, wherein L2 is an optionally substituted C4.7 alkenylene.
9. The compound of Claim 4, wherein L2 is an optionally substituted heteroalkylene.
10. The compound of Claim 9, wherein L2 is an optionally substituted -(CH2)3- 0-, an optionally substituted -(CH2)4-0- an optionally substituted -(CH2)5-0-, an optionally substituted -(CH2)3-S-, an optionally substituted -(CH )4-S-, an optionally substituted -(CH2)5-S-, an optionally substituted -(CH2)3-NH-, an optionally substituted -(CH2)4-NH-, or an optionally substituted -(CH2)5-NH-.
1 1 . The compound of Claim 9, wherein L is an optionally substituted -(CH2)3-0-, an optionally substituted -(CH2)4-0- or an optionally substituted -(CH2)5-0-.
12. The compound of Claim 4, wherein L" is optionally substituted heteroalkenylene.
13. The compound of Claim 12. wherein L2 is an optionally substituted -(CH2)(CH=CH)(CH2)-0-. an optionally substituted -(CH2)2(CH=CH)(CH2)-0-. an optionally substituted -(CH2)(CH=CH)(CH2)2-0- an optionally substituted -(CH2)2(CH=CH)(CH2)2-0-, an optionally substituted -(CH2)2(CH=CH)(CH2)-S- an optionally substituted -(CH2)(CH=CH)(CH2)2-S-, an optionally substituted -(CH2)2(CH=CH)(CH2)2-S an optionally substituted -(CH2)2(CH=CH)(CH2)-NH-, an optionally substituted -(CH2)(CH=CH)(CH2)2-NH- or an optionally substituted -(CH2)2(CH=CH)(CH2)2-NH-.
14. The compound of Claim 13, wherein L2 is an optionally substituted C3 oxygen containing heteroalkenylene, an optionally substituted C4 oxygen containing heteroalkenylene, or an optionally substituted C5 oxygen containing heteroalkenylene.
1 5. The compound of Claim 4,
wherein:
L1 is -ΐΑΐΛΐΛ;
L3 is an optionally substituted C alkylene;
L4 is optionally substituted cycloalkyl. optionally substituted aryl, or optionally substituted heteroaryl; and
L? is an optionally substituted C M alkylene.
16. The compound of Claim 4,
wherein:
L1 is -ΐΑΐΛΐΛ;
L3 is an optionally substituted C alkylene;
L4 is O (oxygen), S (sulfur), or NR1 '; and
is an optionally substituted C |-4 alkylene.
1 7. The compound of Claim 4,
wherein:
L1 is -L3-L4-L5-;
L3 is optionally substituted C2-4 alkylene;
L4 is optionally substituted cycloalkyl, optionally substituted aryl. optionally substituted heteroaryl. optionally substituted heterocycly l, O (oxygen). S (sulfur), or NRn; and
L5 is optionally substituted C2-4 alkylene.
1 8. The compound of any one of Claims 4 or 16-17,
wherein:
R1 is R10 where R10 is NR1 1 ; and
R1 1 is H (hydrogen).
19. The compound of Claim 1. wherein R1 is OR6.
20. The compound of Claim 19. wherein R6 is hydrogen.
21. The compound of Claim 19. wherein R6 is C i -6 alkyl.
22. The compound of Claim 19. wherein R6 is -C(0)R7.
23. The compound of Claim 19. wherein R6 is -C(0)NR8R9.
24. The compound of Claim 1. wherein R1 is NH2.
25. The compound of Claim 1 , wherein R1 is an optionally substituted mono- substituted amine.
26. The compound of Claim 1 , wherein R1 is an optionally substituted di- substituted amine.
27. The compound of Claim 1 , wherein R1 is an optionally substituted heterocyclyl.
28. The compound of Claim 27. wherein the heterocyclyl is a 5 to 6 membered heterocyclyl.
29. The compound of Claim 27 or 28. wherein the heterocyclyl contains at least one nitrogen in the ring and is an N-linked heterocyclyl.
30. The compound of Claim 1 , wherein R1 is an optionally substituted N-sulfonamido. The compound of Claim 1. wherein R is R
The compound of Claim 1 . wherein R10 is CH2.
The compound of Claim 1 , wherein R10 is NRn .
34. The compound of any one of Claims 1 - 18, wherein G1 is
Figure imgf000219_0001
35. The compound of Claim 34, wherein R" is hydrogen.
36. The compound of Claim 34, wherein R is Ci-6 alkyl.
37. The compound of any one of Claims 34-36, wherein R3 is hydrogen.
38. The compound of any one of Claims 34-36, wherein R3 is C i-6 alkyl.
2 3
39. The compound of Claim 34, wherein R and R are taken together to form an optionally substituted C3-6 cycloalkyl.
40. The compound of Claim 39, wherein R2 and R3 are taken together to form an unsubstituted C3-6 cycloalkyl.
41. The compound of Claim 39 or 40, wherein R2 and R3 are taken together to form a C5 cycloalkyl.
42. The compound of Claim 34. wherein R2 and R3 are taken together to form an optionally substituted 5 to 6 membered heterocyclyl.
43. The compound of any one of Claims 32-42, wherein R4 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl.
44. The compound of any one of Claims 32-42, wherein R4 is an optionally substituted aryl.
45. The compound of Claim 44, wherein the optionally substituted aryl is an optionally substituted phenyl.
46. The compound of Claim 45, wherein the optionally substituted phenyl is a substituted phenyl.
47. The compound of Claim 46. wherein the substituted phenyl is a mono- substituted phenyl.
48. The compound of Claim 47, wherein the substituted phenyl is an ortho- substituted phenyl.
49. The compound of Claim 47, wherein the substituted phenyl is a meta- substituted phenyl.
50. The compound of Claim 47, wherein the substituted phenyl is a para- substituted phenyl.
51 . The compound of Claim 46, wherein the substituted phenyl is a di-substituted phenyl.
52. The compound of Claim 46, wherein the substituted phenyl is substituted with 3 or more substituents.
53. The compound of any one of Claims 32-42, wherein R4 is an optionally substituted cvcloalkyl.
54. The compound of any one of Claims 32-42, wherein R4 is an optionally substituted heteroaryl.
55. The compound of any one of Claims 32-42, wherein R4 is an optionally substituted heterocyclyl.
56. The compound of any one of Claims 32-55, wherein R4 is substituted with one or more substituents selected from the group consisting of halogen, CV6 alkyl, alkoxy, ary loxy, haloalkyl. haloalkoxy, hydroxyalkyl. N-sulfonamido. S-sulfonamido. sulfonyl, an optionally substituted aryl. an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, carbonyl, C-carboxy. -CH2-(mono-substituted amine) and CH2-(di-substituted amine).
57. The compound of Claim 56. wherein the optionally substituted aryl is a substituted aryl substituted with one or more groups selected from the group consisting of C j. alkyl, alkoxy, aryl. cyano, halogen, haloalkyl and haloalkoxy.
58. The compound of Claim 56, wherein the optionally substituted cycloalkyl is a substituted cycloalkyl substituted with one or more groups selected from the group consisting of C | -6 alkyl. alkoxy, halogen and haloalkyl.
59. The compound of Claim 56, wherein the optionally substituted heterocyclyl is a substituted hcterocyclyl substituted with one or more groups selected from the group consisting of Ci_6 alkyl, alkoxy. halogen, haloalkyl. aryl(C| .6 alkyl) and C-carboxy.
60. The compound of any one of Claims 34-59, wherein Z1 is 0.
61 . The compound of any one of Claims 34-59, wherein Z1 is 1 .
62. The compound of any one of Claims 34-59, wherein Z1 is 2.
63. The compound of any one of Claims 34-59, wherein Z1 is 3.
64. The compound of any one of Claims 34-59, wherein Z1 is 4.
65. The compound of any one of Claims 34-64, wherein 7? is 0.
66. The compound of any one of Claims 34-64, wherein 7? is 1 .
67. The compound of any one of Claims 34-64, wherein 7? is 2.
68. The compound of any one of Claims 34-64, wherein 7? is 3.
69. The compound of any one of Claims 34-64, wherein Z2 is 4.
70. The compound of any one of Claims 1 -18, wherein G 1 is R~\
71. The compound of Claim 70. wherein R is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl.
72. The compound of Claim 70, wherein R? is an optionally substituted aryl.
73. The compound of Claim 72, wherein the optionally substituted aryl is an optionally substituted phenyl.
74. The compound of Claim 73. wherein the optionally substituted phenyl is a substituted phenyl.
75. The compound of Claim 74. wherein the substituted phenyl is a mono- substituted phenyl.
76. The compound of Claim 75. wherein the substituted phenyl is an ortho- substituted phenyl.
77. The compound of Claim 75, wherein the substituted phenyl is a meta- substituted phenyl.
78. The compound of Claim 75, wherein the substituted phenyl is a para- substituted phenyl.
79. The compound of Claim 74, wherein the substituted phenyl is a di-substituted phenyl.
80. The compound of Claim 74, wherein the substituted phenyl is substituted with 3 or more substituents.
81 . The compound of Claim 70. wherein R5 is an optionally substituted cycloalkyl.
82. The compound of Claim 70. wherein R5 is an optionally substituted heteroary .
83. The compound of Claim 70. wherein R3 is an optionally substituted heterocyclyl.
84. The compound of any one of Claims 70-83, wherein R5 is substituted with one or more substituents selected from the group consisting of halogen, C i-6 alkyl, alkoxy, aryloxy, haloalkvl, haloalkoxy, hvdroxyalkyl, N-sulfonamido, S-sulfonamido, sulfonyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, carbonyl, C-carboxy, -CH2-(mono-substituted amine) and CH2-(di-substituted amine).
85. The compound of Claim 84, wherein the optionally substituted aryl is a substituted aryl substituted with one or more groups selected from the group consisting of Cj_ 6 alkyl. alkoxy, halogen and haloalkyl.
86. The compound of Claim 84, wherein the optionally substituted cycloalkyl is a substituted cycloalkyl substituted with one or more groups selected from the group consisting of C] _6 alkyl, alkoxy. halogen and haloalkyl.
87. The compound of Claim 84, wherein the optionally substituted heterocyclyl is a substituted heterocyclyl substituted with one or more groups selected from the group consisting of Ci-6 alkyl, alkoxy, halogen, haloalkyl, aryKC , alkyl) and C-carboxy.
88. The compound of any one of Claims 1 -87, wherein G3 is hydrogen.
89. The compound of Claim 1 , wherein the compound is selected from the group consisting of:
Figure imgf000223_0001
Figure imgf000224_0001
-222-
Figure imgf000225_0001
Figure imgf000226_0001
■224-
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
-227-
90. The compound of Claim 1 , wherein the compound is selected from the group consisting of:
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
-231-
Figure imgf000234_0001
92. The compound of Claim 1 , wherein the compound is selected from the group consisting of:
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
-236-
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000240_0002
Figure imgf000241_0001
-239-
Figure imgf000242_0001
-240-
Figure imgf000243_0001
-241- 2015/038660
Figure imgf000244_0001
of any of the foregoing.
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
-245- WO 2015/038660
Figure imgf000248_0001
Figure imgf000249_0001
-247-
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
-251-
Figure imgf000254_0001
Figure imgf000255_0001
-253-
Figure imgf000256_0001
Figure imgf000257_0001
-255-
Figure imgf000258_0001
-256-
Figure imgf000259_0001
Figure imgf000260_0001
-258-
Figure imgf000261_0001
-259-
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
-264-
94. A compound of Formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000267_0001
wherein:
G, A is selected from the group consisting of .
Figure imgf000267_0002
,6A
R1A is selected from the group consisting of OR" \ NH2, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted mono- substituted amine, an optionally substituted di-substituted amine, an optionally substituted heterocycly l and an optionally substituted N-sulfonamido. or RI0A;
WA is -CH- or -N-;
R" is hydrogen or C|_(, alky l;
R A is hydrogen or C|_6 alky l;
or R2A and R3A are taken together to form an optionally substituted C3- d cycloalkyl or an optionally substituted 5 to 6 membered heterocyclyl:
R4A is selected from the group consisting of an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;
RsA is selected from the group consisting of an optionally substituted aryl. an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;
R6A is selected from the group consisting of hydrogen. Ci- alkyl, -C(0)R7A and -C(0)NR8AR9A;
R7A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(C|- alkyl), heteroaryl (C I -6 alkyl) and heterocyclyl(C| -6 alkyl); R8A and R9A are independently selected from the group consisting of hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. aryl(Ci-6 alkyl), heteroaryl(Ci -6 alkyl) and heterocyclyl(Ci -6 alkyl);
or R8A and R9A are taken together to form an optionally substituted heterocyclyl;
wherein when RIA is RI 0A, then RI0A and R A are taken together and include LI A, where LI A connects RI0A and R A to form an 1 1 - to 20-membered ring, or wherein wrhen RIA is RI0A, then RI 0A and RsA are taken together and
I A 5A
include LIA, where Ll ¾ connects Rl ¾ and R?¾ to form an 1 1 - to 20-membered wherein RI0A is optionally substituted -CH2-, optionally substituted
1 1 A .
CH=CH-, O (oxygen), S (sulfur), or NR
wherein RI I A is hydrogen or C i-6 alkyl; and
ZI A and Z2A are independently 0, 1 , 2, 3 or 4.
95. The compound of Claim 94. having the structure of Formula (lie) or Formula (lid), or a pharmaceutically acceptable salt thereof:
Figure imgf000268_0001
w7herein:
, Ι Λ · , 2 A , 3Λ , , 5Λ
L is -L -, or -L -L -L -;
L2A is selected from the group consisting of an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted heteroalkylene and an optionally substituted heteroalkenylene;
L3A is an optionally substituted C |-6 alkylene; L4A is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl. an optionally substituted heterocyclyl, O (oxygen), S (sulfur), or NR1 IA; and
L5A is an optionally substituted C| -6 alkylene or an optionally substituted heteroalkylene.
96. The compound of Claim 95, wherein L" is an optionally substituted alkylene.
97. The compound of Claim 95, wherein L2A is an optionally substituted C4-7 alkylene.
98. The compound of Claim 95, wherein L2A is an optionally substituted alkenylene.
2 A ·
99. The compound of Claim 95, wherein L is an optionally substituted C4.7 alkenylene.
100. The compound of Claim 95, wherein L2A is an optionally substituted heteroalkylene.
101. The compound of Claim 100, wherein L2A is an optionally substituted - (CH2)3-0-, an optionally substituted -(CH2)4-0-. an optionally substituted -(CH2)s-0-, an optionally substituted -{CH2)3-S-, an optionally substituted -(CH2)4-S-, an optionally substituted -(CH )s-S-, an optionally substituted -(CH2) -NH-, an optionally substituted - (CH2)4-NH- or an optionally substituted -(CI I2)5-NH-
102. The compound of Claim 100, wherein L" is an optionally substituted
-(CH2)3-0-„ an optionally substituted -(CH2)4-0-, or an optionally substituted -(CH2)5-0-
103. The compound of Claim 95, wherein L" is optionally substituted heteroalkenylene.
104. The compound of Claim 103. wherein L is an optionally substituted -(CH2)(CH=CH)(CH2)-0-. an optionally substituted -(CH2)2(CH=CH)(CH2)-0-. an optionally substituted -(CH2)(CH=CH)(CH2)2-0- an optionally substituted -(CH2)2(CH=CH)(CH2)2-0-. an optionally substituted -(CH2)2(CH=CH)(CH2)-S-. an optionally substituted -(CH2)(CH=CH)(CH2)2-S-. an optionally substituted -(CH2)2(CH=CH)(CH2)2-S an optionally substituted -(CH2)2(CH=CH)(CH2)-NH- an optionally substituted -(CH2)(CH=CH)(CH2)2-NH- or an optionally substituted -(CH2)2(CH=CH)(CH2)2-NH-.
105. The compound of Claim 103. wherein L is an optionally substituted C3 oxygen containing heteroalkenylene, an optionally substituted C4 oxygen containing heteroalkenylene. or an optionally substituted C5 oxygen containing heteroalkenylene.
106. The compound of Claim 95,
wherein:
L is -L -L -L -;
L3A is an optionally substituted C alkylene;
L A is optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Ι^Α is an optionally substituted C [_4 alkylene.
107. The compound of Claim 95,
w7herein:
L is L -L -L -;
L A is an optionally substituted C alkylene;
L4A is O (oxygen), S (sulfur), or NR1 IA; and
L5A is an optionally substituted C M alkylene.
108. The compound of Claim 95,
wherein:
L,A is ~L3A-L4A-L5A-;
L3A is optionally substituted C2-4 alky lene;
L4A is optionally substituted cycloalkyl. optionally substituted aryl. optionally substituted heteroaryl. optionally substituted heterocycly l, O (oxygen). S (sulfur), or NRn; and
L5A is optionally substituted C2-4 alky lene.
109. The compound of any one of Claims 94 or 107-108,
wherein:
RI A is RI 0A where RI0A is NR1 IA; and
R1 IA is H (hydrogen).
1 10. The compound of Claim 94, wherein RIA is NH2, an optionally substituted mono-substituted amine or an optionally substituted di-substituted amine.
1 1 1 . The compound of Claim 94, wherein R, A is an optionally substituted mono- substituted amine.
1 12. The compound of Claim 94, wherein RIA is an optionally substituted alkyl.
1 13. The compound of Claim 94, wherein RIA is RI0A
1 14. The compound of Claim 1 13. wherein R,0A is CH7.
1 15. The compound of Claim 1 13. wherein Rl0A is NR1 IA.
1 16. The compound of any one of Claims 94- 1 15, wherein
Figure imgf000271_0001
1 17. The compound of Claim 1 16, wherein R2A and R3A are taken together to form an optionally substituted Cj_6 cycloalkyl.
1 18. TThhee ccoommppoouunndd ooJf Claim 1 17, wherein R2A and R3A are taken together to form an unsubstituted C3-6 cycloalkyl.
2 V 3 V
11 1199.. TThhee ccoommpound of Claim 1 1 7 or 1 1 8, wherein R and R are taken together to form a C5 cycloalky l.
4 V
120. The compound of any one of Claims 94- 1 19, wherein R ' is selected from the group consisting of an optionally substituted arvl, an optionally substituted heteroary l and an optionally substituted heterocyclyl.
121 . The compound of any one of Claims 94-1 19, wherein R A is an optionally substituted aryl.
1 22. The compound of Claim 121. wherein the optionally substituted aryl is an optionally substituted phenyl.
123. The compound of Claim 121 , wherein the optionally substituted aryl is a substituted aryl substituted with one or more groups selected from the group consisting of C 1 . 6 alkyl, alkoxy, aryl, cyano, halogen, haloalkvl and haloalkoxy.
124. The compound of any one of Claims 94-1 19, wherein RJA is an optionally substituted heteroarvl.
125. The compound of any one of Claims 94- 124, wherein Z ' is O.
126. The compound of any one of Claims 94- 124, wherein ZI A is 1 .
127. The compound of any one of Claims 94- 126, wherein Z2A is O.
128. The compound of any one of Claims 94- 126, wherein Z2A is 1 .
129. The compound of any one of Claims 94- 1 1 5. wherein GI A is R5A.
130. The compound of Claim 129. wherein ΚλΑ is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl.
131 . The compound of Claim 130. wherein R"",A is an optionally substituted aryl.
132. The compound of Claim 1 31. wherein the optionally substituted aryl is an optionally substituted phenyl.
133. The compound of Claim 94, wherein the compound is selected from the group consisti
Figure imgf000272_0001
or a pharmaceutically acceptable salt of any of the foregoing.
134. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1 - 133, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient. or combination thereof
135. Use of an effective amount of a compound of any one of Claims 1 -133. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 134 in the preparation of a medicament for ameliorating or treating an orthomyxovirus viral infection.
1 36. Use of an effective amount of a compound of any one of Claims 1-1 3. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 134 in the preparation of a medicament for inhibiting replication of an orthomyxovirus virus.
137. Use of an effective amount of a compound of any one of Claims 1- 133, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 134 in the preparation of a medicament for contacting a cell infected with an orthomyxovirus virus.
138. Use of an effective amount of a compound of any one of Claims 1- 133, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 134 in the preparation of a medicament for ameliorating or treating an orthomyxovirus viral infection in combination with one or more agents comprising administering or contacting a cell with an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
139. Use of an effective amount of a compound of any one of Claims 1 -133. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 134 in the preparation of a medicament for inhibiting endonuclease activity of an influenza endonuclease.
140. The use of any one of Claims 135-137, wherein the orthomyxovirus viral infection is influenza.
141. The use of Claim 138, wherein the orthomyxovirus viral iniection is an influenza virus infection; and wherein the one or more agents is selected from the group consisting of a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, amantadine, rimantadine, zanamivir. oseltamivir, peramivir, laninamivir, laninamivir octanoate. favipiravir, fludase, ADS-8902, an immuno-modulator, beraprost, Neugene®, ribavirin, CAS Reg. No. 1422050-75-6, CAS Reg. No. 1259366-34- 1 (VX-787), FluMist Quadrivalent® (Medlmmunc), Fluarix® Quadrivalent (GlaxoSmithKlinc), Fluzone® Quadrivalent (Sanofi Pasteur), Flucelvax® (Novartis) and FluBlok® (Protein Sciences).
142. The use of 141. wherein the one or more agents is oseltamivir.
143. The use of any one of Claims 140-141 , wherein the influenza is influenza A.
144. The use of any one of Claims 140-141 , wherein the influenza is influenza B.
145. The use of any one of Claims 140-141 , wherein the influenza is influenza C.
146. The use of any one of Claims 140-141 , wherein the influenza is selected from the group consisting of H1 1 , H3N2, H5N 1 and H7N9.
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