WO2018151830A1 - Inhibiteurs de kinase de régulation du signal apoptotique à base de pyridinyle - Google Patents

Inhibiteurs de kinase de régulation du signal apoptotique à base de pyridinyle Download PDF

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WO2018151830A1
WO2018151830A1 PCT/US2018/000044 US2018000044W WO2018151830A1 WO 2018151830 A1 WO2018151830 A1 WO 2018151830A1 US 2018000044 W US2018000044 W US 2018000044W WO 2018151830 A1 WO2018151830 A1 WO 2018151830A1
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optionally substituted
compound
alkyl
another embodiment
heterocycloalkyl
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PCT/US2018/000044
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English (en)
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Bohan Jin
Qing Dong
Gene Hung
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Fronthera U.S. Pharmaceuticals Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders or conditions associated with apoptosis signal- regulating kinase 1 inhibitors.
  • Apoptosis signal-regulating kinase 1 (ASK1) activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory, autoimmunity and metabolic disorders.
  • ASK1 has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain and kidney.
  • ASK1 has also been identified as an important signaling pathway in non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease (NAFLD), chronic obstructive pulmonary disease (COPD), hypertension, multiple sclerosis, Alzheimer's disease, Parkinson's disease, platelet activation, Sickle cell disease, kidney disease and oxidative stress. Therefore, therapeutic agents that function as inhibitors of ASK1 have potential to remedy or improve the lives of patients suffering from such conditions.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • COPD chronic obstructive pulmonary disease
  • Y 2 is NR Y3 ;
  • R 63 is O or S
  • R Y3 is hydrogen or optionally substituted alkyl
  • R 64 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 63 and R 64 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
  • R 65 is optionally substituted fused bicyclic heterocycloalkyl or optionally substituted fused bicyclic heteroaryl;
  • each R 67 and R 68 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 67 and R 68 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
  • R 69 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • s3 is 0-3.
  • Amino refers to the -NH 2 radical.
  • Niro refers to the -N0 2 radical.
  • Alkoxy refers to a radical of the formula -OR j where R j is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2- dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alky
  • -6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • an alkyl group may be optionally substituted as described below, for example, with oxo, amino, nitrile, nitro, hydroxyl, alkyl, alkylene, alkynyl, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein a sp2 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as "C 2 -C 6 alkenyl” or "C 2 - 6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted as described below.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as "C 2 -C 6 alkynyl” or "C 2 - 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted as described below.
  • alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below.
  • Heteroalkyl or “heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom.
  • Heteroalkylene or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below.
  • Alkylamino refers to a radical of the formula -NHR or -NR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the aryl radical may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of benzene, indane, indene, and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.
  • Cycloalkyl or “carbocycle” or “carbocyclyl” refers to a stable, monocyclic or polycyclic carbocyclic ring, which may include fused or bridged ring systems, which is saturated or unsaturated.
  • Representative cycloalkyls or carbocycles include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms, from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, from three to five carbon atoms, or three to four carbon atoms.
  • Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,
  • a cycloalkyl or carbocycle group may be optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or "halogen” refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
  • haloalkyl group may be optionally substituted.
  • Haloalkoxy similarly refers to a radical of the formula -OR a where R a is a haloalkyl radical as defined. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted as described below.
  • Perhalo or “perfluoro” refers to a moiety in which each hydrogen atom has been replaced by a halo atom or fluorine atom, respectively.
  • Heterocycloalkyl or “heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to a stable 3- to 24-membered non-aromatic ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl
  • heterocyclyl group may be optionally substituted.
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
  • the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,
  • All the above groups may be either substituted or unsubstituted.
  • substituted as used herein means any of the above groups (e.g. alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent.
  • a substituted group may include one or more substituents selected from: halogen, oxo, amino, -CO 2 H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N + R 3 ), N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,
  • alkyldiarylsilyl groups triarylsilyl groups, perfluoroalkyl or perfluoroalkoxy, for example,
  • the substituent group one or more substituents selected from: halogen, oxo, amino, -CO 2 H, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, or heteroaryl.
  • the substituent group one or more substituents selected from: halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, or alkoxy.
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond ⁇ e.g.
  • a double- or triple-bond to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, cycloalkyl, haloalkyl, heterocyclyl and heteroaryl.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms.
  • an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group.
  • an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • R 15 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl.
  • an optionally substituted group may be un- substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , - CH 2 CF 3 , -CF 2 C3 ⁇ 4, -CFHCHF 2) etc).
  • un- substituted e.g., -CH 2 CH 3
  • fully substituted e.g., -CF 2 CF 3
  • mono-substituted e.g., -CH 2 CH 2 F
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the term "pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound disclosed herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound disclosed herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • subject or "patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the kallikrein inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds disclosed herein, are pharmaceutically acceptable acid addition salts and
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable carrier
  • pharmaceutically acceptable excipient refers to a pharmaceutically acceptable carrier
  • each component is "pharmaceutically acceptable" in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • each X 1 , X 2 , X 3 , X 4 and X 5 is independently N, S, O or CR 4 ; provided that at least one X 1 , X 2 , X 3 , X 4 and X 5 is N, S, C or O;
  • each R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • p 0-3;
  • Z is N or C
  • Y is N or C
  • W is N or C
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • n 0-4;
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; Ring C is a five membered heteroaryl or a six membered heteroaryl substituted with -(R b ) q ;
  • each X 6 , X 7 , X 8 , X 9 and X 10 is independently N, S, O or CR 4 ; provided that at least one X 6 , X 7 , X 8 , X 9 and X 10 is N, S, C or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ring A is and bound to the 6' position of the pyridine, Ring B is
  • Ring C is and bound para to Y
  • Y is C
  • Z is C
  • R 1 is H, then R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and . optionally substituted heteroaryl;
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.
  • each Ring A and Ring C is optionally substituted and independently selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrolidine, dioxolane, oxoazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isozole, isothiazole, oxadiazole, triazole, thiadiazole, tetrazole, oxatriazole, and thiatriazole.
  • Ring C is imidazole, pyrazole, triazole, or thiophene.
  • Ring C is imidazole. In some embodiments of Formula (I), Ring C is pyridine, pyrimidine, pyrazine, or pyridazine.In some embodiments of Formula (I), Ring C is pyridine.
  • Ring A is triazole, tetrazole, or isoxazole. In some embodiments of a compound of Formula (I), Ring A is triazole. [0045] In some embodiments of Formula (I), Ring A and Ring B are connected to the 2' and 6' position of the pyridine ring.
  • Ring C is positioned para to Y.
  • each R a is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. In some embodiments of a compound of Formula (I), R a is optionally substituted cycloalkyl.
  • each R b is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. In some embodiments of a compound of Formula (I), R b is optionally substituted alkyl.
  • p is 1. In some embodiments of a compound of Formula (I), p is 2. In some embodiments of a compound of Formula (I), p is 3. In some embodiments of a compound of Formula (I), p is 4.
  • q is 1. In some embodiments of a compound of Formula (I), q is 2. In some embodiments of a compound of Formula (I), q is 3. In some embodiments of a compound of Formula (I), q is 4.
  • between W and CR 6 is a double bond
  • between CR 6 and Z is a single bond
  • between Z and Y is a double bond
  • W is C.
  • Z is N and R 3 is absent. In some embodiments of a compound of Formula (I), Z is C.
  • Y is N and R 2 is absent. In some embodiments of a compound of Formula (I), Y is C.
  • R' is selected from the group consisting of hydrogen and optionally substituted alkyl.
  • R 2 when present, is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
  • n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3. In some embodiments of a compound of Formula (I), n is 4.
  • m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4.
  • R 3 whenpresent, is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
  • R 2 and R 3 are taken together to form an optionally substituted carbocycle.
  • R 2 and R 3 are taken together to form an optionally substituted heterocycle.
  • R 2 and R 3 are taken together to form an optionally substituted aryl.
  • R 2 and R 3 are taken together to form an optionally substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
  • R 7 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
  • R 3 and R 6 are taken together to form an optionally substituted carbocycle. In some embodiments of a compound of Formula (I), R 3 and R 6 are taken together to form an optionally substituted heterocycle. In some embodiments of a compound of Formula (I), R 3 and R 6 are taken together to form an optionally substituted aryl. In some embodiments of a compound of Formula (I), R 3 and R 6 are taken together to form an optionally substituted heteroaryl.
  • each X 1 , X 2 , X 3 and X 4 is independently N, S, O or CR 4 ;
  • X 5 is N or C
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • p 0-3;
  • Z is N or C
  • Y is N or C
  • W is N or C
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • n 0-4;
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; each X 6 , X 7 , X 9 and X 10 is each independently N, S, O or CR 4 ;
  • X s is N or C
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • p is 1, and R a is bonded to X 4 . In another embodiment, q is 1 and R b is bonded to X 10 . In some embodiments of Formula (II), p is 2. In some embodiments of Formula (II), p is 3.
  • X 1 is N, X 2 , X 3 and X 4 is CR 4 and X 5 is C.
  • X 2 is N, X 1 , X 3 and X 4 is CR 4 and X 5 is C.
  • X 3 is N, X 1 , X 2 and X 4 is CR 4 and X 5 is C.
  • X 4 is N, X 1 , X 2 and X 3 is CR 4 and X 5 is C.
  • X 5 is N, X 1 , X 2 , X 3 , and X 4 is CR 4 .
  • X 1 and X 2 is N, and X 3 , X 4 is CR 4 and X 5 is C.
  • X 1 and X 3 is N, and X 2 , X 4 is CR 4 and X 5 is C.
  • X 1 and X 4 is N, and X 2 , X 3 is CR 4 and X 5 is C.
  • X 1 and X 5 is N, and X 2 , X 3 and X 4 is CR 4 .
  • X 2 and X 3 is N, X 1 and X 4 is CR 4 and X 5 is C.
  • X 2 and X 4 is N, X 1 and X 3 is CR 4 and X 5 is C. In another embodiment, X 2 and X 5 is N, and ⁇ ', X 3 and X 4 is CR 4 . In another embodiment, X 3 and X 4 is N, X 1 and X 2 is CR 4 and X 5 is C. In another embodiment, X 3 and X 5 is N, and X 1 , X 2 and X 4 is CR 4 . In another embodiment, X 4 and X 5 is N, and X 1 , X 2 and X 3 is CR 4 . In another embodiment, X 4 and X 5 is N, and X 1 , X 2 and X 3 is CR 4 .
  • X 1 , X 2 and X 3 is N, X 4 is CR 4 and X 5 is C.
  • X 1 , X 2 and X 4 is N
  • X 3 is CR 4 and X 5 is C.
  • X 1 , X 2 and X 5 is N
  • X 3 and X 4 is CR 4 .
  • X 1 , X 3 and X 4 is N
  • X 2 is CR 4 and X 5 is C.
  • X 1 , X 3 and X 5 is N, and X 2 and X 4 is CR 4 .
  • X 1 , X 4 and X 5 is N, and X 2 and X 3 is CR 4 .
  • X 2 , X 3 and X 4 is N, X 1 is CR 4 and X 5 is C.
  • X 2 , X 3 and X 5 is N, and X 1 and X 4 is CR 4 .
  • X 2 , X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 , X 4 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 1 , X 2 , X 3 and X 4 is N, and X 5 is C.
  • X 1 , X 2 , X 3 and X 5 is N, and X 4 is CR 4 .
  • X 2 , X 3 , X 4 and X 5 is N, and X 1 is CR 4 .
  • X 1 , X 3 , X 4 and X 5 is N, and X 2 is CR 4 .
  • X 1 , X 2 , X 4 and X 5 is N, and X 3 is CR 4 .
  • X 1 is O, X 2 is N, X 3 and X 4 is CR 4 and X 5 is C.
  • X 1 is O, X 3 is N, X 2 and X 4 is CR 4 and X 5 is C.
  • X 1 is O, X 4 is N, X 2 and X 3 is CR 4 and X 5 is C.
  • X 1 is O, X 5 is N, and X 2 , X 3 and X 4 is CR 4 .
  • X 1 is O, X 2 and X 3 is N, X 4 is CR 4 and X 5 is C.
  • X 1 is O, X 2 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is O, X 2 and X 5 is N, and X 3 and X 4 is CR 4 . In another embodiment, X 1 is O, X 3 and X 4 is N, X 2 is CR 4 and X s is C. In another embodiment, X 1 is O, X 3 and X 5 is N, and X 2 and X 4 is CR 4 .In another embodiment, X 1 is O, X 4 and X 5 is N, and X 2 and X 3 is CR 4 .
  • X 2 is O, X 1 is N, X 3 and X 4 is CR 4 and X 5 is C. In another embodiment, X 2 is O, X 3 is N, X 1 and X 4 is CR 4 and X 5 is C. In another embodiment, X 2 is O, X 4 is N, X 1 and X 3 is CR 4 and X 5 is C. In another embodiment, X 2 is O, X 5 is N, and X 1 , X 3 and X 4 is CR 4 . In another embodiment, X 2 is O, X 1 and X 3 is N, X 4 is CR 4 and X 5 is C.
  • X 2 is O, X 1 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 2 is O, X 1 and X 5 is N, and X 3 and X 4 is CR 4 . In another embodiment, X 2 is O, X 3 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 2 is O, X 3 and X 5 is N, and X 1 and X 4 is CR 4 . In another embodiment, X 2 is O, X 4 and X 5 is N, and X 1 and X 3 is CR 4 . In another embodiment, X 2 is O, X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 is O, X 1 is N, X 2 and X 4 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 2 is N, X 1 and X 4 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 4 is N, X 1 and X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 5 is N, and X 1 , X 2 and X 4 is CR 4 . In another embodiment, X 3 is O, X 1 and X 2 is N, X 4 is CR 4 and X 5 is C.
  • X 3 is O, X 1 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 1 and X 5 is N, and X 2 and X 4 is CR 4 . In another embodiment, X 3 is O, X 2 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 2 and X 5 is N, and X 1 and X 4 is CR 4 . In another embodiment, X 3 is O, X 4 and X s is N, and X 1 and X 2 is CR 4 .
  • X 4 is O, X 1 is N, X 2 and X 3 is CR 4 and X 5 is C. In another embodiment, X 4 is O, X 2 is N, X 1 and X 3 is CR 4 and X 5 is C. In another embodiment, X 4 is O, X 3 is N, X 1 and X 2 is CR 4 and X 5 is C. In another embodiment, X 4 is O, X 5 is N, and X 1 , X 2 and X 3 is CR 4 . In another embodiment, X 4 is O, X 1 and X 2 is N, X 3 is CR 4 and X 5 is C.
  • X 4 is O, X 1 and X 3 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 4 is O, X 1 and X 5 is N, and X 2 and X 3 is CR 4 . In another embodiment, X 4 is O, X 2 and X 3 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 4 is O, X 2 and X 5 is N, and X 1 and X 3 is CR 4 . In another embodiment, X 4 is O, X 3 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 1 is S, X 2 is N, X 3 and X 4 is CR 4 and X 5 is C.
  • X 1 is S, X 3 is N, X 2 and X 4 is CR 4 and X 5 is C.
  • X 1 is S, X 4 is N, X 2 and X 3 is CR 4 and X 5 is C.
  • X 1 is S, X 5 is N, and X 2 , X 3 and X 4 is CR 4 .
  • X 1 is S, X 2 and X 3 is N, X 4 is CR 4 and X 5 is C.
  • X 1 is S, X 2 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is S, X 2 and X 5 is N, and X 3 and X 4 is CR 4 . In another embodiment, X 1 is S, X 3 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 1 is S, X 3 and X 5 is N, and X 2 and X 4 is CR 4 . In another embodiment, X 1 is S, X 4 and X 5 is N, and X 2 and X 3 is CR 4 . In another embodiment, X 1 is S, X 4 and X 5 is N, and X 2 and X 3 is CR 4 .
  • X 2 is S, X 1 is N, X 3 and X 4 is CR 4 and X 5 is C. In another embodiment, X 2 is S, X 3 is N, X 1 and X 4 is CR 4 and X 5 is C. In another embodiment, X 2 is S, X 4 is N, X 1 and X 3 is CR 4 and X 5 is C. In another embodiment, X 2 is S, X 5 is N, and X 1 , X 3 and X 4 is CR 4 . In another embodiment, X 2 is S, X 1 and X 3 is N, X 4 is CR 4 and X 5 is C.
  • X 2 is S, X 1 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 2 is S, X 1 and X 5 is N, and X 3 and X 4 is CR 4 . In another embodiment, X 2 is S, X 3 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 2 is S, X 3 and X 5 is N, and X 1 and X 4 is CR 4 . In another embodiment, X 2 is S, X 4 and X 5 is N, and X 1 and X 3 is CR 4 . In another embodiment, X 2 is S, X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 is S, X 1 is N, X 2 and X 4 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 2 is N, X 1 and X 4 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 4 is N, X 1 and X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 5 is N, and X 1 , X 2 and X 4 is CR 4 . In another embodiment, X 3 is S, X 1 and X 2 is N, X 4 is CR 4 and X 5 is C.
  • X 3 is S, X 1 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 1 and X 5 is N, and X 2 and X 4 is CR 4 . In another embodiment, X 3 is S, X 2 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 2 and X 5 is N, and X 1 and X 4 is CR 4 . In another embodiment, X 3 is S, X 4 and X 5 is N, and X 1 and X 2 is CR 4 . In another embodiment, X 3 is S, X 4 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 4 is S, X 1 is N, X 2 and X 3 is CR 4 and X 5 is C. In another embodiment, X 4 is S, X 2 is N, X 1 and X 3 is CR 4 and X 5 is C. In another embodiment, X 4 is S, X 3 is N, X 1 and X 2 is CR 4 and X 5 is C. In another embodiment, X 4 is S, X 5 is N, and X 1 , X 2 and X 3 is CR 4 . In another embodiment, X 4 is S, X 1 and X 2 is N, X 3 is CR 4 and X 5 is C.
  • X 4 is S, X 1 and X 3 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 4 is S, X 1 and X 5 is N, and X 2 and X 3 is CR 4 . In another embodiment, X 4 is S, X 2 and X 3 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 4 is S, X 2 and X 5 is N, and X 1 and X 3 is CR 4 . In another embodiment, X 4 is S, X 3 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 6 is N, X 7 , X 10 and X 9 is CR 4 and X 8 is C.
  • X 7 is N
  • X 6 , X 10 and X 9 is CR 4 and X 8 is C.
  • X 10 is N, X 6 , X 7 and X 9 is CR 4 and X 8 is C.
  • X 9 is N, X 6 , X 7 and X 10 is CR 4 and X s is C.
  • X 8 is N, X 6 , X 7 , X 10 , and X 9 is CR 4 .
  • X 6 and X 7 is N, and X 10 , X 9 is CR 4 and X 8 is C.
  • X 6 and X 10 is N, and X 7 , X 9 is CR 4 and X 8 is C.
  • X 6 and X 9 is N, and X 7 , X 9 is CR 4 and X 8 is C.
  • X 6 and X 8 is N, and X 7 , X 9 and X 10 is CR 4 .
  • X 7 and X 10 is N, X 6 and X 9 is CR 4 and X 8 is C.
  • X 7 and X 9 is N, X 6 and X 10 is CR 4 and X 8 is C. In another embodiment, X 7 and X 10 is N, and X 6 , X 8 and X 9 is CR 4 . In another embodiment, X 10 and X 9 is N, X 6 and X 7 is CR 4 and X 8 is C. In another embodiment, X 10 and X 8 is N, and X 6 , X 7 and X 9 is CR 4 . In another embodiment, X 9 and X 10 is N, and X 6 , X 7 and X 8 is CR 4 . In another embodiment, X 9 and X 10 is N, and X 6 , X 7 and X 8 is CR 4 .
  • X 6 , X 7 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 6 , X 7 and X 9 is N
  • X 10 is CR 4 and X 8 is C.
  • X 6 , X 7 and X 8 is N
  • X 10 and X 9 is CR 4 .
  • X 6 , X 10 and X 9 is N
  • X 6 , X 10 and X 8 is N, and X 7 and X 9 is CR 4 .
  • X 6 , X 9 and X 8 is N, and X 7 and X 10 is CR 4 .
  • X 7 , X 10 and X 9 is N
  • X 6 is CR 4 and X 8 is C.
  • X 7 , X 10 and X 8 is N
  • X 6 and X 9 is CR 4 .
  • X 7 , X 8 and X 9 is N
  • X 6 and X 10 is CR 4 .
  • X 10 , X 9 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 6 , X 7 , X 10 and X 9 is N, and X 8 is C.
  • X 6 , X 7 , X 10 and X 8 is N, and X 9 is CR 4 .
  • X 7 , X 10 , X 9 and X 8 is N, and X 6 is CR 4 .
  • X 6 , X 10 , X 9 and X 8 is N, and X 7 is CR 4 .
  • X 6 , X 7 , X 9 and X s is N, and X 10 is CR 4 .
  • X 6 is O, X 7 is N, X 10 and X 9 is CR 4 and X 8 is C.
  • X 6 is O, X 10 is N, X 7 and X 9 is CR 4 and X 8 is C.
  • X 6 is O, X 9 is N, X 7 and X 10 is CR 4 and X 8 is C.
  • X 6 is O, X 8 is N, and X 7 , X 10 and X 9 is CR 4 .
  • X 6 is O, X 7 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 6 is O, X 7 and X 9 is N, X 10 is CR 4 and X 8 is C. In another embodiment, X 6 is O, X 7 and X 8 is N, and X 10 and X 9 is CR 4 . In another embodiment, X 6 is O, X 10 and X 9 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 6 is O, X 8 and X 10 is N, and X 7 and X 9 is CR 4 . In another embodiment, X 6 is O, X 9 and X 8 is N, and X 7 and X 10 is CR 4 .
  • X 7 is O, X 6 is N, X 10 and X 9 is CR 4 and X 8 is C. In another embodiment, X 7 is O, X 10 is N, X 6 and X 9 is CR 4 and X 8 is C. In another embodiment, X 7 is O, X 9 is N, X 6 and X 10 is CR 4 and X 8 is C. In another embodiment, X 7 is O, X 8 is N, and X 6 , X 10 and X 9 is CR 4 . In another embodiment, X 7 is O, X 6 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 7 is O, X 6 and X 9 is N, X 10 is CR 4 and X 8 is C. In another embodiment, X 7 is O, X 6 and X 8 is N, and X 10 and X 9 is CR 4 . In another embodiment, X 7 is O, X 10 and X 9 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 7 is O, X 8 and X 10 is N, and X 6 and X 9 is CR 4 . In another embodiment, X 7 is O, X 9 and X 8 is N, and X 6 and X 10 is CR 4 . In another embodiment, X 7 is O, X 9 and X 8 is N, and X 6 and X 10 is CR 4 .
  • X 10 is O, X 6 is N, X 7 and X 9 is CR 4 and X s is C. In another embodiment, X 10 is O, X 7 is N, X 6 and X 9 is CR 4 and X 8 is C. In another embodiment, X 10 is O, X 9 is N, X 6 and X 7 is CR 4 and X 8 is C. In another embodiment, X 10 is O, X 8 is N, and X 6 , X 7 and X 9 is CR 4 . In another embodiment, X 10 is O, X 6 and X 7 is N, X 9 is CR 4 and X 8 is C.
  • X 10 is O, X 6 and X 9 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 10 is O, X 6 and X 8 is N, and X 7 and X 9 is CR 4 . In another embodiment, X 10 is O, X 7 and X 9 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 10 is O, X 7 and X 8 is N, and X 6 and X 9 is CR 4 . In another embodiment, X 10 is O, X 9 and X 8 is N, and X 6 and X 7 is CR 4 . In another embodiment, X 10 is O, X 9 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 9 is O, X 6 is N, X 7 and X 10 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 7 is N, X 6 and X 10 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 10 is N, X 6 and X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 8 is N, and X 6 , X 7 and X 10 is CR 4 . In another embodiment, X 9 is O, X 6 and X 7 is N, X 10 is CR 4 and X 8 is C.
  • X 9 is O, X 6 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 6 and X 8 is N, and X 7 and X 10 is CR 4 . In another embodiment, X 9 is O, X 7 and X 10 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 7 and X 8 is N, and X 6 and X 10 is CR 4 . In another embodiment, X 9 is O, X 8 and X 10 is N, and X 6 and X 7 is CR 4 .
  • X 6 is S, X 7 is N, X 10 and X 9 is CR 4 and X 8 is C.
  • X 6 is S, X 10 is N, X 7 and X 9 is CR 4 and X 8 is C.
  • X 6 is S, X 9 is N, X 7 and X 10 is CR 4 and X 8 is C.
  • X 6 is S, X 8 is N, and X 7 , X 10 and X 9 is CR 4 .
  • X 6 is S, X 7 and X 10 is N, X 9 is CR 4 and X s is C.
  • X 6 is S, X 7 and X 9 is N, X 10 is CR 4 and X 8 is C. In another embodiment, X 6 is S, X 7 and X s is N, and X 10 and X 9 is CR 4 . In another embodiment, X 6 is S, X 10 and X 9 is N, X 7 is CR 4 and X s is C. In another embodiment, X 6 is S, X 8 and X 10 is N, and X 7 and X 9 is CR 4 . In another embodiment, X 6 is S, X 9 and X 8 is N, and X 7 and X 10 is CR 4 .
  • X 7 is S, X 6 is N, X 10 and X 9 is CR 4 and X 8 is C.
  • X 7 is S, X 10 is N, X 6 and X 9 is CR 4 and X 8 is C.
  • X 7 is S, X 9 is N, X 6 and X 10 is CR 4 and X 8 is C.
  • X 7 is S, X 8 is N, and X 6 , X 10 and X 9 is CR 4 .
  • X 7 is S, X 6 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 7 is S, X 6 and X 9 is N, X 10 is CR 4 and X s is C. In another embodiment, X 7 is S, X 6 and X 8 is N, and X 10 and X 9 is CR 4 . In another embodiment, X 7 is S, X 10 and X 9 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 7 is S, X s and X 10 is N, and X 6 and X 9 is CR 4 . In another embodiment, X 7 is S, X 9 and X 8 is N, and X 6 and X 10 is CR 4 .
  • X 10 is S, X 6 is N, X 7 and X 9 is CR 4 and X 8 is C. In another embodiment, X 10 is S, X 7 is N, X 6 and X 9 is CR 4 and X 8 is C. In another embodiment, X 10 is S, X 9 is N, X 6 and X 7 is CR 4 and X 8 is C. In another embodiment, X 10 is S, X 8 is N, and X 6 , X 7 and X 9 is CR 4 . In another embodiment, X 10 is S, X 6 and X 7 is N, X 9 is CR 4 and X 8 is C.
  • X 10 is S, X 6 and X 9 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 10 is S, X 6 and X 8 is N, and X 7 and X 9 is CR 4 . In another embodiment, X 10 is S, X 7 and X 9 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 10 is S, X 7 and X 8 is N, and X 6 and X 9 is CR 4 . In another embodiment, X 10 is S, X 9 and X 8 is N, and X 6 and X 7 is CR 4 . In another embodiment, X 10 is S, X 9 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 9 is S, X 6 is N, X 7 and X 10 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 7 is N, X 6 and X 10 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 10 is N, X 6 and X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 8 is N, and X 6 , X 7 and X 10 is CR 4 . In another embodiment, X 9 is S, X 6 and X 7 is N, X 10 is CR 4 and X 8 is C.
  • X 9 is S, X 6 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 6 and X 8 is N, and X 7 and X 10 is CR 4 . In another embodiment, X 9 is S, X 7 and X 10 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 7 and X 8 is N, and X 6 and X 10 is CR 4 . In another embodiment, X 9 is S, X s and X 10 is N, and X 6 and X 7 is CR 4 .
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • Y is N or C
  • W is N or C
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • n 0-4;
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl; each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • X 6 , X 7 and X 9 is each independently N, S, O or CR 4 ;
  • X s and X 10 is each independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l ,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.
  • R 7 is H, between Y and Z is a double bond, Y is C,
  • R 1 is H
  • between Y and Z is a single bond
  • Y is C
  • between Y and Z is a double bond
  • Y is C
  • R 1 and R 2 are taken together to form - R c -.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X s , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 2 is not hydrogen or methyl
  • the compound is not 5-(4-cyclopropyl-lH-irnidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 2 and R 3 are taken together to form an optionally substituted heterocycle. In an additional embodiment, R 6 is hydrogen or an optionally substituted alkyl.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; and
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.
  • R a is isopropyl.
  • R a is an alkyl substituted with at least one hydroxyl group.
  • R b is an alkyl substituted with at least one hydroxyl group.
  • X 1 , X 2 , X 3 and X 4 is N, and X 5 is C.
  • X 1 , X 2 , X 3 and X 5 is N, and X 4 is C.
  • X 1 , X 2 and X 5 is N, and X 3 , X 4 is C.
  • X 2 , X 3 and X 5 is N, and X 1 , X 4 is C. In another embodiment, X 2 , X 3 and X 4 is N, and X 1 , X 5 is C. In another embodiment, X 2 is N, X 3 , X 4 and X 5 is C, and X 1 is O. In another embodiment, X 2 is N, X 3 , X 4 and X 5 is C, and X 1 is S.
  • Z is C or N
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; and
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 2 and R 3 are taken together to form an optionally substituted heterocycle.
  • R 6 is hydrogen or an optionally substituted alkyl.
  • X 9 and X 10 is N, and X 6 , X 7 and X 8 is C.
  • R b is an alkyl substituted with at least one hydroxyl group.
  • Z is C or N
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 2 is not hydrogen or methyl
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.
  • R a is isopropyl. In another embodiment, R a is an alkyl substituted with at least one hydroxyl group. In another embodiment, X 1 , X 2 , X 3 and X 4 is N, and X 5 is C. In another embodiment, X 1 , X 2 , X 3 and X 5 is N, and X 4 is C. In another embodiment, X 1 , X 2 and X 5 is N, and X 3 , X 4 is C. In another embodiment, wherein X 2 , X 3 and X 5 is N, and X 1 , X 4 is C.
  • X 2 , X 3 and X 4 is N, and X 1 , X 5 is C.
  • X 2 is N, X 3 , X 4 and X 5 is C, and X 1 is O.
  • X 2 is N, X 3 , X 4 and X 5 is C, and X 1 is S.
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 2 and R 3 are taken together to form an optionally substituted heterocycle. In another embodiment, R 6 is hydrogen or an optionally substituted alkyl.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • W is N or C
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • X a is O.
  • Z is N.
  • X 6 and X 10 is N, and X 7 , X 8 and X 9 is C.
  • X 6 and X 8 is N, and X 7 , X 9 and X 10 is C.
  • Rb is cyclopropyl.
  • W is N or C; each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X s and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is methyl, and R 6 , R 7 is hydrogen.
  • X 6 and X 10 is N, and X 7 , X 8 and X 9 is C.
  • X 6 and X 8 is N, and X 7 , X 9 and X 10 is C.
  • R b is cyclopropyl.
  • W is N or C
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X s and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is methyl, and R 6 , R 7 is hydrogen.
  • X 6 and X 10 is N, and X 7 , X s and X 9 is C.
  • X 6 and X 8 is N, and X 7 , X 9 and X 10 is C.
  • R b is cyclopropyl.
  • W is N or C
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is methyl, and R 6 , R 7 is hydrogen.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • W is C
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • X 6 , X 7 and X 9 is each independently N, S, O or CR 4 ;
  • X 8 and X 10 is each independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • W is C
  • n 0-4;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • n is 1 or 2 and R 4 and R 5 is hydrogen.
  • Z is N or C
  • W is C
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X d , X 7 , X s , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • -R c - is -CH 2 CH 2 - or -CH 2 -.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • W is C
  • n 0-4;
  • t 0-4;
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle; and
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
  • VIE Formula (VIE), or a pharmaceutically acce table salt, tautomer, stereoisomer, or solvate thereof:
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R" is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C
  • W is C
  • X b is CR 4 or N
  • X c is CR 4 or N
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X 8 and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • X b is CR 4 and X c is CR 4 .
  • X b is CH and X c is CH.
  • X b is CR 4 and X c is N.
  • X b is CH and X c is N.
  • X b is N and X c is CR 4 .
  • X b is N and X c is CH.
  • Z is N or C
  • W is C
  • X b is CR 4 or N
  • X c is CR 4 or N
  • v 0-2;
  • R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • each R 6 and R 7 is independently selected from the group consisting of hydrogen, halogen, -CN, -
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
  • each X 6 , X 7 and X 9 is independently N, S, O or CR 4 ;
  • each X s and X 10 is independently N or C;
  • X 6 , X 7 , X 8 , X 9 and X 10 is N, S or O;
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • X b is CR 4 and X c is CR 4 .
  • X b is CH and X° is CH.
  • X b is CR 4 and X c is N.
  • X b is CH and X c is N.
  • X b is N and X c is CR 4 .
  • X b is N and X c is CH.
  • each X 1 , X 2 and X 3 is independently N, S, O or CR 4 ;
  • each X 4 and X 5 is independently N or C;
  • X 1 , X 2 , X 3 , X 4 and X 5 is N, S or O;
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
  • Z is N or C; W is C;
  • X b is CR 4 or N
  • X c is CR 4 or N
  • v 0-2;
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
  • R 3 and R 6 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
  • X b is CR 4 and X is CR 4 .
  • X b is CH and X° is CH.
  • X b is CR 4 and X° is N.
  • X b is CH and X c is N.
  • X b is N and X° is CR 4 .
  • X b is N and X c is CH.
  • X 1 is N, X 2 , X 3 and X 4 is CR 4 and X 5 is C.
  • X 2 is N, X 1 , X 3 and X 4 and X 5 is C.
  • X 3 is N, X 1 , X 2 is CR 4 , and X 4 and X s is C.
  • X 4 is N, X 1 , X 2 and X 3 is CR 4 and X 5 is C.
  • X 5 is N, X 1 , X 2 and X 3 is CR 4 , and X 4 is C.
  • X 1 and X 2 is N, X 3 is CR 4 , and X 4 and X 5 is C.
  • X 1 and X 3 is N, X 2 is CR 4 , and X 4 and X 5 is C.
  • X 1 and X 4 is N, and X 2 , X 3 is CR 4 and X 5 is C.
  • X 1 and X 5 is N, X 2 , X 3 is CR 4 and X 5 is C.
  • X 1 and X 5 is N, X 2 , X 3 is CR 4 , and X 4 is C.
  • X 2 and X 3 is N, X 1 is CR 4 , and X 4 and X s is C.
  • X 2 and X 4 is N, X 1 and X 3 is CR 4 , and X 5 is C.
  • X 2 and X 5 is N, and X 1 , X 3 is CR 4 , and X 4 is C.
  • X 3 and X 4 is N, X 1 and X 2 is CR 4 , and X 5 is C.
  • X 3 and X 5 is N, and X 1 , X 2 is CR 4 , and X 4 is C.
  • X 4 and X 5 is N, and X 1 , X 2 and X 3 is CR 4 .
  • X 1 , X 2 and X 3 is N
  • X 4 is CR 4 and X 5 is C
  • X 1 , X 2 and X 4 is N
  • X 3 is CR 4 and X 5 is C
  • X 1 , X 2 and X 5 is N
  • X 3 is CR 4 and X 4 is C.
  • X 1 , X 3 and X 4 is N, X 2 is CR 4 and X s is C. In another embodiment, X 1 , X 3 and X 5 is N, X 2 is CR 4 and X 4 is C. In another embodiment, X 1 , X 4 and X 5 is N, and X 2 and X 3 is CR 4 . In another embodiment, X 2 , X 3 and X 4 is N, X 1 is CR 4 and X s is C. In another embodiment, X 2 , X 3 and X 5 is N, X 1 is CR 4 and X 4 is C.
  • X 2 , X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 , X 4 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 1 , X 2 , X 3 and X 4 is N, and X 5 is C.
  • X 1 , X 2 , X 3 and X 5 is N, and X 4 is C.
  • X 2 , X 3 , X 4 and X 5 is N, and X 1 is CR 4 .
  • X 1 , X 3 , X 4 and X s is N, and X 2 is CR 4 .
  • X 1 , X 2 , X 4 and X 5 is N, and X 3 is CR 4 .
  • X 1 is O, X 2 is N, X 3 is CR 4 and X 4 and X 5 is C. In another embodiment, X 1 is O, X 3 is N, X 2 is CR 4 and X 4 and X 5 is C. In another embodiment, X 1 is O, X 4 is N, X 2 and X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is O, X 4 is N, X 2 and X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is O, X 5 is N, X 2 , X 3 is CR 4 and X 4 is C.
  • X 1 is O, X 2 and X 3 is N, X 4 and X 5 is C. In another embodiment, X 1 is O, X 2 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is O, X 2 and X 5 is N, X 3 is CR 4 , and X 4 is C. In another embodiment, X 1 is O, X 3 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 1 is O, X 3 and X 5 is N, and X 2 is CR 4 and X 4 is C.
  • X 1 is O, X 4 and X 5 is N, and X 2 and X 3 is CR 4 .
  • X 2 is O, X 1 is N, X 3 is CR 4 and X 4 and X 5 is C.
  • X 2 is O, X 3 is N, X 1 is CR 4 and X 4 and X 3 is C.
  • X 2 is O, X 4 is N, X 1 and X 3 is CR 4 and X 5 is C.
  • X 2 is O, X 5 is N, X 1 , X 3 is CR 4 and X 4 is C.
  • X 2 is O, X 1 and X 3 is N, and X 4 and X 5 is C.
  • X 2 is O, X 1 and X 4 is N, X 3 is CR 4 and X 5 is C.
  • X 2 is O, X 1 and X 5 is N, X 3 is CR 4 and X 4 is C.
  • X 2 is O, X 3 and X 4 is N, X 1 is CR 4 and X 5 is C.
  • X 2 is O, X 3 and X 5 is N, X 1 is CR 4 and X 5 is C.
  • X 2 is O, X 3 and X 5 is N, X 1 is CR 4 and X 4 is C.
  • X 2 is O, X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 is O, X 1 is N, X 2 is CR 4 and X 4 and X 5 is C.
  • X 3 is O, X 2 is N, X 1 is CR 4 and X 4 and X 5 is C.
  • X 3 is O, X 4 is N, X 1 and X 2 is CR 4 and X 5 is C.
  • X 3 is O, X 5 is N, and X 1 , X 2 is CR 4 and X 4 is C.
  • X 3 is O, X 1 and X 2 is N, X 4 and X 5 is C. In another embodiment, X 3 is O, X 1 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 1 and X 5 is N, X 2 is CR 4 and X 4 is C. In another embodiment, X 3 is O, X 2 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 3 is O, X 2 and X 5 is N, X 1 is CR 4 and X 4 is C. In another embodiment, X 3 is O, X 4 and X 5 is N, X 1 is CR 4 and X 4 is C. In another embodiment, X 3 is O, X 4 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 1 is S, X 2 is N, X 3 is CR 4 and X 4 and X 5 is C.
  • X 1 is S, X 3 is N, X 2 is CR 4 and X 4 and X 5 is C.
  • X 1 is S, X 4 is N, X 2 and X 3 is CR 4 and X 5 is C.
  • X 1 is S, X 5 is N, X 2 , X 3 is CR 4 and X 4 is C.
  • X 1 is S, X 2 and X 3 is N, X 4 and X 5 is C. In another embodiment, X 1 is S, X 2 and X 4 is N, X 3 is CR 4 and X 5 is C. In another embodiment, X 1 is S, X 2 and X 5 is N, X 3 is CR 4 , and X 4 is C. In another embodiment, X 1 is S, X 3 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 1 is S, X 3 and X 5 is N, and X 2 is CR 4 and X 4 is C.
  • X 1 is S, X 4 and X 5 is N, and X 2 and X 3 is CR 4 .
  • X 2 is S, X 1 is N, X 3 is CR 4 and X 4 and X 5 is C.
  • X 2 is S, X 3 is N, X 1 is CR 4 and X 4 and X 5 is C.
  • X 2 is S, X 4 is N, X 1 and X 3 is CR 4 and X 5 is C.
  • X 2 is S, X 5 is N, X 1 , X 3 is CR 4 and X 4 is C.
  • X 2 is S, X 1 and X 3 is N, and X 4 and X 5 is C.
  • X 2 is S, X 1 and X 4 is N, X 3 is CR 4 and X 5 is C.
  • X 2 is S, X 1 and X 5 is N, X 3 is CR 4 and X 4 is C.
  • X 2 is S, X 3 and X 4 is N, X 1 is CR 4 and X 5 is C.
  • X 2 is S, X 3 and X 5 is N, X 1 is CR 4 and X 5 is C.
  • X 2 is S, X 3 and X 5 is N, X 1 is CR 4 and X 4 is C.
  • X 2 is S, X 4 and X 5 is N, and X 1 and X 3 is CR 4 .
  • X 3 is S, X 1 is N, X 2 is CR 4 and X 4 and X s is C.
  • X 3 is S, X 2 is N, X 1 is CR 4 and X 4 and X 5 is C.
  • X 3 is S, X 4 is N, X 1 and X 2 is CR 4 and X 3 is C.
  • X 3 is S, X 5 is N, and X 1 , X 2 is CR 4 and X 4 is C.
  • X 3 is S, X 1 and X 2 is N, X 4 and X 5 is C. In another embodiment, X 3 is S, X 1 and X 4 is N, X 2 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 1 and X 5 is N, X 2 is CR 4 and X 4 is C. In another embodiment, X 3 is S, X 2 and X 4 is N, X 1 is CR 4 and X 5 is C. In another embodiment, X 3 is S, X 2 and X 5 is N, X 1 is CR 4 and X 4 is C. In another embodiment, X 3 is S, X 4 and X 5 is N, X 1 is CR 4 and X 4 is C. In another embodiment, X 3 is S, X 4 and X 5 is N, and X 1 and X 2 is CR 4 .
  • X 6 is N, X 7 , X 9 and X 10 is CR 4 and X 8 is C.
  • X 7 is N
  • X 6 , X 9 is CR 4 and X 10 and X 8 is C.
  • X 9 is N
  • X 6 , X 7 is CR 4 and X 10 and X s is C.
  • X 10 is N, X 6 , X 7 and X 9 is CR 4 and X 8 is C.
  • X 8 is N, X 6 , X 7 and X 9 is CR 4 , and X 10 is C.
  • X 6 and X 7 is N, X 9 is CR 4 , and X 10 and X 8 is C.
  • X 6 and X 9 is N, X 7 is CR 4 , and X 10 and X 8 is C.
  • X 6 and X 10 is N, and X 7 , X 9 is CR 4 and X 8 is C.
  • X 6 and X 8 is N, X 7 , X 9 is CR 4 , and X 10 is C.
  • X 7 and X 9 is N, X 6 is CR 4 , and X 10 and X 8 is C.
  • X 7 and X 10 is N, X 6 and X 9 is CR 4 , and X 8 is C.
  • X 7 and X 8 is N, and X 6 , X 9 is CR 4 , and X 10 is C.
  • X 9 and X 10 is N, X 6 and X 7 is CR 4 , and X 8 is C.
  • X 9 and X 8 is N, and X 6 , X 7 is CR 4 , and X 10 is C.
  • X 10 and X 8 is N, and X 6 , X 7 and X 9 is CR 4 .
  • X 6 , X 7 and X 9 is N, and X 10 and X 8 is C.
  • X 6 , X 7 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 6 , X 7 and X 8 is N, X 9 is CR 4 and X 10 is C.
  • X 6 , X 9 and X 10 is N, X 7 is CR 4 and X 8 is C.
  • X 6 , X 9 and X 10 is N, X 7 is CR 4 and X 8 is C.
  • X 6 , X 9 and X 8 is N, X 7 is CR 4 and X 10 is C. In another embodiment, X 6 , X 10 and X 8 is N, and X 7 and X 9 is CR 4 . In another embodiment, X 7 , X 9 and X 10 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 7 , X 9 and X 8 is N, X 6 is CR 4 and X 10 is C. In another embodiment, X 7 , X 10 and X s is N, and X 6 and X 9 is CR 4 . In another embodiment, X 9 , X 10 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 6 , X 7 , X 9 and X 10 is N, and X 8 is C.
  • X 6 , X 7 , X 9 and X 8 is N, and X 10 is C.
  • X 7 , X 9 , X 10 and X 8 is N, and X 6 is CR 4 .
  • X 6 , X 9 , X 10 and X 8 is N, and X 7 is CR 4 .
  • X 6 , X 7 , X 10 and X 8 is N, and X 9 is CR 4 .
  • X 6 is O, X 7 is N, X 9 is CR 4 and X 10 and X 8 is C. In another embodiment, X 6 is O, X 9 is N, X 7 is CR 4 and X 10 and X 8 is C. In another embodiment, X 6 is O, X 10 is N, X 7 and X 9 is CR 4 and X 8 is C. In another embodiment, X 6 is O, X 8 is N, X 7 , X 9 is CR 4 and X 10 is C.
  • X 6 is O, X 7 and X 9 is N, X 10 and X 8 is C. In another embodiment, X 6 is O, X 7 and X 10 is N, X 9 is CR 4 and X s is C.In another embodiment, X 6 is O, X 7 and X 8 is N, X 9 is CR 4 , and X 10 is C. In another embodiment, X 6 is O, X 9 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 6 is O, X 9 and X 8 is N, and X 7 is CR 4 and X 10 is C.
  • X 6 is O, X 10 and X 8 is N, and X 7 and X 9 is CR 4 .
  • X 7 is O, X 6 is N, X 9 is CR 4 and X 10 and X 8 is C.
  • X 7 is O, X 9 is N, X 6 is CR 4 and X 10 and X 8 is C.
  • X 7 is O, X 10 is N, X 6 and X 9 is CR 4 and X s is C.
  • X 7 is O, X 8 is N, X 6 , X 9 is CR 4 and X 10 is C.
  • X 7 is O, X 6 and X 9 is N, and X 10 and X 8 is C.
  • X 7 is O, X 6 and X 10 is N, X 9 is CR 4 and X 8 is C.
  • X 7 is O, X 6 and X 8 is N, X 9 is CR 4 and X 10 is C.
  • X 7 is O, X 9 and X 10 is N, X 6 is CR 4 and X 8 is C.
  • X 7 is O, X 9 and X 8 is N, X 6 is CR 4 and X 10 is C.
  • X 7 is O, X 10 and X 8 is N, and X 6 and X 9 is CR 4 .
  • X 9 is O, X 6 is N, X 7 is CR 4 and X 10 and X 8 is C.
  • X 9 is O, X 7 is N, X 6 is CR 4 and X 10 and X 8 is C.
  • X 9 is O, X 10 is N, X 6 and X 7 is CR 4 and X s is C.
  • X 9 is O, X 8 is N, and X 6 , X 7 is CR 4 and X 10 is C.
  • X 9 is O, X 6 and X 7 is N, X 10 and X 8 is C. In another embodiment, X 9 is O, X 6 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 6 and X s is N, X 7 is CR 4 and X 10 is C. In another embodiment, X 9 is O, X 7 and X 10 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 9 is O, X 7 and X 8 is N, X 6 is CR 4 and X 10 is C. In another embodiment, X 9 is O, X 10 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 6 is S, X 7 is N, X 9 is CR 4 and X 10 and X 8 is C.
  • X 6 is S, X 9 is N, X 7 is CR 4 and X 10 and X 8 is C.
  • X 6 is S, X 10 is N, X 7 and X 9 is CR 4 and X 8 is C.
  • X 6 is S, X 8 is N, X 7 , X 9 is CR 4 and X 10 is C.
  • X 6 is S, X 7 and X 9 is N, X 10 and X 8 is C. In another embodiment, X 6 is S, X 7 and X 10 is N, X 9 is CR 4 and X 8 is C. In another embodiment, X 6 is S, X 7 and X 8 is N, X 9 is CR 4 , and X 10 is C. In another embodiment, X 6 is S, X 9 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 6 is S, X 9 and X 8 is N, and X 7 is CR 4 and X 10 is C.
  • X 6 is S, X 10 and X 8 is N, and X 7 and X 9 is CR 4 .
  • X 7 is S, X 6 is N, X 9 is CR 4 and X 10 and X 8 is C.
  • X 7 is S, X 9 is N, X 6 is CR 4 and X 10 and X 8 is C.
  • X 7 is S, X 10 is N, X 6 and X 9 is CR 4 and X 8 is C.
  • X 7 is S, X 8 is N, X 6 , X 9 is CR 4 and X 10 is C.
  • X 7 is S, X 6 and X 9 is N, and X 10 and X 8 is C.
  • X 7 is S, X 6 and X 10 is N, X 9 is CR 4 and X s is C.
  • X 7 is S, X 6 and X 8 is N, X 9 is CR 4 and X 10 is C.
  • X 7 is S, X 9 and X 10 is N, X 6 is CR 4 and X 8 is C.
  • X 7 is S, X 9 and X 8 is N, X 6 is CR 4 and X 10 is C.
  • X 7 is S, X 10 and X 8 is N, and X 6 and X 9 is CR 4 .
  • X 9 is S, X 6 is N, X 7 is CR 4 and X 10 and X 8 is C.
  • X 9 is S, X 7 is N, X 6 is CR 4 and X 10 and X 8 is C.
  • X 9 is S, X 10 is N, X 6 and X 7 is CR 4 and X 8 is C.
  • X 9 is S, X 8 is N, and X 6 , X 7 is CR 4 and X 10 is C.
  • X 9 is S, X 6 and X 7 is N, X 10 and X 8 is C. In another embodiment, X 9 is S, X 6 and X 10 is N, X 7 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 6 and X 8 is N, X 7 is CR 4 and X 10 is C. In another embodiment, X 9 is S, X 7 and X 10 is N, X 6 is CR 4 and X 8 is C. In another embodiment, X 9 is S, X 7 and X 8 is N, X 6 is CR 4 and X 10 is C.
  • X 9 is S, X 10 and X 8 is N, and X 6 and X 7 is CR 4 .
  • X 9 is S, X 8 and X 10 is N, and X 6 and X 7 is CR 4 .
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted
  • R 1 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 1 is selected from the group consisting of hydrogen, unsubstituted
  • heterocycloalkyl and unsubstituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 2 is absent or selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R 2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 2 is selected from the group consisting of hydrogen, unsubstituted
  • heterocycloalkyl and unsubstituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
  • R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl.
  • R 3 is selected from the group consisting bf hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.
  • R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl.
  • R 3 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 3 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 3 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 3 is selected from the group consisting of unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl.
  • R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 3 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R 4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 4 is selected from the group consisting of hydrogen, unsubstituted
  • heterocycloalkyl and unsubstituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 5 is selected from the group consisting of hydrogen, unsubstituted
  • heterocycloalkyl and unsubstituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
  • R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 6 is selected from the group consisting of unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl.
  • R 6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 6 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
  • R 7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 7 is selected from the group consisting of unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R 7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl.
  • R 7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R 7 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
  • R a is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 1 is optionally selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 2 is halogen.
  • Y is C and between Y and Z is a single bond.
  • R 3 is optionally selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkynyl.
  • R 2 and R 3 are taken together to form a ring selected from the group consisting of an optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
  • each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R 4 and R 5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle.
  • R b is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
  • R b is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, and optionally substituted cycloalkyl.
  • the compound is not 5-(4-cyclopropyl-lH-irnidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-4-methylbenzamide.
  • the compound is not (R)-5-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-2-fiuoro-4-methyl-N-(6-(4-( 1 -phenylethyl)- 4H-l,2,4-triazol-3-yl)pyridin-2-yl)benzamide.
  • the compound is not (S)-5-(4-cyclopropyl-l H-imidazol- l-yl)-2-fluoro-4-methyl-N-(6-(4-( 1,1,1 - trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)benzamide.
  • the compound is not (S)-5-(4-cyclopropyl-l H-imidazol- l-yl)-2-fluoro-4-methyl-N-(6-(4-( 1,1,1 - trifluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)benzamide.
  • the compound is not 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-4-methylbenzamide.
  • R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 23 and R 22 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
  • R 24 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 25 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl
  • each R 27 and R 28 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
  • R 29 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • s is 0-3.
  • the compound of Formula (VII) is of Formula (VIla)
  • the compound of Formula (VII) is of Formula (Vllb)
  • Ring D is a heterocycloalkyl
  • u is 0-4.
  • each R 30 is independently hydrogen, halogen, -CN, -OR 27 , -NR 2 'R 28 , or optionally substituted alkyl. In one embodiment of Formula (Vllb), each R 30 is
  • each R 30 is hydrogen.
  • u is 0.
  • u is 1.
  • u is 2.
  • the compound of Formula (VII) is of Formula (VIIc)
  • w is 0-2.
  • each R 31 is independently hydrogen, halogen, -CN, -OR 27 , -NR 27 R 28 , or optionally substituted alkyl. In one embodiment of Formula (VIIc), each R 31 is
  • each R 31 is hydrogen.
  • w is 0.
  • w is 1.
  • w is 2.
  • R 21 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 21 is an optionally substituted aryl.
  • R 21 is an optionally substituted phenyl.
  • R 21 is an optionally substituted heteroaryl.
  • R 21 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • R 21 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 21 is an optionally substituted imidazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 21 is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine.
  • R 21 is an optionally substituted pyridine. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 21 is an optionally substituted heteroaryl selected from imidazole, pyrazole, triazole, thiophene, and pyridine.
  • R 2 ' is optionally substituted with 1 or 2 R b ; and R b is halogen, - CN, -OR 27 , -NR 27 R 28 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 21 is optionally substituted with 1 or 2 R b ; and R b is halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • R 21 is optionally substituted with 1 R b ; and R b is cycloalkyl.
  • R 25 is an optionally substituted heteroaryl.
  • R 23 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • R 25 is optionally substituted 5-membered heteroaryl selected from triazole, tetrazole, and isoxazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 25 is an optionally substituted triazole.
  • R 25 is an optionally substituted 5/5 fused bicyclic heteroaryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 25 is an optionally nuhstitutcd 5/6 fu3cd bieyclic heteroaryl.
  • R 25 is optionally substituted with 1 or 2 R a ; and each R a is independently halogen, -CN, -OR 27 , -NR 27 R 28 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted
  • R 25 is optionally substituted with 1 or 2 R a ; and each R a is independently halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; or two R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
  • R is optionally substituted with 1 R a ; and R a is alkyl.
  • R is wherein: each X is independently N or CR a ;
  • Ring E is a 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl
  • alkyl optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-4.
  • Ring E is a 5- to 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
  • Ring E is a 5-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
  • Ring E is a 5-membered heterocycloalkyl.
  • Ring E is a 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
  • E is a 6-membered heterocycloalkyl.
  • Ring E is a 5- to 6- membered heteroaryl comprising 0-2 additional heteroatoms selected from N, O, and S.
  • Ring E is a 5-membered heteroaryl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), Ring E is a 6-membered heteroaryl comprising 0-2 additional heteroatoms selected from N.
  • Ring E is a 6-membered heteroaryl.
  • R is
  • R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-2.
  • s4 is 0 or 1. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s4 is 1. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s4 is 2. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s4 is 3. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s4 is 0-2. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s4 is 1 or 2.
  • X are both N. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), one X is N and the other is CR a . In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), X are both CR a .
  • each R a is independently hydrogen, halogen, -CN, -OR , -NR R , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • each R a is independently hydrogen, halogen, - CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • each R a is independently hydrogen, halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each R a is independently hydrogen or alkyl.
  • two R a on the same carbon form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
  • R is
  • R is hydrogen, halogen, -CN, - OR 27 , -NR 27 R 28 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 20 is hydrogen, halogen, or alkyl.
  • R 20 is hydrogen.
  • R 20 is hydrogen or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 20 is halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 20 is hydrogen or halogen.
  • R 22 is hydrogen, halogen, -CN, - OR 27 , -NR 27 R 28 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 22 is hydrogen, halogen, or alkyl.
  • R 22 is hydrogen or alkyl.
  • R 22 is hydrogen.
  • R 22 is alkyl.
  • R 24 is hydrogen or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 24 is hydrogen. [0182] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s is 0 or 1. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s is 0. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s is 1. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s is 0, 1, or 2. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), s is 2.
  • R 26 is halogen or alkyl.
  • R 27 and R 28 are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R 27 and R 28 are hydrogen. In one embodiment of Formula (VII), (VIla), (Vllb), or (VUc), R 29 is optionally substituted alkyl.
  • Y 1 is N or CR Y1 ;
  • R 43 and R 44 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
  • R 41 is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 45 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl
  • each R 47 and R 4S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R and R , together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
  • R 49 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • si is 0-3.
  • R 43 and R 44 are taken together with the atom to which they are attached to form an optionally substituted 5- or 6-membered heterocycloalkyl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form a 5- membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR 47 , -NR 47 R 48 , -C0 2 R 47 , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R ⁇ and R 44 are taken together with the atom to which they are attached to form a 5-membered heterocycloalkyl optionally substituted with oxo, halogen, or optionally substituted alkyl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form a 6-membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR 47 , -NR 47 R 48 , - C0 2 R 47 , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form a 6- membered heterocycloalkyl optionally substituted with oxo, halogen, or optionally substituted alkyl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form an optionally substituted 6-membered heteroaryl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR 47 , -NR 47 R 48 , -C0 2 R 47 , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 43 and R 44 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, or optionally substituted alkyl.
  • the compound of Formula (VIII) is of Formula (VIlla)
  • R 50 and R 51 are taken together with the atom to which they are attached to form an oxo.
  • R 50 and R 51 are independently hydrogen, halogen, -CN, - OR 47 , -NR 47 R 48 , or optionally substituted alkyl.
  • R 50 and R 51 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , alkyl, or haloalkyl.
  • R 50 and R 51 are hydrogen.
  • R 50 and R 51 are are taken together with the atom to which they are attached to form an oxo.
  • the compound of Formula (VIII) is of Formula (Vlllb)
  • R 50 and R 51 are taken together with the atom to which they are attached to form an oxo; or or R 52 and R 53 are taken together with the atom to which they are attached to form an oxo.
  • R 50 and R 51 are independently hydrogen, halogen, -CN, - OR 47 , -NR 47 R 48 , or optionally substituted alkyl.
  • R 50 and R 51 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , alkyl, or haloalkyl.
  • R 50 and R 51 are hydrogen.
  • R 50 and R 51 are are taken together with the atom to which they are attached to form an oxo.
  • R 52 and R 53 are independently hydrogen, halogen, -CN, - OR 47 , -NR 47 R 48 , or optionally substituted alkyl.
  • R 52 and R 53 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , alkyl, or haloalkyl.
  • R 52 and R 53 are hydrogen.
  • R 52 and R 53 are are taken together with the atom to which they are attached to form an oxo.
  • the compound of Formula (VIII) is of Formula (VIIIc)
  • s2 is 0-2.
  • each R 54 is independently hydrogen, halogen, -CN, - OR 47 , -NR 47 R 48 , or optionally substituted alkyl. In one embodiment of Formula (VIIIc), each R 54 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , alkyl, or haloalkyl. In one embodiment of Formula (VIIIc), each R 54 is hydrogen. In one embodiment of Formula (VIIIc), s2 is 0. In one embodiment of Formula (VIIIc), s2 is 1. In one embodiment of Formula (VIIIc), s2 is 2.
  • the compound of Formula (VIII) is of Formula (Vllld)
  • R 55 is hydrogen, halogen, -CN, -OR 47 , -NR 47 R 48 , or optionally substituted alkyl. In one embodiment of Formula (VHId), R 55 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , alkyl, or haloalkyl. In one embodiment of Formula (VHId), R 55 is hydrogen.
  • R 4 ' is optionally substituted monocyclic optionally substituted aryl or optionally substituted monocyclic heteroaryl.
  • R 41 is an optionally substituted aryl.
  • R 41 is an optionally substituted phenyl.
  • R 41 is an optionally substituted heteroaryl.
  • R 41 is an optionally substituted 5- membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • R 41 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene.
  • R 41 is an optionally substituted imidazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R 41 is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R 41 is an optionally substituted pyridine.
  • R 41 is an optionally substituted heteroaryl selected from imidazole, pyrazole, triazole, thiophene, and pyridine.
  • R 41 is optionally substituted with 1 or 2 R b ; and R b is halogen, -CN, -OR 47 , -NR 47 R 48 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 41 is optionally substituted with 1 or 2 R b ; and R b is halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • R 41 is optionally substituted with 1 R b ; and R b is cycloalkyl.
  • R is an optionally substituted heteroaryl.
  • R 45 is optionally substituted monocyclic heteroaryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R 45 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • R 45 is optionally substituted 5-membered heteroaryl selected from triazole, tetrazole, and isoxazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R 45 is an optionally substituted triazole.
  • R 45 is optionally substituted with 1 or 2 R a ; and R a is halogen, -CN, -OR 47 , -NR 47 R 48 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 45 is optionally substituted with 1 or 2 R a ; and R a is halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • R 45 is optionally substituted with 1 R a ; and R a is alkyl.
  • Y 1 is N.
  • Y 1 is CR Y1 and R Y1 is hydrogen, halogen, -CN, -OR 47 , - NR 47 R 48 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • Y 1 is CR YI and R Yl is hydrogen, halogen, or alkyl.
  • Y l is CR Y1 and R Y1 is hydrogen.
  • Y 1 is CR Y1 and R Y1 is hydrogen or alkyl.
  • Y 1 is CR YI and R Y1 is halogen or alkyl.
  • Y 1 is CR YI and R Y1 is hydrogen or halogen.
  • R 40 is hydrogen, halogen, - CN, -OR 47 , -NR 47 R 48 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 40 is hydrogen, halogen, or alkyl.
  • R 40 is hydrogen.
  • R 40 is hydrogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R 40 is halogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), R 40 is hydrogen or halogen.
  • R is hydrogen, halogen, - CN, -OR 47 , -NR 47 R 48 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 42 is hydrogen, halogen, or alkyl.
  • R 42 is hydrogen or alkyl.
  • R 42 is hydrogen. In one embodiment of Formula (VIII), (Vina), (Vlllb), or (VIIIc), R 42 is alkyl.
  • si is 0 or 1. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), si is 0. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), si is 1. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (Vine), si is 0, 1, or 2. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), si is 2.
  • R 46 is halogen or alkyl.
  • R 47 and R 48 are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (Vine), R 47 and R 48 are hydrogen. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIUc), R 49 is optionally substituted alkyl.
  • Y 2 is N or CR Y2 ;
  • Y 2 is NR Y3 ;
  • R 63 is O or S
  • R Y3 is hydrogen or optionally substituted alkyl
  • R 64 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, . optionally substituted aryl, or optionally substituted heteroaryl;
  • R 63 and R 64 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
  • R 65 is optionally substituted fused bicyclic heterocycloalkyl or optionally substituted fused bicyclic heteroaryl;
  • each R 67 and R 68 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 67 and R 68 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
  • R 69 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • s3 is 0-3. [0206] In one embodiment of Formula (IX), In one embodiment of
  • Formula (IX), and Y 2 is In one embodiment of Formula (IX),
  • R63 is hydrogen, halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted
  • alkyl optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl,
  • Formula (IX) Y is NR Y3 ; and R is optionally substituted alkyl. In one 63
  • R 63 is S.
  • R 61 is -OR 67 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 61 is an optionally substituted aryl.
  • R 61 is an optionally substituted phenyl.
  • R 61 is an optionally substituted heteroaryl.
  • R 61 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, or isoxazole.
  • R 61 is an optionally substituted 5- membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene.
  • R is an optionally substituted imidazole.
  • R is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine.
  • R 61 is an optionally substituted pyridine.
  • R 61 is optionally substituted with 1 or 2 R b ; and each R b is independently halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 61 is optionally substituted with 1 or 2 R b ; and each R b is independently halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • R 61 is optionally substituted with 1 R b ; and R b is cycloalkyl.
  • R 60 is hydrogen, halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 60 is hydrogen, halogen, or alkyl. The compound of any one of claims 1-27, wherein R 60 is hydrogen.
  • R 62 is hydrogen, halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • R 62 is hydrogen, halogen, or alkyl.
  • R 62 is hydrogen or alkyl.
  • R 62 is alkyl.
  • R 64 is hydrogen or alkyl.
  • R 63 and R 64 are taken together with the atom to which they are attached to form an optionally substituted 5- or 6-membered heterocycloalkyl.
  • R 63 and R 64 are taken together with the atom to which they are attached to form a 5- membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR 67 , -NR 67 R 68 , -C0 2 R 67 , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 63 and R 64 are taken together with the atom to which they are attached to form a 6-membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR , -NR R , -C0 2 R , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • R 63 and R 64 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, - OR 67 , -NR 67 R 68 , -C0 2 R 67 , optionally substituted alkyl, or optionally substituted heteroalkyl.
  • s3 is 0 or 1. In one embodiment of Formula (IX), s3 is 0. In one embodiment of Formula (IX), s3 is 1. In one embodiment of Formula (IX), s3 is 2. In one embodiment of Formula (IX), s3 is 3.
  • R 66 is hydrogen, halogen, or alkyl. In one embodiment of Formula (IX), R 66 is hydrogen.
  • R 65 is an optionally substituted 5/5 fused bicyclic heteroaryl. In one embodiment of Formula (IX), R 65 is an optionally substituted 5/6 fused bicyclic heteroaryl.
  • R 65 is optionally substituted with 1 or 2 R a ; and each R a is independently halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; or two R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
  • R 65 is optionally substituted with 1 or 2 R a ; and each R a is independently halogen, -CN, - OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; or two R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
  • R 65 is optionally substituted with 1 R a ; and R a is alkyl.
  • R is wherein:
  • each X is independently N or CR a ;
  • Ring E is a 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl
  • R a form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-4.
  • Ring E is a 5- to 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (IX), Ring E is a 5- membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (IX), Ring E is a 5-membered heterocycloalkyl. In one embodiment of Formula (IX), Ring E is a 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (IX), E is a 6-membered heterocycloalkyl.
  • Ring E is a 5- to 6-membered heteroaryl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (IX), Ring E is a 5-membered heteroaryl comprising 0- 2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (IX), Ring E is a 6- membered heteroaryl comprising 0-2 additional heteroatoms selected from N.
  • Ring E is a 6-membered heteroaryl.
  • R is
  • s4 is 0 or 1. In one embodiment of Formula (IX), s4 is 1. In one embodiment of Formula (IX), s4 is 2. In one embodiment of Formula (IX), s4 is 3. In one embodiment of Formula (IX), s4 is 0-2. In one embodiment of Formula (IX), s4 is 1 or 2.
  • X are both N. In one embodiment of Formula (IX), one X is N and the other is CR a . In one embodiment of Formula (IX), X are both CR a .
  • each R a is independently hydrogen, halogen, -CN, -OR 67 , -NR 67 R 68 , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • each R a is independently hydrogen, halogen, -CN, -OH, -NH 2 , alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
  • each R a is independently hydrogen, halogen, or alkyl.
  • each R a is independently hydrogen or alkyl.
  • two R a on the same carbon form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
  • R is
  • R and R are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (IX), R 67 and R 68 are hydrogen. In one embodiment of Formula (IX), R 69 is optionally substituted alkyl.
  • the compound is selected from the following compounds:
  • the compound is selected from the following compounds:
  • composition refers to a preparation of one or more of the components described herein, or pharmaceutically acceptable salts thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to a patient or subject.
  • excipient refers to an inert or inactive substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the present teachings further comprise pharmaceutical compositions comprising one or more of the compounds of the present disclosure.
  • a pharmaceutical composition comprises one or more of the compounds of the present disclosure and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of disclosed herein and at least one pharmaceutically acceptable carrier.
  • compositions are administered to humans, human patients or subjects.
  • active ingredient generally refers to a compound to be delivered as a compound described herein.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, eye drop or an ear drop.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals.
  • Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, non-human mammals, including cattle, pigs, cats, dogs, mice, and rats.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's
  • compositions comprising a compound described herein, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds described are administered as pharmaceutical compositions in which compounds described herein, are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include one or more compounds described herein.
  • one or more compounds described herein is formulated in an aqueous solutions.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • one or more compound described herein is formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or nonaqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • compounds described herein are formulated for oral administration.
  • Compounds described herein, including compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push-fit capsules contain the active ingredients in admixture with one or more filler.
  • Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers.
  • Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions comprising a compound described herein are formulated in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds are prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.
  • the compounds described herein are administered topically.
  • the compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the transdermal delivery of the compounds described herein is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of the compounds described herein.
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compounds described herein are formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders.
  • Pharmaceutical compositions comprising a compound described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g. , dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds described herein are formulated in rectal
  • compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used
  • compositions comprising a compound described herein are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions include at least one pharmaceutically acceptable. carrier, diluent or excipient and at least one compound described herein as an active ingredient.
  • the active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein.
  • the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
  • compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • composition comprising at least one compound described herein, illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix.
  • a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
  • useful aqueous suspension contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound described herein.
  • the term "solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as
  • citrate/dextrose sodium bicarbonate and ammonium chloride.
  • Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g. , polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • compositions include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • aqueous suspension compositions are packaged in single-dose non- reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • the present disclosure provides methods comprising administering compounds of the disclosure to a subject in need thereof.
  • Compounds as described herein may be administered to a subject using any amount and any route of administration effective for treating a disease, a disorder, or a condition (e.g., a disease, a disorder, or a condition relating to gram-negative bacterial infections).
  • compositions in accordance with the disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective or prophylactically effective dose level for any particular subject will depend upon a variety of factors including the species, age, body weight, general health, sex and diet of the subject; the disorder or disease being treated and the severity of the disorder or disease; the activity of the specific compound employed; the specific composition employed; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • described herein is a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein.
  • the disease is selected from the group consisting of a blood disease, an autoimmune disorder, a pulmonary disorder, hypertension, an inflammatory disease, a fibrotic disease, diabetes, diabetic nephropathy, a renal disease, a respiratory disease, a cardiovascular disease, acute lung injury, acute or chronic liver disease, and a neurodegenerative disease.
  • the liver disease is selected from the group consisting of fascioliasis, hepatitis, non-alcoholic steatohepatitis (NASH) with or without fibrosis, hepatic steatosis, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, Alagille syndrome, biliary atresia, galactosemia, gallstones, hemochromatosis, liver cancer, lysosomal acid lipase deficiency (LALD), porphyria, acetaminophen hepatotoxicity, Reye's syndrome, sarcoidosis, tyrosinemia, Wilson disease, Gilbert's syndrome, cirrhosis and primary sclerosing cholangitis.
  • fascioliasis hepatitis
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • fatty liver disease FLD
  • the liver disease is non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the liver disease is acute liver injury.
  • the liver disease is hepatic steatosis.
  • the pulmonary disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, bronchitis, emphysema, lung cancer, pneumonia, cystic fibrosis, pulmonary embolism, pulmonary arterial hypertension, pulmonary edema and pulmonary hemorrhage.
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • asthma bronchitis
  • emphysema emphysema
  • lung cancer pneumonia
  • cystic fibrosis pulmonary embolism
  • pulmonary arterial hypertension pulmonary edema
  • pulmonary hemorrhage
  • the autoimmune disorder is selected from the group consisting of alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, myocarditis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, granulomatosis with polyangiitis (Wegener's).
  • the inflammatory disease is selected from the group consisting of Alzheimer's, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), atherosclerosis, arteriosclerosis, cholestasis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, cardiac inflammation, and ulcerative colitis.
  • arthritis osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis
  • atherosclerosis arteriosclerosis
  • cholestasis cholestasis
  • Crohn's disease colitis
  • dermatitis diverticulitis
  • fibromyalgia irritable bowel syndrome
  • SLE systemic lupus erythematous
  • nephritis Parkinson
  • the renal disease is selected from the group consisting of Alport syndrome, renal fibrosis, kidney disease, diabetic nephropathy, fabry disease, diabetic kidney disease, diabetic nephropathy, renal inflammation, renal fibrosis focal segmental glomerulosclerosis, glomerulonephritis, IgA nephropathy (Berger's disease), kidney stones, minimal change disease, nephrotic syndrome, and polycystic kidney disease (PKD).
  • Alport syndrome renal fibrosis
  • kidney disease diabetic nephropathy
  • fabry disease diabetic kidney disease
  • diabetic nephropathy diabetic nephropathy
  • renal inflammation renal fibrosis focal segmental glomerulosclerosis
  • glomerulonephritis IgA nephropathy (Berger's disease)
  • kidney stones minimal change disease
  • nephrotic syndrome nephrotic syndrome
  • PPD polycystic kidney disease
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, multiple sclerosis, optical neuritis, amyotrophic lateral sclerosis, Friedreich's ataxia, amyotrophic lateral sclerosis (ALS), Huntington's disease, Lewy body disease, Parkinson's disease and spinal muscular atrophy.
  • the neurodegenerative disease is multiple sclerosis.
  • the neurodegenerative disease is amyotrophic lateral sclerosis.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease is Parkinson's disease.
  • the cardiovascular disease is selected from the group consisting of endothelial dysfunction, metabolic syndrome, atherosclerosis, coronary artery disease, heart failure, peripheral artery disease, cardiac inflammation, cardiac fibrosis, cerebrovascular disease and coronary syndrome.
  • the blood disease is sickle cell disease.
  • described herein is a method for reducing neuronal cell death following ischemic injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein.
  • described herein is a method for modulating platelets in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein.
  • the compound modulates platelet activation, platelet granule secretion, thromboxane A2 generation, or thrombosis modulation.
  • described herein is a method for modulating the level of a reactive oxidative species in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein.
  • the oxidative species is a reactive oxygen species. In another embodiment, the oxidative species contains a radical on the oxygen atom.
  • the disease is a cancer. In one embodiment, the disease is a Sickle cell disease. In one embodiment, the disease is a renal fibrosis. In one embodiment, the disease is a kidney disease. In one embodiment, the disease is a function of oxidative stress. In one embodiment, the disease is liver ischemia.
  • the compounds disclosed herein are prepared as a pharmaceutically acceptable acid addition salt (which is a type of a pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane
  • inorganic acids such as
  • pharmaceutically acceptable refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a formulation 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.
  • pharmaceutically acceptable salts are obtained by reacting a compound the compounds disclosed herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • salts are also obtained by reacting a compound the compounds disclosed herein 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-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • 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-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • the compounds disclosed herein are prepared as a pharmaceutically acceptable salts by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine,
  • diethanolamine triethanolamine, tromethamine, N-methylglucamine, and the like, or with an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are optionally formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • hydrates of compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, ethanol, or methanol.
  • organic solvents including, but not limited to, dioxane, tetrahydrofuran, ethanol, or methanol.
  • 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.
  • the compounds disclosed herein are prepared in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms.
  • compounds the compounds disclosed herein include crystalline forms, also known as polymorphs.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the compounds disclosed herein are prepared as prodrugs.
  • a "prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. In certain embodiments, the prodrug of a compound described herein is bioavailable by oral administration whereas the parent is not. Furthermore, in some embodiments, the prodrug of a compound described herein has improved solubility in pharmaceutical compositions over the parent drug.
  • prodrugs are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
  • the design of prodrugs to date is to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent.
  • appropriate prodrugs are prepared by reacting a non- derivatized compounds disclosed herein with a suitable carbamylating agent, such as, but not limited to,
  • sites on the aromatic ring portion of any compounds disclosed herein are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds disclosed herein possess one or more stereocenters and each center exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • compounds disclosed herein are prepared as their individual stereoisomers.
  • compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent
  • dissociable complexes are utilized (e.g., crystalline diastereomeric salts).
  • Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are, in specific embodiments, separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds provided herein exist as geometric isomers.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein exist as tautomers. All tautomers are intended to be within the scope of the molecular formulas described herein.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are envisioned.
  • Example la (10.0 g, 71.87 mmol) and NIS (21.0 g, 93.43 mmol) in DMF (125 mL) was stirred at room temperature for 1 h and at 50°C for 20 h. Most of DMF was removed in vacuo and water (150 mL) was added to the mixture. The mixture was stirred at 0°C for 1 h and filtered. The cake was washed with water (30 mL*3). The solid was suspended in MeOH (100 mL) and stirred at room temperature for 2 h, filtered, washed with MeOH (15 mL) and dried in vacuo to afford the desired product Example lb (16.7 g, 88% yield) as a yellow solid.
  • LC-MS [M+H] + 265.9
  • Example lb (1.00 g, 3.77 mmol)
  • Example lc (0.51 g, 4.72 mmol) and Cs 2 C0 3 (3.69 g, 11.32 mmol) in DMF (12.5 mL)
  • Cul 72 mg, 0.37 mmol
  • (1R,2S)-N',N 2 - dimethylcyclohexane-l,2-diamine 107 mg, 0.75 mmol
  • the reaction mixture was heated to 130°C and stirred for 16 h.
  • the reaction mixture was cooled to room temperature and diluted with MeOH and filtered.
  • the cake was washed with MeOH and the filtrate was concentrated to afford crude product Example Id (1.00 g, containing DMF, crude yield >100%), which was used for the next step without further purification.
  • LC-MS [M+H] + 246.0
  • Example lg (282 mg, 1.39 mmol), DIEA (996 mg, 7.70 mmol), DMAP (19 mg, 0.15 mmol) and HATU (880 mg, 2.31 mmol) in DMF (15 mL) was heated to 40°C and stirred for 16 h.
  • Example 2a To a solution of Example 2a (2.0 g, 11.5 mmol) in DCM (50 mL) was added TEA dropwise (4.8mL, 34.4 mmol) at 5 °C. Thenisobutyryl chloride (1.4 mL,13.4mmol)was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. TLC showed the starting materiall was consumed, and a new point was formed. The mixture was diluted with EtOAc (150 mL), washed with aq. NH 4 C1, brine, dried over anhydrous Na 2 SC> 4 . The solvent was removed under reduced pressure. The residue was purified by biotage-flash to afford 2.1 g of the title compound. Yield: 75.1%.
  • Example 2b (1.85 g, 7.6 mmol) was dissolved in CH 3 CN (20 mL), and SiCL, (9.2 mL, 80.1 mmol) was added dropwise, followed by NaN 3 (8.17g, 125.7mmol). Then the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was added to a solution of sodium carbonate in water slowly. The suspension was stirred for 1 hour, and then diluted with 300 mL of ethyl acetate. The water phase and the suspension were separated, and extracted with 200 mL of EA. The combined organic phase was washed with water, brine, and dried over anhydrous Na 2 S0 4 . The solvent was removed under reduced pressure, and the residue was purified by biotage flash to afford 1.46 g of white solid.
  • Example 2c 54 mg, 0.20 mmol
  • tert-Butyl carbamate 67 mg, 0.57 mmol
  • Pd(AcO) 2 5 mg, 0.02 mmol
  • BINAP 25 mg, 0.04 mmol
  • Example 2d To a solution of Example 2d (52 mg, 0.17 mmol) in 1 mL of DCM was added TFA (0.2 mL, 2.7 mmol) dropwise. Then the reaction mixture was stirred at room temperature for 4 hours. TLC showed the reaction was completed. The reaction mixture was concentrated to afford 45 mg of yellow oil. The oil was used at next step without further purification.
  • Example 2f (210 mg, 0.81 mmol) in SOCl 2 (3 mL, 41.3 mmol) was heated to refluxed, stirred for 1.5 hours. Then the reaction mixture was concentrated. The obtained white solid was added to a solution of Example 2e (150 mg, 0.73 mmol) and TEA (0.4 mL, 2.9 mmol) in DCM in portions. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was diluted with DCM, and washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure.
  • Example 3d To a solution of Example 3d (800 mg,3.9 mmol) in DCM (50 mL) was added m-CPBA(l g, 5.9 mmol), The mixture was stirred at room temperature for 18h. Water (5 mL) was added to the mixture, then extracted with DCM (50 mL*2) and combined the organic phase, washed with brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give the crude product and further purified by silica chromatography to give the product 200mg as a yellow solid.
  • Example 3j 600 mg, 2.4 mmol
  • Example 3i 400 mg, 3.6 mmol
  • Cul 45 mg, 0.24 mmol
  • K 3 P0 4 (1 g, 4.8 mmol)
  • TBAB 486 mg, 1.2 mmol
  • Example 3k 210 mg, 0.77 mmol
  • DIEA 200.6 mg, 1.54 mmol
  • HBTU 410 mg, 1.15 mmol
  • Example 5d (444 mg, 2.0 mmol)and tert-butyl carbamate (370 mg, 3.16 mmol) in 6 mL of toluene wereadded Pd(OAc) 2 (23 mg, 0.1 mmol), BINAP (146 mg, 0.2 mmol), Cs 2 C0 3 (914 mg, 2.8 mmol) , and then stirred at 100 °C overnight.
  • the mixture was diluted by DCM, washed with water, dried and stripped of solvent. The residue was purified by flash chromatography to give product Example 5f (550 mg yield: 91%).
  • LCMS [M+l] + 304.0
  • Example 5j To a solution of Example 5j (92 mg, 0.35 mmol) in 5mL of DMF were added isobutyl carbonochloridate (61 mg, 0.44 mmol) and Et3N (101 mg, 1.0 mmol) at 0 °C and stirred for lh. Then added Example 5i (102 mg, 0.5 mmol) and stirred 100oC for 4h. The mixture was diluted by DCM, washed with water, dried and stripped of solvent.
  • Example 6a (5.00 g, 36.47 mmol) and NIS (9.55 g, 42.44 mmol) in DMF (50 mL) was stirred at room temperature for 1 h and at 50°C for 48 h. The reaction mixture was cooled to room temperature and poured into water (150 mL) with stirring and filtered. The cake was washed with water (30 mL*3) and dried in vacuo to afford the desired product Example 6b (7.8 g, yield 86% ) as a yellow solid.
  • LC-MS [M+l] + 280
  • Example 6b To a suspension of Example 6b (1.00 g, 3.58 mmol), Example lc (483 mg, 4.48 mmol) and Cs 2 C0 3 (3.50 g, 10.75 mmol) in DMF (12.5 mL) was added Cul (68 mg, 0.36 mmol) and (1R,2S)-N',N 2 - dimethylcyclohexane-l,2-diamine (112 mg, 0.79mmol) under N 2 at room temperature. The reaction mixture was heated to 130°C and stirred for 10 h. The reaction mixture was cooled to room temperature and diluted with MeOH (20 mL) and filtered.
  • Example 6d To a mixture of Example 6d (70 mg, 0.24 mmol) in MeOH (4.0 mL) was added a solution of NaOH (39 mg, 0.97 mmol) in water (1.0 mL) at room temperature, which was stirred for 4 h. The mixture was concentrated under reduced pressure and water was added. The resulting solution was extracted with EtOAc (10 mL*4). The aqueous layer was adjusted with aqueous HC1 solution (2.0 N) to pH about 4, and then concentrated to afford the crude product Example 6e (66 mg, crude yield 100%) as a white solid.
  • LC-MS [M+l] + 274
  • Example 6e A mixture of Example 6e (66 mg, 0.24 mmol), Example lg (44 mg, 0.22 mmol), DIEA (156 mg, 1.21 mmol), DMAP (3 mg, 0.024 mmol) and HATU (138 mg, 0.36 mmol) in DMF (3 mL) was heated to 45°C and stirred for 16 h.
  • LC-MS [M+l] + 459.0
  • Example 7a (12.5 g, 87.07 mmol) and con.HCl (30mL) in 100 mL of water and 50 mL of ether was cooled to 0 °C.
  • a solution of NaNC>2 (9.6 g, 175 mmol)in 10 mL of water was added dropwise, the temperature was maintained below 5 °C at which the reaction was allowed to proceed for 2 hours , and then the organic phase was separated. The aqueous phase was extracted with ether. The ether solution were combined, washed with water, dried over Na 2 S0 4 and stripped of solvent. The residue was purified by flash chromatography (PE/EA 4/1) to give product Example 7b (10.0 g, yield: 75%).
  • LCMS [M+l] + 155.0

Abstract

Selon l'invention, l'activation et la signalisation de la kinase 1 de régulation du signal apoptotique jouent un rôle important dans une vaste gamme de maladies comprenant les troubles neurodégénératifs, cardiovasculaires, inflammatoires, auto-immuns et métaboliques. L'invention concerne la synthèse d'agents thérapeutiques issus de pyridinyle servant d'inhibiteurs de ASK1, ainsi que des compositions pharmaceutiques et des méthodes d'utilisation associées.
PCT/US2018/000044 2017-02-17 2018-02-16 Inhibiteurs de kinase de régulation du signal apoptotique à base de pyridinyle WO2018151830A1 (fr)

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