WO2018151830A1 - Pyridinyl based apoptosis signal-regulation kinase inhibitors - Google Patents

Pyridinyl based apoptosis signal-regulation kinase inhibitors Download PDF

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Publication number
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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French (fr)
Inventor
Bohan Jin
Qing Dong
Gene Hung
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Fronthera U.S. Pharmaceuticals Llc
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Publication of WO2018151830A1 publication Critical patent/WO2018151830A1/en

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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

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. Disclosed herein is the synthesis of pyridinyl derived therapeutic agents that function as inhibitors of ASK 1 as well as their pharmaceutical compositions and methods of use.

Description

PYRIDINYL BASED APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS
CROSS-REFERENCE
[0001] This patent application claims the benefit of US Provisional Application No. 62/460,527, filed February 17, 2017; US Provisional Application No. 62/531,336, filed July 11, 2017, and US Provisional Application No. 62/621,374, filed January 24, 2018; each of which is incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] 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. In addition, 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.
SUMMARY OF THE INVENTION
[0003] In one aspect, provided herein are compounds having the structure of Formula (IX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000002_0001
R63 is hydrogen, halogen, -CN, -OR , -SR67, -S(=0)R69, -N02, -NR R , -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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; and
RY2 is hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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
Figure imgf000003_0001
Y2 is NRY3;
R63 is O or S; and
RY3 is hydrogen or optionally substituted alkyl;
R60, R61, and R62 are independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, - NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, - C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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;
R64 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;
or R63 and R64 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R65 is optionally substituted fused bicyclic heterocycloalkyl or optionally substituted fused bicyclic heteroaryl;
each R66 is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -0C02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
each R67 and R68 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 R67 and R68, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R69 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; and
s3 is 0-3.
DETAILED DESCRIPTION OF THE INVENTION
Chemical Terminology
[0004] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to." Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
[0005] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term
"or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
[0006] The terms below, as used herein, have the following meanings, unless indicated otherwise:
[0007] "Amino" refers to the -NH2 radical.
[0008] "Cyano" refers to the -CN radical.
[0009] "Hydroxy" or "hydroxyl" refers to the -OH radical.
[0010] "Nitro" refers to the -N02 radical.
[0011] "Oxo" refers to the =0 substituent.
[0012] "Thioxo" refers to the =S substituent.
[0013] "Imido" refers to the =NR| wherein R; is hydrogen, alkyl, alkoxy, hydroxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and heteroaryl.
[0014] "Alkoxy" refers to a radical of the formula -ORj where Rj is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below.
[0015] "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 alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" or "C| -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. Unless stated otherwise specifically in the specification, 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.
[0016] "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. Examples include, but are not limited to ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 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. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted as described below.
[0017] "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. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 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.
[0018] "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.
[0019] "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.
[0020] "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.
[0021] "Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. As used herein, 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) π-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.
[0022] "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,
bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise stated specifically in the specification, a cycloalkyl or carbocycle group may be optionally substituted.
[0023] "Fused" refers to any ring structure described herein which is fused to an existing ring structure. When 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.
[0024] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
[0025] "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,
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
[0026] "Haloalkoxy" similarly refers to a radical of the formula -ORa where Ra is a haloalkyl radical as defined. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted as described below.
[0027] "Perhalo" or "perfluoro" refers to a moiety in which each hydrogen atom has been replaced by a halo atom or fluorine atom, respectively. [0028] "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. Unless stated otherwise specifically in the specification, 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. Examples of such 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,
1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 12-crown-4, 15-crown-5, 18-crown-6, 21-crown-7, aza-18-crown-6, diaza-18-crown-6, aza-21-crown-7, and diaza-21-crown-7. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted. The term 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. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, 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.
[0029] "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. As used herein, 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) π-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. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of 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,
1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,
5,6,6a,7,8,9, 10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
5.6.7.8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted as described below.
[0030] All the above groups may be either substituted or unsubstituted. The term "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. Unless stated specifically in the specification, a substituted group may include one or more substituents selected from: halogen, oxo, amino, -CO2H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N+R3), 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,
trifluoromethyl or trifluoromethoxy. In some embodiments, the substituent group one or more substituents selected from: halogen, oxo, amino, -CO2H, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, or heteroaryl. In some embodiments, 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. For example,
"substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with - NH2, -NRgC(=0)NRgRh, -NRgC(=0)ORh, -NRgS02Rh, -OC(=0)NRgRh, -ORg, -SRg, -SORg, -S02Rg, - OS02Rg, -S02ORg, =NS02Rg, and -S02NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, cycloalkyl, haloalkyl, heterocyclyl and heteroaryl. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents. Furthermore, any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms. For example, an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group. Similarly, an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents. In some embodiments, optional substituents are independently selected from hydrogen, halogen, -CN, -OH, -N02, -N(R12)-R13, -C(=0)-N(R12)-R13, -NR12C(=0)R", -C(=0)-0-R", - O- C(=0)-R", -BR12, -S(=0)R", -S(=0)2RU, -N(R,2)S(=0)2R", -S(=0)2-N(R12)-R13, -C(=0)Ru, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; each of R12 and R13 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted
heterocycloalkyl; R15 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. In some embodiments, optional substituents are independently selected from hydrogen, halogen, -CN, -OH, -N02, -N(R12)-R13, -C(=0)-N(R12)-R13, - NR12C(=0)R", -C(=0)-0-R", - 0-C(=0)-R", -SR12, -S(=0)Rn, -S(=0)2RU, -N(RI2)S(=0)2RU, - S(=0)2-N(R,2)-R13, -C(=0)R13, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl; each of R12 and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl; or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl; R15 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl.
[0031] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2C¾, -CFHCHF2) etc). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, 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.
[0032] The terms "co-administration" or the like, as used herein, 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.
[0033] The terms "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. For example, 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.
[0034] 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. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
[0035] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.
[0036] The terms "treat," "treating" or "treatment," as used herein, 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.
[0037] 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:
Figure imgf000011_0001
[0038] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
[0039] "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 base addition salts.
[0040] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a
pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, 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. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al, Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook o Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.
[0041] 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. Compounds of the Disclosure
[0042] In one aspect, provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000012_0001
wherein:
Figure imgf000012_0002
wherein:
each X1, X2, X3, X4 and X5 is independently N, S, O or CR4; provided that at least one X1, X2, X3, X4 and X5 is N, S, C or O;
each Ra 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 is 0-3;
Ring B is
Figure imgf000012_0003
wherein:
Z is N or C;
Y is N or C;
W is N or C;
is a single or double bond;
Figure imgf000012_0004
R1 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; and
R2 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)-R5, -C(=0)-0-R4, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R2 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Y is C and = between Y and Z is a single bond; or
R1 and R2 are taken together to form -Rc- such that -Rc- is selected from the group consisting of - (CR4R5)„-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m-(CR4R5)t -, -NR4-(CR4R5)n-, -(CR4R5)n-NR4-, - (CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)n-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, -(CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)- (CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)n-C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n- C(=0)-0-(CR4R5)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, -(CR4R5)n-S-(CR4R5)m-, -S(0)v-, -S(0)v-(CR4R5)n-, - (CR4R5)n-S(0)v-, -0-, -(CR4R5)n-0-,-0-(CR4R5)n-, -(CR4R5)n-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,- C(=0)-(CR4R5)„-, and -(CR4R5)n-C(=0)-(CR4R5)m-;
n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R3 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Z is C, between Y and Z is a single bond, and between CR6 and Z is a single bond; or
R2 and R3 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 R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 -(Rb)q;
Figure imgf000014_0001
wherein:
each X6, X7, X8, X9 and X10 is independently N, S, O or CR4; provided that at least one X6, X7, X8, X9 and X10 is N, S, C or O;
Rb 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;
q is 0-3;
provided that when Ring A is
Figure imgf000014_0002
and bound to the 6' position of the pyridine, Ring B is
bound to the 2' position of the pyridine, Ring C is
Figure imgf000014_0003
and bound para to Y, Y is C, Z is C and
R1 is H, then R2 and R3 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 the case where Ring A is and bound to the 6' position of the pyridine, then Y is C,
Figure imgf000014_0004
between Y and Z is a double bond and R2 is not hydrogen or methyl; 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.
[0043] In some embodiments of Formula (I), 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. In some embodiments of Formula (I), Ring C is imidazole, pyrazole, triazole, or thiophene. In some embodiments of Formula (I), 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.
[0044] In some embodiments of a compound of Formula (I), 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.
[0046] In some embodiments of Formula (I), Ring C is positioned para to Y.
[0047] In some embodiments of a compound of Formula (I), each Ra is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. In some embodiments of a compound of Formula (I), Ra is optionally substituted cycloalkyl.
[0048] In some embodiments of a compound of Formula (I), each Rb is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. In some embodiments of a compound of Formula (I), Rb is optionally substituted alkyl.
[0049] In some embodiments of a compound of Formula (I), 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.
[0050] In some embodiments of a compound of Formula (I), 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.
[0051] In some embodiments of a compound of Formula (I), between W and CR6 is a double bond, between CR6 and Z is a single bond, between Z and Y is a double bond, and W is C.
[0052] In some embodiments of a compound of Formula (I), Z is N and R3 is absent. In some embodiments of a compound of Formula (I), Z is C.
[0053] In some embodiments of a compound of Formula (I), Y is N and R2 is absent. In some embodiments of a compound of Formula (I), Y is C.
[0054] In some embodiments of a compound of Formula (I), R' is selected from the group consisting of hydrogen and optionally substituted alkyl.
[0055] In some embodiments of a compound of Formula (I), R2, when present, is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
[0056] In some embodiments of a compound of Formula (I), R1 and R2 are taken together to form -R°- such that -R°- is selected from the group consisting of -(CR4R5)„-, -(CR4=CR5)m-, -N=N-, -N=CR4-, - CR4=N-, and -C(=0)-.
[0057] In some embodiments of a compound of Formula (I), 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.
[0058] In some embodiments of a compound of Formula (I), 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.
[0059] In some embodiments of a compound of Formula (I), R3, whenpresent, is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl. [0060] In some embodiments of a compound of Formula (I), R2 and R3 are taken together to form an optionally substituted carbocycle. In some embodiments of a compound of Formula (I), R2 and R3 are taken together to form an optionally substituted heterocycle. In some embodiments of a compound of Formula (I), R2 and R3 are taken together to form an optionally substituted aryl. In some embodiments of a compound of Formula (I), R2 and R3 are taken together to form an optionally substituted heteroaryl.
[0061] In some embodiments of a compound of Formula (I), R6 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl. In some embodiments of a compound of Formula (I), R7 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.
[0062] In some embodiments of a compound of Formula (I), R3 and R6 are taken together to form an optionally substituted carbocycle. In some embodiments of a compound of Formula (I), R3 and R6 are taken together to form an optionally substituted heterocycle. In some embodiments of a compound of Formula (I), R3 and R6 are taken together to form an optionally substituted aryl. In some embodiments of a compound of Formula (I), R3 and R6 are taken together to form an optionally substituted heteroaryl.
[0063] In another aspect, provided herein are compounds having the structure of Formula (II), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
R3 (Formula II)
wherein:
each X1, X2, X3 and X4 is independently N, S, O or CR4;
X5 is N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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 is 0-3;
Z is N or C;
Y is N or C;
W is N or C;
is a single or double bond;
R1 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; and
R2 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)-R5, -C(=0)-0-R4, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R2 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Y is C and between Y and Z is a single bond; or
R1 and R2 are taken together to form -Rc- such that -Rc- is selected from the group consisting of - (CR4R5)n-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m-(CR4R5), -, -NR4-(CR4R5)n-, -(CR4R5)n-NR4-, - (CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)n-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, -(CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)- (CR4R5)„-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)n-C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n- C(=0)-0-(CR4R5)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, -(CR4R5)n-S-(CR4R5)m-, -S(0)v-, -S(0)v-(CR4R5)n-, - (CR4R5)n-S(0)v-, -0-, -(CR4R5)n-0-,-0-(CR4R5)n-, -(CR4R5)n-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,- C(=0)-(CR4R5)n-, and -(CR4R5)n-C(=0)-(CR4R5)m-;
n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R3 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Z is C, =^=-= between Y and Z is a single bond, and
Figure imgf000017_0001
between CR6 and Z is a single bond; or
R2 and R3 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 R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R\ -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7, X 9 and X10 is each independently N, S, O or CR4;
Xs is N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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;
q is 0-3;
in the case where X1, X2, X4, X6 and X8 are N, X3, X5, X7, X9 and X10 are C, Ra is isopropyl, Rb is cyclopropyl, R1 is H, X4 is bonded to Ra, and X10 is bonded to Rb, then R2 and R3 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 the case where Χ', Χ2 and X4 are N, X3 and X5 are C, X4 is bonded to Ra, and Ra is cyclopropyl, then Y is C, between Y and Z is a double bond and R2 is not hydrogen or methyl; 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.
[0064] In some embodiments of Formula (II), p is 1, and Ra is bonded to X4. In another embodiment, q is 1 and Rb is bonded to X10. In some embodiments of Formula (II), p is 2. In some embodiments of Formula (II), p is 3.
[0065] In one embodiment of a compound of Formula (II), X1 is N, X2, X3 and X4 is CR4 and X5 is C. In another embodiment, X2 is N, X1, X3 and X4 is CR4 and X5 is C. In another embodiment, X3 is N, X1, X2 and X4 is CR4 and X5 is C. In another embodiment, X4 is N, X1, X2 and X3 is CR4 and X5 is C. In another embodiment, X5 is N, X1, X2, X3, and X4 is CR4.
[0066] In one embodiment of a compound of Formula (Π), X1 and X2 is N, and X3, X4 is CR4 and X5 is C. In another embodiment, X1 and X3 is N, and X2, X4 is CR4 and X5 is C. In another embodiment, X1 and X4 is N, and X2, X3 is CR4 and X5 is C. In another embodiment, X1 and X5 is N, and X2, X3 and X4 is CR4. In another embodiment, X2 and X3 is N, X1 and X4 is CR4 and X5 is C. In another embodiment, X2 and X4 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X2 and X5 is N, and Χ', X3 and X4 is CR4. In another embodiment, X3 and X4 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X3 and X5 is N, and X1, X2 and X4 is CR4. In another embodiment, X4 and X5 is N, and X1, X2 and X3 is CR4.
[0067] In one embodiment of a compound of Formula (II), X1, X2 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X1, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1, X2 and X5 is N, and X3 and X4 is CR4. In another embodiment, X1, X3 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X1, X3 and X5 is N, and X2 and X4 is CR4. In another embodiment, X1, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2, X3 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X2, X3 and X5 is N, and X1 and X4 is CR4. In another embodiment, X2, X4 and X5 is N, and X1 and X3 is CR4.In another embodiment, X3, X4 and X5 is N, and X1 and X2 is CR4. [0068] In one embodiment of a compound of Formula (Π), X1, X2, X3 and X4 is N, and X5 is C. In another embodiment, X1, X2, X3 and X5 is N, and X4 is CR4. In another embodiment, X2, X3, X4 and X5 is N, and X1 is CR4. In another embodiment, X1, X3, X4 and X5 is N, and X2 is CR4. In another embodiment, X1, X2, X4 and X5 is N, and X3 is CR4.
[0069] In one embodiment of a compound of Formula (II), X1 is O, X2 is N, X3 and X4 is CR4 and X5 is C. In another embodiment, X1 is O, X3 is N, X2 and X4 is CR4 and X5 is C. In another embodiment, X1 is O, X4 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X1 is O, X5 is N, and X2, X3 and X4 is CR4. In another embodiment, X1 is O, X2 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X1 is O, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1 is O, X2 and X5 is N, and X3 and X4 is CR4. In another embodiment, X1 is O, X3 and X4 is N, X2 is CR4 and Xs is C. In another embodiment, X1 is O, X3 and X5 is N, and X2 and X4 is CR4.In another embodiment, X1 is O, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2 is O, X1 is N, X3 and X4 is CR4 and X5 is C. In another embodiment, X2 is O, X3 is N, X1 and X4 is CR4 and X5 is C. In another embodiment, X2 is O, X4 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X2 is O, X5 is N, and X1, X3 and X4 is CR4. In another embodiment, X2 is O, X1 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X2 is O, X1 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X2 is O, X1 and X5 is N, and X3 and X4 is CR4. In another embodiment, X2 is O, X3 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X2 is O, X3 and X5 is N, and X1 and X4 is CR4. In another embodiment, X2 is O, X4 and X5 is N, and X1 and X3 is CR4. In another embodiment, X3 is O, X1 is N, X2 and X4 is CR4 and X5 is C. In another embodiment, X3 is O, X2 is N, X1 and X4 is CR4 and X5 is C. In another embodiment, X3 is O, X4 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X3 is O, X5 is N, and X1, X2 and X4 is CR4. In another embodiment, X3 is O, X1 and X2 is N, X4 is CR4 and X5 is C. In another embodiment, X3 is O, X1 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X3 is O, X1 and X5 is N, and X2 and X4 is CR4. In another embodiment, X3 is O, X2 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X3 is O, X2 and X5 is N, and X1 and X4 is CR4. In another embodiment, X3 is O, X4 and Xs is N, and X1 and X2 is CR4. In another embodiment, X4 is O, X1 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X4 is O, X2 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X4 is O, X3 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X4 is O, X5 is N, and X1, X2 and X3 is CR4. In another embodiment, X4 is O, X1 and X2 is N, X3 is CR4 and X5 is C. In another embodiment, X4 is O, X1 and X3 is N, X2 is CR4 and X5 is C. In another embodiment, X4 is O, X1 and X5 is N, and X2 and X3 is CR4. In another embodiment, X4 is O, X2 and X3 is N, X1 is CR4 and X5 is C. In another embodiment, X4 is O, X2 and X5 is N, and X1 and X3 is CR4. In another embodiment, X4 is O, X3 and X5 is N, and X1 and X2 is CR4.
[0070] In one embodiment of a compound of Formula (II), X1 is S, X2 is N, X3 and X4 is CR4 and X5 is C. In another embodiment, X1 is S, X3 is N, X2 and X4 is CR4 and X5 is C. In another embodiment, X1 is S, X4 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X1 is S, X5 is N, and X2, X3 and X4 is CR4. In another embodiment, X1 is S, X2 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X1 is S, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1 is S, X2 and X5 is N, and X3 and X4 is CR4. In another embodiment, X1 is S, X3 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X1 is S, X3 and X5 is N, and X2 and X4 is CR4. In another embodiment, X1 is S, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2 is S, X1 is N, X3 and X4 is CR4 and X5 is C. In another embodiment, X2 is S, X3 is N, X1 and X4 is CR4 and X5 is C. In another embodiment, X2 is S, X4 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X2 is S, X5 is N, and X1, X3 and X4 is CR4. In another embodiment, X2 is S, X1 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X2 is S, X1 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X2 is S, X1 and X5 is N, and X3 and X4 is CR4. In another embodiment, X2 is S, X3 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X2 is S, X3 and X5 is N, and X1 and X4 is CR4. In another embodiment, X2 is S, X4 and X5 is N, and X1 and X3 is CR4. In another embodiment, X3 is S, X1 is N, X2 and X4 is CR4 and X5 is C. In another embodiment, X3 is S, X2 is N, X1 and X4 is CR4 and X5 is C. In another embodiment, X3 is S, X4 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X3 is S, X5 is N, and X1, X2 and X4 is CR4. In another embodiment, X3 is S, X1 and X2 is N, X4 is CR4 and X5 is C. In another embodiment, X3 is S, X1 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X3 is S, X1 and X5 is N, and X2 and X4 is CR4. In another embodiment, X3 is S, X2 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X3 is S, X2 and X5 is N, and X1 and X4 is CR4. In another embodiment, X3 is S, X4 and X5 is N, and X1 and X2 is CR4. In another embodiment, X4 is S, X1 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X4 is S, X2 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X4 is S, X3 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X4 is S, X5 is N, and X1, X2 and X3 is CR4. In another embodiment, X4 is S, X1 and X2 is N, X3 is CR4 and X5 is C. In another embodiment, X4 is S, X1 and X3 is N, X2 is CR4 and X5 is C. In another embodiment, X4 is S, X1 and X5 is N, and X2 and X3 is CR4. In another embodiment, X4 is S, X2 and X3 is N, X1 is CR4 and X5 is C. In another embodiment, X4 is S, X2 and X5 is N, and X1 and X3 is CR4. In another embodiment, X4 is S, X3 and X5 is N, and X1 and X2 is CR4.
[0071] In one embodiment of a compound of Formula (II), X6 is N, X7, X10 and X9 is CR4 and X8 is C. In another embodiment, X7 is N, X6, X10 and X9 is CR4 and X8 is C. In another embodiment, X10 is N, X6, X7 and X9 is CR4 and X8 is C. In another embodiment, X9 is N, X6, X7 and X10 is CR4 and Xs is C. In another embodiment, X8 is N, X6, X7, X10, and X9 is CR4.
[0072] In one embodiment of a compound of Formula (II), X6 and X7 is N, and X10, X9 is CR4 and X8 is C. In another embodiment, X6 and X10 is N, and X7, X9 is CR4 and X8 is C. In another embodiment, X6 and X9 is N, and X7, X9 is CR4 and X8 is C. In another embodiment, X6 and X8 is N, and X7, X9 and X10 is CR4. In another embodiment, X7 and X10 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X7 and X9 is N, X6 and X10 is CR4 and X8 is C. In another embodiment, X7 and X10 is N, and X6, X8 and X9 is CR4. In another embodiment, X10 and X9 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X10 and X8 is N, and X6, X7 and X9 is CR4. In another embodiment, X9 and X10 is N, and X6, X7 and X8 is CR4.
[0073] In one embodiment of a compound of Formula (II), X6, X7 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X6, X7 and X9 is N, X10 is CR4 and X8 is C. In another embodiment, X6, X7 and X8 is N, and X10 and X9 is CR4. In another embodiment, X6, X10 and X9 is N, X7 is CR4 and X8 is C. In another embodiment, X6, X10 and X8 is N, and X7 and X9 is CR4. In another embodiment, X6, X9 and X8 is N, and X7 and X10 is CR4. In another embodiment, X7, X10 and X9 is N, X6 is CR4 and X8 is C. In another embodiment, X7, X10 and X8 is N, and X6 and X9 is CR4. In another embodiment, X7, X8 and X9 is N, and X6 and X10 is CR4. In another embodiment, X10, X9 and X8 is N, and X6 and X7 is CR4.
[0074] In one embodiment of a compound of Formula (II), X6, X7, X10 and X9 is N, and X8 is C. In another embodiment, X6, X7, X10 and X8 is N, and X9 is CR4. In another embodiment, X7, X10, X9 and X8 is N, and X6 is CR4. In another embodiment, X6, X10, X9 and X8 is N, and X7 is CR4. In another embodiment, X6, X7, X9 and Xs is N, and X10 is CR4.
[0075] In one embodiment of a compound of Formula (II), X6 is O, X7 is N, X10 and X9 is CR4 and X8 is C. In another embodiment, X6 is O, X10 is N, X7 and X9 is CR4 and X8 is C. In another embodiment, X6 is O, X9 is N, X7 and X10 is CR4 and X8 is C. In another embodiment, X6 is O, X8 is N, and X7, X10 and X9 is CR4. In another embodiment, X6 is O, X7 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X6 is O, X7 and X9 is N, X10 is CR4 and X8 is C. In another embodiment, X6 is O, X7 and X8 is N, and X10 and X9 is CR4. In another embodiment, X6 is O, X10 and X9 is N, X7 is CR4 and X8 is C. In another embodiment, X6 is O, X8 and X10 is N, and X7 and X9 is CR4.In another embodiment, X6 is O, X9 and X8 is N, and X7 and X10 is CR4. In another embodiment, X7 is O, X6 is N, X10 and X9 is CR4 and X8 is C. In another embodiment, X7 is O, X10 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X7 is O, X9 is N, X6 and X10 is CR4 and X8 is C. In another embodiment, X7 is O, X8 is N, and X6, X10 and X9 is CR4. In another embodiment, X7 is O, X6 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X7 is O, X6 and X9 is N, X10 is CR4 and X8 is C. In another embodiment, X7 is O, X6 and X8 is N, and X10 and X9 is CR4. In another embodiment, X7 is O, X10 and X9 is N, X6 is CR4 and X8 is C. In another embodiment, X7 is O, X8 and X10 is N, and X6 and X9 is CR4. In another embodiment, X7 is O, X9 and X8 is N, and X6 and X10 is CR4. In another embodiment, X10 is O, X6 is N, X7 and X9 is CR4 and Xs is C. In another embodiment, X10 is O, X7 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X10 is O, X9 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X10 is O, X8 is N, and X6, X7 and X9 is CR4. In another embodiment, X10 is O, X6 and X7 is N, X9 is CR4 and X8 is C. In another embodiment, X10 is O, X6 and X9 is N, X7 is CR4 and X8 is C. In another embodiment, X10 is O, X6 and X8 is N, and X7 and X9 is CR4. In another embodiment, X10 is O, X7 and X9 is N, X6 is CR4 and X8 is C. In another embodiment, X10 is O, X7 and X8 is N, and X6 and X9 is CR4. In another embodiment, X10 is O, X9 and X8 is N, and X6 and X7 is CR4. In another embodiment, X9 is O, X6 is N, X7 and X10 is CR4 and X8 is C. In another embodiment, X9 is O, X7 is N, X6 and X10 is CR4 and X8 is C. In another embodiment, X9 is O, X10 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X9 is O, X8 is N, and X6, X7 and X10 is CR4. In another embodiment, X9 is O, X6 and X7 is N, X10 is CR4 and X8 is C. In another embodiment, X9 is O, X6 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X9 is O, X6 and X8 is N, and X7 and X10 is CR4. In another embodiment, X9 is O, X7 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X9 is O, X7 and X8 is N, and X6 and X10 is CR4. In another embodiment, X9 is O, X8 and X10 is N, and X6 and X7 is CR4. In one embodiment of a compound of Formula (II), X6 is S, X7 is N, X10 and X9 is CR4 and X8 is C. In another embodiment, X6 is S, X10 is N, X7 and X9 is CR4 and X8 is C. In another embodiment, X6 is S, X9 is N, X7 and X10 is CR4 and X8 is C. In another embodiment, X6 is S, X8 is N, and X7, X10 and X9 is CR4. In another embodiment, X6 is S, X7 and X10 is N, X9 is CR4 and Xs is C. In another embodiment, X6 is S, X7 and X9 is N, X10 is CR4 and X8 is C. In another embodiment, X6 is S, X7 and Xs is N, and X10 and X9 is CR4. In another embodiment, X6 is S, X10 and X9 is N, X7 is CR4 and Xs is C. In another embodiment, X6 is S, X8 and X10 is N, and X7 and X9 is CR4. In another embodiment, X6 is S, X9 and X8 is N, and X7 and X10 is CR4. In another embodiment, X7 is S, X6 is N, X10 and X9 is CR4 and X8 is C. In another embodiment, X7 is S, X10 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X7 is S, X9 is N, X6 and X10 is CR4 and X8 is C. In another embodiment, X7 is S, X8 is N, and X6, X10 and X9 is CR4. In another embodiment, X7 is S, X6 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X7 is S, X6 and X9 is N, X10 is CR4 and Xs is C. In another embodiment, X7 is S, X6 and X8 is N, and X10 and X9 is CR4. In another embodiment, X7 is S, X10 and X9 is N, X6 is CR4 and X8 is C. In another embodiment, X7 is S, Xs and X10 is N, and X6 and X9 is CR4.In another embodiment, X7 is S, X9 and X8 is N, and X6 and X10 is CR4. In another embodiment, X10 is S, X6 is N, X7 and X9 is CR4 and X8 is C. In another embodiment, X10 is S, X7 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X10 is S, X9 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X10 is S, X8 is N, and X6, X7 and X9 is CR4. In another embodiment, X10 is S, X6 and X7 is N, X9 is CR4 and X8 is C. In another embodiment, X10 is S, X6 and X9 is N, X7 is CR4 and X8 is C. In another embodiment, X10 is S, X6 and X8 is N, and X7 and X9 is CR4. In another embodiment, X10 is S, X7 and X9 is N, X6 is CR4 and X8 is C. In another embodiment, X10 is S, X7 and X8 is N, and X6 and X9 is CR4. In another embodiment, X10 is S, X9 and X8 is N, and X6 and X7 is CR4. In another embodiment, X9 is S, X6 is N, X7 and X10 is CR4 and X8 is C. In another embodiment, X9 is S, X7 is N, X6 and X10 is CR4 and X8 is C. In another embodiment, X9 is S, X10 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X9 is S, X8 is N, and X6, X7 and X10 is CR4. In another embodiment, X9 is S, X6 and X7 is N, X10 is CR4 and X8 is C. In another embodiment, X9 is S, X6 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X9 is S, X6 and X8 is N, and X7 and X10 is CR4. In another embodiment, X9 is S, X7 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X9 is S, X7 and X8 is N, and X6 and X10 is CR4. In another embodiment, X9 is S, Xs and X10 is N, and X6 and X7 is CR4.
[0076] In an additional aspect, provided herein are compounds having the structure of Formula (III), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
wherein:
Figure imgf000022_0001
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O; Ra 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;
is a single or double bond;
R1 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; and
R2 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)-R5, -C(=0)-0-R4, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R2 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Y is C and between Y and Z is a single bond; or
R1 and R2 are taken together to form -R°- such that -R°- is selected from the group consisting of - (CR4R5)n-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m-(CR4R5), -, -NR4-(CR4R5)n-, -(CR4R5)n-NR4-, - (CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)„-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, -(CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)- (CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)n-C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n- C(=0)-0-(CR4R5)m-,-S-, -iCR4R5)n-S-,-S-(CR4RV, -(CR4R5)n-S-(CR4R5)m-, -S(0)v-, -S(0)v-(CR4R5)„-, - (CR4R5)n-S(0)v-, -0-, -(CR4R5)„-0-,-0-(CR4R5)„-, -(CR4R5)n-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,- C(=0)-(CR4R5)n-, and -(CR4R5)n-C(=0)-(CR4R5)m-;
n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R3 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Z is C, between Y and Z is a single bond, and between CR6 and Z is a single bond; or
R2 and R3 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 R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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;
X6, X7 and X9 is each independently N, S, O or CR4;
Xs and X10 is each independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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;
in the case where X1, X2, X4, X6 and Xs are N, X3, X5, X7, X9 and X10 are C, Ra is isopropyl, Rb is cyclopropyl, R1 is H, then R2 and R3 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 the case where X1, X2 and X4 are N, X3 and X5 are C, and Ra is cyclopropyl, then Y is C, between Y and Z is a double bond and R2 is not hydrogen or methyl; 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.
[0077] In one embodiment of Formula (III), R7 is H, between Y and Z is a double bond, Y is C,
Figure imgf000024_0001
and Z is C. In another embodiment, R1 is H,
Figure imgf000024_0002
between Y and Z is a single bond, Y is C, and R2 is Xa, wherein Xa is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl. In an additional embodiment, between Y and Z is a double bond, Y is C, and R1 and R2 are taken together to form - Rc-.
[0078] In one aspect, provided herein are compounds having the structure of Formula (IV A), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof: wherein:
Figure imgf000025_0001
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
R1 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;
R2 is selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)-R5, -C(=0)- O-R4, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; and
R3 is selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, -C(=0)-0- R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R2 and R3 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 is 0-2;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
R6 selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, -C(=0)-0- R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, Xs, X9 and X10 is N, S or O;
Rb 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;
in the case where X1, X2, X4, X6 and Xs are N, X3, X5, X7, X9 and X10 are C, Ra is isopropyl, Rb is cyclopropyl, R1 is H, then R2 and R3 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 the case where X1, X2 and X4 are N, X3 and X5 are C, and Ra is cyclopropyl, then R2 is not hydrogen or methyl; and
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.
[0079] In one embodiment of Formula (IV A), R2 and R3 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, R2 and R3 are taken together to form an optionally substituted heterocycle. In an additional embodiment, R6 is hydrogen or an optionally substituted alkyl.
[0080] In one aspect, provided herein are compounds having the structure of Formula (ΓνΈ), or a pharmaceutically acce table salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000026_0001
(Formula IVB) wherein:
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O; Ra 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;
R4 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O;
Rb 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.
[0081] In one embodiment of Formula (IVB), Ra is isopropyl. In another embodiment, Ra is an alkyl substituted with at least one hydroxyl group. In another embodiment, Rb is an alkyl substituted with at least one hydroxyl group. In another embodiment, X1, X2, X3 and X4 is N, and X5 is C. In another embodiment, X1, X2, X3 and X5 is N, and X4 is C. In another embodiment, X1, X2 and X5 is N, and X3, X4 is C. In another embodiment, X2, X3 and X5 is N, and X1, X4 is C. In another embodiment, X2, X3 and X4 is N, and X1, X5 is C. In another embodiment, X2 is N, X3, X4 and X5 is C, and X1 is O. In another embodiment, X2 is N, X3, X4 and X5 is C, and X1 is S.
[0082] In one aspect, provided herein are compounds having the structure of Formula (IVC), or a pharmaceutically acc
Figure imgf000027_0001
wherein:
Z is C or N;
R2 is selected from the group consisting of halogen, -CN, -C(=0)-N(R4)-R5, -C(=0)-0-R4, optionally substituted alkyl other than -CH3, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; and
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R2 and R3 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 is 0-2;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
R6 is selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, -C(=0)-0- R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O;
Rb 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
[0083] In one embodiment of Formula (IVC), R2 and R3 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, R2 and R3 are taken together to form an optionally substituted heterocycle. In another embodiment, R6 is hydrogen or an optionally substituted alkyl. In another embodiment, X9 and X10 is N, and X6, X7 and X8 is C. In another embodiment, Rb is an alkyl substituted with at least one hydroxyl group.
[0084] In one aspect, provided herein are compounds having the structure of Formula (IVD), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000029_0001
wherein:
Z is C or N;
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
R2 is selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)-R5, -C(=0)- O-R4, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; and
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R2 and R3 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 is 0-2;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
Rfi is selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R3, -C(=0)-0- R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or R3 and R6 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 the case where X1, X2 and X4 are N, X3 and X5 are C, and Ra is cyclopropyl, then R2 is not hydrogen or methyl; 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.
[0085] In one embodiment of Formula (IVD), Ra is isopropyl. In another embodiment, Ra is an alkyl substituted with at least one hydroxyl group. In another embodiment, X1, X2, X3 and X4 is N, and X5 is C. In another embodiment, X1, X2, X3 and X5 is N, and X4 is C. In another embodiment, X1, X2 and X5 is N, and X3, X4 is C. In another embodiment, wherein X2, X3 and X5 is N, and X1, X4 is C. In another embodiment, wherein X2, X3 and X4 is N, and X1, X5 is C. In another embodiment, wherein X2 is N, X3, X4 and X5 is C, and X1 is O. In another embodiment, wherein X2 is N, X3, X4 and X5 is C, and X1 is S.
[0086] In one embodiment of Formula (IVD), R2 and R3 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, R2 and R3 are taken together to form an optionally substituted heterocycle. In another embodiment, R6 is hydrogen or an optionally substituted alkyl.
[0087] In one aspect, provided herein are compounds having the structure of Formula (VA), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000030_0001
wherein:
is a single or double bond;
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
=Xa is optionally selected from the group consisting of (=0), (=S), optionally substituted imido, and optionally substituted alkenyl; R3 is absent or selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R )R5, -N3, -N(R )R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0088] In one embodiment of Formula (VA), Xa is O. In another embodiment, Z is N. In another embodiment, X6 and X10 is N, and X7, X8 and X9 is C. In another embodiment, X6 and X8 is N, and X7, X9 and X10 is C. In another embodiment, Rb is cyclopropyl.
[0089] In another aspect, provided herein are compounds having the structure of Formula (VB), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000031_0001
wherein:
is a single or double bond;
W is N or C; each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each Xs and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0090] In one embodiment of Formula (VB), R3 is methyl, and R6, R7 is hydrogen. In another embodiment, X6 and X10 is N, and X7, X8 and X9 is C. In another embodiment, X6 and X8 is N, and X7, X9 and X10 is C. In another embodiment, Rb is cyclopropyl.
[0091] In an additional aspect, provided herein are compounds having the structure of Formula (VC), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000033_0001
(Formula VC) wherein:
is a single or double bond;
W is N or C;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each Xs and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0092] In one embodiment of Formula (VC), R3 is methyl, and R6, R7 is hydrogen. In another embodiment, X6 and X10 is N, and X7, Xs and X9 is C. In another embodiment, X6 and X8 is N, and X7, X9 and X10 is C. In another embodiment, Rb is cyclopropyl. [0093] In one aspect, provided herein are compounds having the structure of Formula (VD), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000034_0001
wherein:
is a single or double bond;
W is N or C;
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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.
[0094] In one embodiment of Formula (VD), R3 is methyl, and R6, R7 is hydrogen.
[0095] In one aspect, provided herein are compounds having the structure of Formula (VIA), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof: wherein:
Figure imgf000035_0001
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
-Rc- is selected from the group consisting of -(CR4R5)n-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m- (CR4R5),-, -NR4-(CR4R5)n-, -(CR4R5)n-NR4-, -(CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)„-, -(CR4R5)„- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, - (CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)-(CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)n- C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n-C(=0)-0-(CR4R5)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, - (CR4R5)„-S-(CR4R5)m-, -S(0)v, -S(0)v-(CR4R5)n-, -(CR4R5)n-S(0)v-, -0-, -(CR4R5)„-0-,-0-(CR4R5)n-, - (CR4R5)„-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,-C(=0)-(CR4R5)n-, and -(CR4R5)n-C(=0)-(CR4R5)m-; n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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;
X6, X7 and X9 is each independently N, S, O or CR4;
X8 and X10 is each independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0096] In one embodiment of Formula (VIA), -Rc- is -(CR4=CR5)m- or -(CR4R5)n-. In another embodiment, -Rc- is -CH2CH2-, -CH2- or -CH=CH-. In another embodiment, -Rc- is -N=CR4- or - CR4=N-. In another embodiment, -Rc- is -N=CH- or -CH=N-.
[0097] In one aspect, provided herein are compounds having the structure of Formula (VIB), or a pharmaceutically acce table salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000036_0001
wherein:
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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 is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0098] In one embodiment of Formula (VIB), n is 1 or 2 and R4 and R5 is hydrogen.
[0099] In one aspect, provided herein are compounds having the structure of Formula (VIC), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000037_0001
wherein:
Z is N or C;
W is C;
-Rc- is selected from the group consisting of -(CR4R5)„-, -(CR4=CR5)m-, -(CR4R5)„-(CR4=CR5)m- (CR4R5)t-, -NR4-(CR4R5)n-, -(CR4R5)n-NR4-, -(CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)n-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, - (CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)-(CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)„- C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n-C(=0)-0-(CR4R5)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, - (CR4R5)„-S-(CR4R5)m-, -S(0)V-, -S(0)v-(CR4R5)n-, -(CR4R5)n-S(0)v-, -0-, -(CR4R5)n-0-,-0-(CR4R5)n-, - (CR4R5)n-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,-C(=0)-(CR4R5)n-, and -(CR4R5)n-C(=0)-(CR4R5)m-; n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of Xd, X7, Xs, X9 and X10 is N, S or O; and
Rb 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.
[0100] In one embodiment of Formula (VIC), -Rc- is -CH2CH2- or -CH2-.
[0101] In one aspect, provided herein are compounds having the structure of Formula (VID), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000039_0001
wherein:
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
-Rc- is selected from the group consisting of -(CR4R5)„-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m- (CR4R5), -, -NR4-(CR4R5)n-, -(CR4R5)„-NR4-, -(CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, -N=CR4-(CR4R5)n-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, - (CR4R5)n-C(=0)-N(R4)-,-C(=0)-N(R4)-(CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)„- C(=0)-0-, -C(=0)-0-CR4R5)n -,-(CR4R5)n-C(=0)-0-(CR4R5)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, - (CR4R5)n-S-(CR4R5)m-, -S(0)v-, -S(0)v-(CR4R5)n-, -(CR4R5)n-S(0)v-, -0-, -(CR4R5)n-0-,-0-(CR4R5)n-, - (CR4R5)n-0-(CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,-C(=0)-(CR4R5)n-, and -(CR4R5)„-C(=0)-(CR4R5)m-; n is 0-4;
m is 0-4;
t is 0-4;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle; and
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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.
[0102] In one embodiment of Formula (VID), -Rc- is -(CR4=CR5)m- or -(CR4R5)n-. In another embodiment, -Rc- is -CH2CH2-, -CH2- or -CH=CH-. In another embodiment, -R°- is -N=CR4- or - CR4=N-. In another embodiment, -Rc- is -N=CH- or -CH=N-.
[0103] In one aspect, provided herein are compounds having the structure of Formula (VIE), or a pharmaceutically acce table salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000040_0001
(Formula VIE) wherein:
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 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;
Xb is CR4 or N;
Xc is CR4 or N;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle; each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each X8 and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0104] In one embodiment of Formula (VIE), Xb is CR4 and Xc is CR4. In another embodiment, Xb is CH and Xc is CH. In another embodiment, Xb is CR4 and Xc is N. In another embodiment, Xb is CH and Xc is N. In another embodiment, Xb is N and Xc is CR4. In another embodiment, Xb is N and Xc is CH.
[0105] In one aspect, provided herein are compounds having the structure of Formula (VIF), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
wherein:
Figure imgf000041_0001
Z is N or C;
W is C;
Xb is CR4 or N;
Xc is CR4 or N;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; each R4 and R5 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
R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, -
C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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 X6, X7 and X9 is independently N, S, O or CR4;
each Xs and X10 is independently N or C;
provided that at least one of X6, X7, X8, X9 and X10 is N, S or O; and
Rb 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.
[0106] In one embodiment of Formula (VIF), Xb is CR4 and Xc is CR4. In another embodiment, Xb is CH and X° is CH. In another embodiment, Xb is CR4 and Xc is N. In another embodiment, Xb is CH and Xc is N. In another embodiment, Xb is N and Xc is CR4. In another embodiment, Xb is N and Xc is CH.
[0107] In one aspect, provided herein are compounds having the structure of Formula (VIG), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
wherein:
Figure imgf000042_0001
each X1, X2 and X3 is independently N, S, O or CR4;
each X4 and X5 is independently N or C;
provided that at least one of X1, X2, X3, X4 and X5 is N, S or O;
Ra 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;
Xb is CR4 or N;
Xc is CR4 or N;
v is 0-2;
R3 is absent or selected from the group consisting of hydrogen, halogen, -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl;
each R4 and R5 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 R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle;
each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, - C(=0)-N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl; or
R3 and R6 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.
[0108] In one embodiment of Formula (VIG), Xb is CR4 and X is CR4. In another embodiment, Xb is CH and X° is CH. In another embodiment, Xb is CR4 and X° is N. In another embodiment, Xb is CH and Xc is N. In another embodiment, Xb is N and X° is CR4. In another embodiment, Xb is N and Xc is CH.
[0109] In one embodiment of a compound of Formula (I), (Π), (UI), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1 is N, X2, X3 and X4 is CR4 and X5 is C. In another embodiment, X2 is N, X1, X3 and X4 and X5 is C. In another embodiment, X3 is N, X1, X2 is CR4, and X4 and Xs is C. In another embodiment, X4 is N, X1, X2 and X3 is CR4 and X5 is C. In another embodiment, X5 is N, X1, X2 and X3 is CR4, and X4 is C.
[0110] In one embodiment of a compound of Formula (I), (II), (ΠΙ), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1 and X2 is N, X3 is CR4, and X4 and X5 is C. In another embodiment, X1 and X3 is N, X2 is CR4, and X4 and X5 is C. In another embodiment, X1 and X4 is N, and X2, X3 is CR4 and X5 is C. In another embodiment, X1 and X5 is N, X2, X3 is CR4, and X4 is C. In another embodiment, X2 and X3 is N, X1 is CR4, and X4 and Xs is C. In another embodiment, X2 and X4 is N, X1 and X3 is CR4, and X5 is C. In another embodiment, X2 and X5 is N, and X1, X3 is CR4, and X4 is C. In another embodiment, X3 and X4 is N, X1 and X2 is CR4, and X5 is C. In another embodiment, X3 and X5 is N, and X1, X2 is CR4, and X4 is C. In another embodiment, X4 and X5 is N, and X1, X2 and X3 is CR4. [0111] In one embodiment of a compound of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1, X2 and X3 is N, X4 is CR4 and X5 is C. In another embodiment, X1, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1, X2 and X5 is N, X3 is CR4 and X4 is C. In another embodiment, X1, X3 and X4 is N, X2 is CR4 and Xs is C. In another embodiment, X1, X3 and X5 is N, X2 is CR4 and X4 is C. In another embodiment, X1, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2, X3 and X4 is N, X1 is CR4 and Xs is C. In another embodiment, X2, X3 and X5 is N, X1 is CR4 and X4 is C. In another embodiment, X2, X4 and X5 is N, and X1 and X3 is CR4. In another embodiment, X3, X4 and X5 is N, and X1 and X2 is CR4.
[0112] In one embodiment of a compound of Formula (I), (II), (ΙΙΓ), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1, X2, X3 and X4 is N, and X5 is C. In another embodiment, X1, X2, X3 and X5 is N, and X4 is C. In another embodiment, X2, X3, X4 and X5 is N, and X1 is CR4. In another embodiment, X1, X3, X4 and Xs is N, and X2 is CR4. In another embodiment, X1, X2, X4 and X5 is N, and X3 is CR4.
[0113] In one embodiment of a compound of Formula (I), (Π), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1 is O, X2 is N, X3 is CR4 and X4 and X5 is C. In another embodiment, X1 is O, X3 is N, X2 is CR4 and X4 and X5 is C. In another embodiment, X1 is O, X4 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X1 is O, X5 is N, X2, X3 is CR4 and X4 is C. In another embodiment, X1 is O, X2 and X3 is N, X4 and X5 is C. In another embodiment, X1 is O, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1 is O, X2 and X5 is N, X3 is CR4, and X4 is C. In another embodiment, X1 is O, X3 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X1 is O, X3 and X5 is N, and X2 is CR4 and X4 is C. In another embodiment, X1 is O, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2 is O, X1 is N, X3 is CR4 and X4 and X5 is C. In another embodiment, X2 is O, X3 is N, X1 is CR4 and X4 and X3 is C. In another embodiment, X2 is O, X4 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X2 is O, X5 is N, X1, X3 is CR4 and X4 is C. In another embodiment, X2 is O, X1 and X3 is N, and X4 and X5 is C. In another embodiment, X2 is O, X1 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X2 is O, X1 and X5 is N, X3 is CR4 and X4 is C. In another embodiment, X2 is O, X3 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X2 is O, X3 and X5 is N, X1 is CR4 and X4 is C. In another embodiment, X2 is O, X4 and X5 is N, and X1 and X3 is CR4. In another embodiment, X3 is O, X1 is N, X2 is CR4 and X4 and X5 is C. In another embodiment, X3 is O, X2 is N, X1 is CR4 and X4 and X5 is C. In another embodiment, X3 is O, X4 is N, X1 and X2 is CR4 and X5 is C. In another embodiment, X3 is O, X5 is N, and X1, X2 is CR4 and X4 is C. In another embodiment, X3 is O, X1 and X2 is N, X4 and X5 is C. In another embodiment, X3 is O, X1 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X3 is O, X1 and X5 is N, X2 is CR4 and X4 is C. In another embodiment, X3 is O, X2 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X3 is O, X2 and X5 is N, X1 is CR4 and X4 is C. In another embodiment, X3 is O, X4 and X5 is N, and X1 and X2 is CR4.
[0114] In one embodiment of a compound of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X1 is S, X2 is N, X3 is CR4 and X4 and X5 is C. In another embodiment, X1 is S, X3 is N, X2 is CR4 and X4 and X5 is C. In another embodiment, X1 is S, X4 is N, X2 and X3 is CR4 and X5 is C. In another embodiment, X 1 is S, X5 is N, X2, X3 is CR4 and X4 is C. In another embodiment, X1 is S, X2 and X3 is N, X4 and X5 is C. In another embodiment, X1 is S, X2 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X1 is S, X2 and X5 is N, X3 is CR4, and X4 is C. In another embodiment, X1 is S, X3 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X1 is S, X3 and X5 is N, and X2 is CR4 and X4 is C. In another embodiment, X1 is S, X4 and X5 is N, and X2 and X3 is CR4. In another embodiment, X2 is S, X1 is N, X3 is CR4 and X4 and X5 is C. In another embodiment, X2 is S, X3 is N, X1 is CR4 and X4 and X5 is C. In another embodiment, X2 is S, X4 is N, X1 and X3 is CR4 and X5 is C. In another embodiment, X2 is S, X5 is N, X1, X3 is CR4 and X4 is C. In another embodiment, X2 is S, X1 and X3 is N, and X4 and X5 is C. In another embodiment, X2 is S, X1 and X4 is N, X3 is CR4 and X5 is C. In another embodiment, X2 is S, X1 and X5 is N, X3 is CR4 and X4 is C. In another embodiment, X2 is S, X3 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X2 is S, X3 and X5 is N, X1 is CR4 and X4 is C. In another embodiment, X2 is S, X4 and X5 is N, and X1 and X3 is CR4. In another embodiment, X3 is S, X1 is N, X2 is CR4 and X4 and Xs is C. In another embodiment, X3 is S, X2 is N, X1 is CR4 and X4 and X5 is C. In another embodiment, X3 is S, X4 is N, X1 and X2 is CR4 and X3 is C. In another embodiment, X3 is S, X5 is N, and X1, X2 is CR4 and X4 is C. In another embodiment, X3 is S, X1 and X2 is N, X4 and X5 is C. In another embodiment, X3 is S, X1 and X4 is N, X2 is CR4 and X5 is C. In another embodiment, X3 is S, X1 and X5 is N, X2 is CR4 and X4 is C. In another embodiment, X3 is S, X2 and X4 is N, X1 is CR4 and X5 is C. In another embodiment, X3 is S, X2 and X5 is N, X1 is CR4 and X4 is C. In another embodiment, X3 is S, X4 and X5 is N, and X1 and X2 is CR4.
[0115] In one embodiment of a compound of Formula (I), (II), (ΠΙ), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X6 is N, X7, X9 and X10 is CR4 and X8 is C. In another embodiment, X7 is N, X6, X9 is CR4 and X10 and X8 is C. In another embodiment, X9 is N, X6, X7 is CR4 and X10 and Xs is C. In another embodiment, X10 is N, X6, X7 and X9 is CR4 and X8 is C. In another embodiment, X8 is N, X6, X7 and X9 is CR4, and X10 is C.
[0116] In one embodiment of a compound of Formula (I), (Π), (III), (IVA)-(IVD), (VA)-(VD), and (VLA)-(VIG), X6 and X7 is N, X9 is CR4, and X10 and X8 is C. In another embodiment, X6 and X9 is N, X7 is CR4, and X10 and X8 is C. In another embodiment, X6 and X10 is N, and X7, X9 is CR4 and X8 is C. In another embodiment, X6 and X8 is N, X7, X9 is CR4, and X10 is C. In another embodiment, X7 and X9 is N, X6 is CR4, and X10 and X8 is C. In another embodiment, X7 and X10 is N, X6 and X9 is CR4, and X8 is C. In another embodiment, X7 and X8 is N, and X6, X9 is CR4, and X10 is C. In another embodiment, X9 and X10 is N, X6 and X7 is CR4, and X8 is C. In another embodiment, X9 and X8 is N, and X6, X7 is CR4, and X10 is C. In another embodiment, X10 and X8 is N, and X6, X7 and X9 is CR4.
[0117] In one embodiment of a compound of Formula (I), (Π), (ΠΙ), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X6, X7 and X9 is N, and X10 and X8 is C. In another embodiment, X6, X7 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X6, X7 and X8 is N, X9 is CR4 and X10 is C. In another embodiment, X6, X9 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X6, X9 and X8 is N, X7 is CR4 and X10 is C. In another embodiment, X6, X10 and X8 is N, and X7 and X9 is CR4. In another embodiment, X7, X9 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X7, X9 and X8 is N, X6 is CR4 and X10 is C. In another embodiment, X7, X10 and Xs is N, and X6 and X9 is CR4. In another embodiment, X9, X10 and X8 is N, and X6 and X7 is CR4.
[0118] In one embodiment of a compound of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X6, X7, X9 and X10 is N, and X8 is C. In another embodiment, X6, X7, X9 and X8 is N, and X10 is C. In another embodiment, X7, X9, X10 and X8 is N, and X6 is CR4. In another embodiment, X6, X9, X10 and X8 is N, and X7 is CR4. In another embodiment, X6, X7, X10 and X8 is N, and X9 is CR4.
[0119] In one embodiment of a compound of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X6 is O, X7 is N, X9 is CR4 and X10 and X8 is C. In another embodiment, X6 is O, X9 is N, X7 is CR4 and X10 and X8 is C. In another embodiment, X6 is O, X10 is N, X7 and X9 is CR4 and X8 is C. In another embodiment, X6 is O, X8 is N, X7, X9 is CR4 and X10 is C. In another embodiment, X6 is O, X7 and X9 is N, X10 and X8 is C. In another embodiment, X6 is O, X7 and X10 is N, X9 is CR4 and Xs is C.In another embodiment, X6 is O, X7 and X8 is N, X9 is CR4, and X10 is C. In another embodiment, X6 is O, X9 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X6 is O, X9 and X8 is N, and X7 is CR4 and X10 is C. In another embodiment, X6 is O, X10 and X8 is N, and X7 and X9 is CR4. In another embodiment, X7 is O, X6 is N, X9 is CR4 and X10 and X8 is C. In another embodiment, X7 is O, X9 is N, X6 is CR4 and X10 and X8 is C. In another embodiment, X7 is O, X10 is N, X6 and X9 is CR4 and Xs is C. In another embodiment, X7 is O, X8 is N, X6, X9 is CR4 and X10 is C. In another embodiment, X7 is O, X6 and X9 is N, and X10 and X8 is C. In another embodiment, X7 is O, X6 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X7 is O, X6 and X8 is N, X9 is CR4 and X10 is C. In another embodiment, X7 is O, X9 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X7 is O, X9 and X8 is N, X6 is CR4 and X10 is C. In another embodiment, X7 is O, X10 and X8 is N, and X6 and X9 is CR4. In another embodiment, X9 is O, X6 is N, X7 is CR4 and X10 and X8 is C. In another embodiment, X9 is O, X7 is N, X6 is CR4 and X10 and X8 is C. In another embodiment, X9 is O, X10 is N, X6 and X7 is CR4 and Xs is C. In another embodiment, X9 is O, X8 is N, and X6, X7 is CR4 and X10 is C. In another embodiment, X9 is O, X6 and X7 is N, X10 and X8 is C. In another embodiment, X9 is O, X6 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X9 is O, X6 and Xs is N, X7 is CR4 and X10 is C. In another embodiment, X9 is O, X7 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X9 is O, X7 and X8 is N, X6 is CR4 and X10 is C. In another embodiment, X9 is O, X10 and X8 is N, and X6 and X7 is CR4.
[0120] In one embodiment of a compound of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), X6 is S, X7 is N, X9 is CR4 and X10 and X8 is C. In another embodiment, X6 is S, X9 is N, X7 is CR4 and X10 and X8 is C. In another embodiment, X6 is S, X10 is N, X7 and X9 is CR4 and X8 is C. In another embodiment, X6 is S, X8 is N, X7, X9 is CR4 and X10 is C. In another embodiment, X6 is S, X7 and X9 is N, X10 and X8 is C. In another embodiment, X6 is S, X7 and X10 is N, X9 is CR4 and X8 is C. In another embodiment, X6 is S, X7 and X8 is N, X9 is CR4, and X10 is C. In another embodiment, X6 is S, X9 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X6 is S, X9 and X8 is N, and X7 is CR4 and X10 is C. In another embodiment, X6 is S, X10 and X8 is N, and X7 and X9 is CR4. In another embodiment, X7 is S, X6 is N, X9 is CR4 and X10 and X8 is C. In another embodiment, X7 is S, X9 is N, X6 is CR4 and X10 and X8 is C. In another embodiment, X7 is S, X10 is N, X6 and X9 is CR4 and X8 is C. In another embodiment, X7 is S, X8 is N, X6, X9 is CR4 and X10 is C. In another embodiment, X7 is S, X6 and X9 is N, and X10 and X8 is C. In another embodiment, X7 is S, X6 and X10 is N, X9 is CR4 and Xs is C. In another embodiment, X7 is S, X6 and X8 is N, X9 is CR4 and X10 is C. In another embodiment, X7 is S, X9 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X7 is S, X9 and X8 is N, X6 is CR4 and X10 is C. In another embodiment, X7 is S, X10 and X8 is N, and X6 and X9 is CR4. In another embodiment, X9 is S, X6 is N, X7 is CR4 and X10 and X8 is C. In another embodiment, X9 is S, X7 is N, X6 is CR4 and X10 and X8 is C. In another embodiment, X9 is S, X10 is N, X6 and X7 is CR4 and X8 is C. In another embodiment, X9 is S, X8 is N, and X6, X7 is CR4 and X10 is C. In another embodiment, X9 is S, X6 and X7 is N, X10 and X8 is C. In another embodiment, X9 is S, X6 and X10 is N, X7 is CR4 and X8 is C. In another embodiment, X9 is S, X6 and X8 is N, X7 is CR4 and X10 is C. In another embodiment, X9 is S, X7 and X10 is N, X6 is CR4 and X8 is C. In another embodiment, X9 is S, X7 and X8 is N, X6 is CR4 and X10 is C. In another embodiment, X9 is S, X10 and X8 is N, and X6 and X7 is CR4. In another embodiment, X9 is S, X8 and X10 is N, and X6 and X7 is CR4.
[0121] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R1 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, R1 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R1 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, R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0122] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted
heterocycloalkyl and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0123] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R1 is selected from the group consisting of hydrogen, unsubstituted
heterocycloalkyl and unsubstituted heteroaryl.
[0124] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 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, R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R2 is absent or selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0125] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0126] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R2 is selected from the group consisting of hydrogen, unsubstituted
heterocycloalkyl and unsubstituted heteroaryl.
[0127] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R3 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 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R3 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, R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R3 is selected from the group consisting bf hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0128] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R3 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0129] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R3 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R3 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
[0130] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R4 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, R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R4 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, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0131] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R4 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0132] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R4 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R4 is selected from the group consisting of hydrogen, unsubstituted
heterocycloalkyl and unsubstituted heteroaryl.
[0133] In one embodiment of Formula (I), (II), (IU), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R5 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, R5 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R5 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, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0134] In one embodiment of Formula (I), (II), (III), (IVA)-(rVD), (VA)-(VD), and (VIA)-(VIG), R5 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0135] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R5 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R5 is selected from the group consisting of hydrogen, unsubstituted
heterocycloalkyl and unsubstituted heteroaryl.
[0136] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R6 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, R6 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R6 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, R6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0137] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R6 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0138] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R6 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R6 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
[0139] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R7 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, R7 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R7 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, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted
heterocycloalkyl and optionally substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl and optionally substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl and optionally substituted heteroaryl.
[0140] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R7 is selected from the group consisting of hydrogen, halogen, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted cycloalkyl, substituted heterocycloalkyl, haloalkyl, substituted aryl, and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted alkyl, substituted heterocycloalkyl and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl and substituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted alkyl and substituted cycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, substituted heterocycloalkyl and substituted heteroaryl.
[0141] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R7 is selected from the group consisting of hydrogen, halogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, haloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted heterocycloalkyl and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl and unsubstituted heteroaryl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted alkyl, ubsubstituted alkynyl, unsubstituted cycloalkyl, and unsubstituted heterocycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl. In another embodiment, R7 is selected from the group consisting of hydrogen, unsubstituted heterocycloalkyl and unsubstituted heteroaryl.
[0142] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), Ra 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.
[0143] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R1 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.
[0144] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 is optionally selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, -C(=0)-N(R4)-R5, - C(=0)-0-R4, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R2 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Y is C and between Y and Z is a single bond. In one embodiment of Formula (I), (II), (ΙΠ), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 is optionally selected from the group consisting of hydrogen, halogen, (=0), and optionally substituted alkyl, provided that when R2 is (=0), Y is C and between Y and Z is a single bond. In one embodiment of Formula (I), (II), (III), (IV A)- (rVD), (VA)-(VD), and (VIA)-(VIG), R2 is halogen. In one embodiment of Formula (I), (II), (III), (IVA)- (IVD), (VA)-(VD), and (VIA)-(VIG), R2 is (=0), Y is C and
Figure imgf000057_0001
between Y and Z is a single bond.
[0145] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R1 and R2 are taken together to form -R°- such that -Rc- is selected from the group consisting of -Rc- is selected from the group consisting of -(CR4R5)n-, -(CR4=CR5)m-, -(CR4R5)n-(CR4=CR5)m-(CR4R5), -, - NR4-(CR4R5)„-, -(CR4R5)n-NR4-, -(CR4=CR5)m -NR4-, -NR4-(CR4=CR5)m-, -N=N-, -N=CR4-, -CR4=N-, - N=CR4-(CR4R5)n-, -(CR4R5)n- N=CR4-, -N=CR4-(CR4=CR5)m-, -(CR4=CR5)m -N=CR4-, -(CR4R5)n- C(=0)-N(R4)-,-C(=0)-N(R4)-(CR4R5)n-, -(CR4R5)n -C(=0)-N(R4)-(CR4R5)m-, -(CR4R5)„-C(=0)-0-, - C(=0)-0-CR4R5)n -,-(CR4R5)n-C(=0)-0-(CR4Rs)m-,-S-, -(CR4R5)n-S-,-S-(CR4R5)n-, -(CR4R5)n-S- (CR4R5)m-, -S(0)v-, -S(0)v-(CR4R5)n-, -(CR4R5)„-S(0)v-, -0-, -(CR4R5)„-0-,-0-(CR4R5)n-, -(CR4R5)„-0- (CR4R5)m-, -C(=0)-, -(CR4R5)n-C(=0)-,-C(=0)-(CR4R5)n-, and -(CR4R5)n-C(=0)-(CR4R5)m-.
[0146] In one embodiment of Formula (I), (II), (III), (IVA)-(IYD), (VA)-(VD), and (VIA)-(VIG), R3 is optionally selected from the group consisting of hydrogen, halogen, (=0), (=S), -CN, -C(=0)-N(R4)R5, - C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted imido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl provided that when R3 is (=0), (=S), optionally substituted imido, or optionally substituted alkenyl, Z is C and between Y and Z is a single bond. In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R3 is optionally selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkynyl.
[0147] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), R2 and R3 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.
[0148] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), each R4 and R5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or R4 and R5 together with the nitrogen or carbon atom to which they are attached form an optionally substituted carbocycle or heterocycle.
[0149] In one embodiment of Formula (I), (II), (HI), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), each R6 and R7 is independently selected from the group consisting of hydrogen, halogen, -CN, -C(=0)- N(R4)R5, -C(=0)-0-R4, -O-R4, -S-R4, S(0)v-R4, S(0)v-N(R4)R5, -N3, -N(R4)R5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted aryl, and optionally substituted heteroaryl.
[0150] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), Rb 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. In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), Rb is selected from the group consisting of optionally substituted alkyl, optionally substituted alkynyl, and optionally substituted cycloalkyl.
[0151] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), 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.
[0152] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), 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.
[0153] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), 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.
[0154] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), 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.
[0155] In one embodiment of Formula (I), (II), (III), (IVA)-(IVD), (VA)-(VD), and (VIA)-(VIG), 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.
[0156] In one aspect, provided herein are compounds having the structure of Formula (VII), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
wherein:
Figure imgf000058_0001
=Y is (=0) or (=S);
or =Y is (=N) and =Y and R are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; 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;
R20 and R22 are independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, -S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, - C(=0)NR27R28, -OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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 R23 and R22 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R21 is halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, -S(=0)2R29, -NR27S(=0)2R29, - S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, -C(=0)NR27R28, -OC(=0)NR2/R2!i, - NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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;
R24 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;
R25 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
each R26 is independently halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, -S(=0)2R29, - NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, -C(=0)NR27R28, - OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
each R27 and R28 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 R27 and R28, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R29 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; and
s is 0-3.
[0157] In one embodiment of Formula (VII), =Y is (=0) and R23 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment of Formula (VII), =Y is (=0) and R23 is alkyl.
[0158] In one embodiment of Formula (VII), the compound of Formula (VII) is of Formula (VIla)
Figure imgf000060_0001
[0159] In one embodiment of Formula (VII), =Y is (=0) and R23 and R22 are taken, together with the atoms to which they are attached, to form an optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), =Y is (=0) and R23 and R22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with halogen or optionally substituted alkyl.
[0160] In one embodiment of Formula (VII), the compound of Formula (VII) is of Formula (Vllb)
Figure imgf000060_0002
Ring D is a heterocycloalkyl;
each R30 is independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, - S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, - C(=0)NR27R28, -OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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; and
u is 0-4.
[0161] In one embodiment of Formula (Vllb), each R30 is independently hydrogen, halogen, -CN, -OR27, -NR2'R28, or optionally substituted alkyl. In one embodiment of Formula (Vllb), each R30 is
independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (Vllb), each R30 is hydrogen. In one embodiment of Formula (Vllb), u is 0. In one embodiment of Formula (Vllb), u is 1. In one embodiment of Formula (Vllb), u is 2.
[0162] In one embodiment of Formula (VII), =Y is (=N) and =Y and R23 are taken, together with the atoms to which they are attached, to form an optionally substituted 5-membered heteroaryl. In one embodiment of Formula (VII), =Y is (=N) and =Y and R23 are taken, together with the atoms to which they are attached, to form a 5-membered heteroaryl an optionally substituted with halogen or optionally substituted alkyl.
[0163] In one embodiment of Formula (VII), the compound of Formula (VII) is of Formula (VIIc)
Figure imgf000061_0001
wherein
each R31 is independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02> -NR27R28, - S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, - C(=0)NR27R28, -OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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; and
w is 0-2.
[0164] In one embodiment of Formula (VIIc), each R31 is independently hydrogen, halogen, -CN, -OR27, -NR27R28, or optionally substituted alkyl. In one embodiment of Formula (VIIc), each R31 is
independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (VIIc), each R31 is hydrogen. In one embodiment of Formula (VIIc), w is 0. In one embodiment of Formula (VIIc), w is 1. In one embodiment of Formula (VIIc), w is 2.
[0165] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted aryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted phenyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted heteroaryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted imidazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted pyridine. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is an optionally substituted heteroaryl selected from imidazole, pyrazole, triazole, thiophene, and pyridine. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is optionally substituted with 1, 2, or 3 Rb; and Rb is halogen, -CN, -OR27, -SR27, - S(=0)R29, -N02j -NR27R28, -S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, - C02R27, -OC02R27, -C(=0)NR27R28, -OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, - NR27C(=0)OR27, 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. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R2' is optionally substituted with 1 or 2 Rb; and Rb is halogen, - CN, -OR27, -NR27R28, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is optionally substituted with 1 or 2 Rb; and Rb is halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R21 is optionally substituted with 1 Rb; and Rb is cycloalkyl.
[0166] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is an optionally substituted heteroaryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R23 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is optionally substituted 5-membered heteroaryl selected from triazole, tetrazole, and isoxazole. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is an optionally substituted triazole.
[0167] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is an optionally substituted 5/5 fused bicyclic heteroaryl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is an optionally nuhstitutcd 5/6 fu3cd bieyclic heteroaryl.
[0168] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is optionally substituted with 1, 2, or 3 Ra; and each Ra is independently halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, - S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R2S, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, - C(=0)NR27R28, -0C(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
[0169] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, -OR27, -NR27R28, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted
heterocycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R is optionally substituted with 1 Ra; and Ra is alkyl.
[0170] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R is wherein: each X is independently N or CRa;
Figure imgf000063_0001
Ring E is a 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl;
each Ra is independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, -S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, -C(=0)NR27R28, - OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-4.
[0171] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R25 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 (VII), (VIla), (Vllb), or (VIIc), Ring E is a 5-membered heterocycloalkyl 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 5-membered heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), Ring E is a 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), E is a 6-membered heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), 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 (VII), (VIla), (Vllb), or (VIIc), 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.
[0172] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), Ring E is a 6-membered heteroaryl.
[0173] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R is
Figure imgf000063_0002
Figure imgf000063_0003
each Ra is independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R , -N02, -NR R , -S(=0)2R29, -NR27S(=0)2R29, -S(=0)2NR27R28, -C(=0)R29, -OC(=0)R29, -C02R27, -OC02R27, -C(=0)NR27R28, - OC(=0)NR27R28, -NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-2.
[0174] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), 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.
[0175] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), X are both N. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), one X is N and the other is CRa. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), X are both CRa.
[0176] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each Ra is independently hydrogen, halogen, -CN, -OR27, -SR27, -S(=0)R29, -N02, -NR27R28, -S(=0)2R29, -NR27S(=0)2R29, - S(=0)2NR27R28, -C(=0)R29, -0C(=0)R29, -C02R27, -OC02R27, -C(=0)NR27R28, -OC(=0)NR27R28, - NR27C(=0)NR27R28, -NR27C(=0)R29, -NR27C(=0)OR27, 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. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each Ra is independently hydrogen, halogen, -CN, -OR , -NR R , optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each Ra is independently hydrogen, halogen, - CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each Ra is independently hydrogen, halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), each Ra is independently hydrogen or alkyl.
[0177] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), two Ra on the same carbon form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. [0178] In one embodiment of Formula (VII), (VIIa), (Vllb), or (VIIc), R is
Figure imgf000065_0001
Figure imgf000065_0002
[0179] In one embodiment of Formula (VII), (VIla), (Vllb), or (VUc), R is hydrogen, halogen, -CN, - OR27, -NR27R28, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R20 is hydrogen, halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R20 is hydrogen. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R20 is hydrogen or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R20 is halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R20 is hydrogen or halogen.
[0180] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R22 is hydrogen, halogen, -CN, - OR27, -NR27R28, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R22 is hydrogen, halogen, or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R22 is hydrogen or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R22 is hydrogen. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R22 is alkyl.
[0181] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R24 is hydrogen or alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R24 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.
[0183] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R26 is halogen or alkyl.
[0184] In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R27 and R28 are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (VII), (VIla), (Vllb), or (VIIc), R27 and R28 are hydrogen. In one embodiment of Formula (VII), (VIla), (Vllb), or (VUc), R29 is optionally substituted alkyl.
[0185] In one aspect, provided herein are compounds having the structure of Formula (VIII), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
wherein:
Figure imgf000066_0001
Y1 is N or CRY1;
R43 and R44 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R40, R42, and RY1 are independently hydrogen, halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, - NR47R48, -S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, - C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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;
R41 is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R45 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
each R46 is independently halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR47R48, -S(=0)2R49, - NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, -C(=0)NR47R48, - OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
each R47 and R4S 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;
R49 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; and
si is 0-3.
[0186] In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form an optionally substituted 5- or 6-membered heterocycloalkyl. In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form a 5- or 6- membered heterocycloalkyl, each optionally substituted with oxo, halogen, -CN, -OR47, -SR47, - S(=0)R49, -N02, -NR47R48, -S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, - C02R47, -OC02R47, -C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, - NR47C(=0)OR47, 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. In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form a 5- membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR47, -NR47R48, -C02R47, optionally substituted alkyl, or optionally substituted heteroalkyl. In one embodiment of Formula (VIII), R^ and R44 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. In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form a 6-membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR47, -NR47R48, - C02R47, optionally substituted alkyl, or optionally substituted heteroalkyl. In one embodiment of Formula (VIII), R43 and R44 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.
[0187] In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form an optionally substituted 6-membered heteroaryl. In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR47R48, - S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, - C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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. In one embodiment of Formula (VIII), R43 and R44 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR47, -NR47R48, -C02R47, optionally substituted alkyl, or optionally substituted heteroalkyl. In one embodiment of Formula (VIII), R43 and R44 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.
[0188] In one embodiment of Formula (VIII), the compound of Formula (VIII) is of Formula (VIlla)
Figure imgf000068_0001
wherein
R50 and R51 are independently hydrogen, halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR47R48, -S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, - C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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 R50 and R51 are taken together with the atom to which they are attached to form an oxo.
[0189] In one embodiment of Formula (VIlla), R50 and R51 are independently hydrogen, halogen, -CN, - OR47, -NR47R48, or optionally substituted alkyl. In one embodiment of Formula (VIlla), R50 and R51 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (VIlla), R50 and R51 are hydrogen. In one embodiment of Formula (VIlla), R50 and R51 are are taken together with the atom to which they are attached to form an oxo.
[0190] In one embodiment of Formula (VIII), the compound of Formula (VIII) is of Formula (Vlllb)
wherein
Figure imgf000068_0002
R50, RS1, R52, and R53 are independently hydrogen, halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NK^R'18, -S(=U)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -CO2R47, -OC02R47, - C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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 R50 and R51 are taken together with the atom to which they are attached to form an oxo; or or R52 and R53 are taken together with the atom to which they are attached to form an oxo. [0191] In one embodiment of Formula (VHIb), R50 and R51 are independently hydrogen, halogen, -CN, - OR47, -NR47R48, or optionally substituted alkyl. In one embodiment of Formula (VHIb), R50 and R51 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (Vlllb), R50 and R51 are hydrogen. In one embodiment of Formula (Vlllb), R50 and R51 are are taken together with the atom to which they are attached to form an oxo.
[0192] In one embodiment of Formula (Vlllb), R52 and R53 are independently hydrogen, halogen, -CN, - OR47, -NR47R48, or optionally substituted alkyl. In one embodiment of Formula (Vlllb), R52 and R53 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (Vlllb), R52 and R53 are hydrogen. In one embodiment of Formula (Vlllb), R52 and R53 are are taken together with the atom to which they are attached to form an oxo.
[0193] In one embodiment of Formula (VIII), the compound of Formula (VIII) is of Formula (VIIIc)
Figure imgf000069_0001
wherein
each R is independently hydrogen, halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR R , - S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, - C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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; and
s2 is 0-2.
[0194] In one embodiment of Formula (VIIIc), each R54 is independently hydrogen, halogen, -CN, - OR47, -NR47R48, or optionally substituted alkyl. In one embodiment of Formula (VIIIc), each R54 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (VIIIc), each R54 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.
[0195] In one embodiment of Formula (VIII), the compound of Formula (VIII) is of Formula (Vllld)
wherein
Figure imgf000069_0002
R is hydrogen, halogen, -CN, -OR , -SR47, -S(=0)R49, -N02, -NR R , -S(=0)2R49, - NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, -C(=0)NR47R48, - OC(=0)NR47R48, -NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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.
[0196] In one embodiment of Formula (VHId), R55 is hydrogen, halogen, -CN, -OR47, -NR47R48, or optionally substituted alkyl. In one embodiment of Formula (VHId), R55 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, alkyl, or haloalkyl. In one embodiment of Formula (VHId), R55 is hydrogen.
[0197] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R4' is optionally substituted monocyclic optionally substituted aryl or optionally substituted monocyclic heteroaryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted aryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted phenyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted heteroaryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted 5- membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (Vine), R41 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted imidazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted pyridine. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is an optionally substituted heteroaryl selected from imidazole, pyrazole, triazole, thiophene, and pyridine. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is optionally substituted with 1, 2, or 3 Rb; and Rb is halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR47R48, -S(=0)2R49, -NR47S(=0)2R49, - S(=0)2NR47R48, -C(=0)R49, -OC(=0)R49, -C02R47, -OC02R47, -C(=0)NR47R48, -OC(=0)NR47R48, - NR47C(=0)NR47R48, -NR47C(=0)R49, -NR47C(=0)OR47, 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. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is optionally substituted with 1 or 2 Rb; and Rb is halogen, -CN, -OR47, -NR47R48, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is optionally substituted with 1 or 2 Rb; and Rb is halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R41 is optionally substituted with 1 Rb; and Rb is cycloalkyl. [0198] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R is an optionally substituted heteroaryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R45 is optionally substituted monocyclic heteroaryl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R45 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R45 is optionally substituted 5-membered heteroaryl selected from triazole, tetrazole, and isoxazole. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R45 is an optionally substituted triazole. In one embodiment of Formula (VIII), (Vina), (Vlllb), or (VIIIc), R45 is optionally substituted with 1, 2, or 3 Ra; and Ra is halogen, -CN, -OR47, -SR47, -S(=0)R49, -N02, -NR47R48, -S(=0)2R49, -NR47S(=0)2R49, -S(=0)2NR47R48, -C(=0)R49, - OC(=0)R49, -C02R47, -OC02R47, -C(=0)NR47R48, -OC(=0)NR47R48, -NR47C(=0)NR47R4S, - NR47C(=0)R49, -NR47C(=0)OR47, 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. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R45 is optionally substituted with 1 or 2 Ra; and Ra is halogen, -CN, -OR47, -NR47R48, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), R45 is optionally substituted with 1 or 2 Ra; and Ra is halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (VIII), (VlUa), (Vlllb), or (VIIIc), R45 is optionally substituted with 1 Ra; and Ra is alkyl.
[0199] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), Y1 is N. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), Y1 is CRY1 and RY1 is hydrogen, halogen, -CN, -OR47, - NR47R48, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), Y1 is CRYI and RYl is hydrogen, halogen, or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), Yl is CRY1 and RY1 is hydrogen. In one embodiment of Formula (VIII), (VIIIa), (Vlllb), or (VIIIc), Y1 is CRY1 and RY1 is hydrogen or alkyl. In one embodiment of Formula (VIII), (VIIIa), (VIIIb), or (VIIIc), Y1 is CRYI and RY1 is halogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), Y1 is CRYI and RY1 is hydrogen or halogen.
[0200] In one embodiment of Formula (VIII), (VHIa), (Vlllb), or (VIIIc), R40 is hydrogen, halogen, - CN, -OR47, -NR47R48, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VIII), (VIIIa), (VIIIb), or (VIIIc), R40 is hydrogen, halogen, or alkyl. In one embodiment of Formula (VIII), (VIIIa), (Vlllb), or (VIIIc), R40 is hydrogen. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), R40 is hydrogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R40 is halogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIIIc), R40 is hydrogen or halogen. [0201] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R is hydrogen, halogen, - CN, -OR47, -NR47R48, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R42 is hydrogen, halogen, or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R42 is hydrogen or alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R42 is hydrogen. In one embodiment of Formula (VIII), (Vina), (Vlllb), or (VIIIc), R42 is alkyl.
[0202] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), 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.
[0203] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R46 is halogen or alkyl.
[0204] In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (VIIIc), R47 and R48 are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (VIII), (VIlla), (Vlllb), or (Vine), R47 and R48 are hydrogen. In one embodiment of Formula (VIII), (VIlla), (VIIIb), or (VIUc), R49 is optionally substituted alkyl.
[0205] In one aspect, provided herein are compounds having the structure of Formula (FX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
Figure imgf000072_0001
Y2 is N or CRY2;
R63 is hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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; and
RY2 is hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -0C(=0)R69, -C02R67, -0C02R67, -C(=0)NR67R68, - 0C(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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
Figure imgf000073_0001
Y2 is NRY3;
R63 is O or S; and
RY3 is hydrogen or optionally substituted alkyl;
R60, R61, and R62 are independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, - NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, - C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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;
R64 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;
or R63 and R64 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R65 is optionally substituted fused bicyclic heterocycloalkyl or optionally substituted fused bicyclic heteroaryl;
each R66 is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -0C(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
each R67 and R68 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 R67 and R68, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R69 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; and
s3 is 0-3. [0206] In one embodiment of Formula (IX), In one embodiment of
Figure imgf000074_0001
Formula (IX), and Y2 is In one embodiment of Formula (IX),
Figure imgf000074_0002
Figure imgf000074_0005
Figure imgf000074_0003
and is hydrogen, halogen, or alkyl. In one embodiment of Formula
Figure imgf000074_0004
(IX),
Figure imgf000074_0006
and is hydrogen. In one embodiment of Formula (IX),
Figure imgf000074_0008
and R63 is hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted
Figure imgf000074_0007
alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl,
Figure imgf000074_0009
[0207] In one embodiment of Formula (IX), In one embodiment of
Figure imgf000074_0010
Formula (IX), Y is NRY3; and R is optionally substituted alkyl. In one
Figure imgf000074_0011
63
embodiment of Formula (IX), is and R is O. In one embodiment of Formula (IX),
Figure imgf000074_0012
and R63 is S.
Figure imgf000074_0013
[0208] In one embodiment of Formula (IX), R61 is -OR67, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment of Formula (IX), R61 is an optionally substituted aryl. In one embodiment of Formula (IX), R61 is an optionally substituted phenyl. In one embodiment of Formula (IX), R61 is an optionally substituted heteroaryl. In one embodiment of Formula (IX), R61 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, or isoxazole. In one embodiment of Formula (IX), R61 is an optionally substituted 5- membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene. In one embodiment of Formula (IX), R is an optionally substituted imidazole. In one embodiment of Formula (IX), R is an optionally substituted 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine. In one embodiment of Formula (IX), R61 is an optionally substituted pyridine.
[0209] In one embodiment of Formula (IX), R61 is optionally substituted with 1, 2, or 3 Rb; and each Rb is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, - S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -OC(=0)NR67R68, - NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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. In one embodiment of Formula (IX), R61 is optionally substituted with 1 or 2 Rb; and each Rb is independently halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (IX), R61 is optionally substituted with 1 or 2 Rb; and each Rb is independently halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (ΓΧ), R61 is optionally substituted with 1 Rb; and Rb is cycloalkyl.
[0210] In one embodiment of Formula (IX), R60 is hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (IX), R60 is hydrogen, halogen, or alkyl. The compound of any one of claims 1-27, wherein R60 is hydrogen.
[0211] In one embodiment of Formula (FX), R62 is hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (FX), R62 is hydrogen, halogen, or alkyl. In one embodiment of Formula (FX), R62 is hydrogen or alkyl. In one embodiment of Formula (IX), R62 is alkyl.
[0212] In one embodiment of Formula (IX), R64 is hydrogen or alkyl.
[0213] In one embodiment of Formula (IX), R63 and R64 are taken together with the atom to which they are attached to form an optionally substituted 5- or 6-membered heterocycloalkyl. In one embodiment of Formula (FX), R63 and R64 are taken together with the atom to which they are attached to form a 5- or 6- membered heterocycloalkyl, each optionally substituted with oxo, halogen, -CN, -OR67, -SR67, - S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, - C02R67, -OC02R67, -C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, - NR67C(=0)OR67, 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. In one embodiment of Formula (IX), R63 and R64 are taken together with the atom to which they are attached to form a 5- membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR67, -NR67R68, -C02R67, optionally substituted alkyl, or optionally substituted heteroalkyl. In one embodiment of Formula (FX), R63 and R64 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 , -C02R , optionally substituted alkyl, or optionally substituted heteroalkyl. In one embodiment of Formula (IX), R63 and R64 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, - S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -0C(=0)NR67R68, - NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)0R67, 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. In one embodiment of Formula (IX), R63 and R64 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, - OR67, -NR67R68, -C02R67, optionally substituted alkyl, or optionally substituted heteroalkyl.
[0214] In one embodiment of Formula (IX), 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.
[0215] In one embodiment of Formula (IX), R66 is hydrogen, halogen, or alkyl. In one embodiment of Formula (IX), R66 is hydrogen.
[0216] In one embodiment of Formula (IX), R65 is an optionally substituted 5/5 fused bicyclic heteroaryl. In one embodiment of Formula (IX), R65 is an optionally substituted 5/6 fused bicyclic heteroaryl.
[0217] In one embodiment of Formula (IX), R65 is optionally substituted with 1, 2, or 3 Ra; and each Ra is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, - S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -0C(=0)NR67R68, - NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
[0218] In one embodiment of Formula (IX), R65 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In one embodiment of Formula (IX), R65 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, - OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In one embodiment of Formula (IX), R65 is optionally substituted with 1 Ra; and Ra is alkyl. [0219] In one embodiment of Formula (IX), R is wherein:
Figure imgf000077_0001
each X is independently N or CRa;
Ring E is a 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl;
each Ra is independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-4.
[0220] In one embodiment of Formula (IX), 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. In one embodiment of Formula (IX), 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.
[0221] In one embodiment of Formula (IX), Ring E is a 6-membered heteroaryl.
[0222] In one embodiment of Formula (IX), R is
Figure imgf000077_0002
wherein:
Figure imgf000077_0003
each Ra is independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NRb/R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-2.
[0223] In one embodiment of Formula (IX), 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.
[0224] In one embodiment of Formula (IX), X are both N. In one embodiment of Formula (IX), one X is N and the other is CRa. In one embodiment of Formula (IX), X are both CRa.
[0225] In one embodiment of Formula (IX), each Ra is independently hydrogen, halogen, -CN, -OR67, - SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, - OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, - NR67C(=0)R69, -NR67C(=0)OR67, 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. In one embodiment of Formula (IX), each Ra is independently hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. In one embodiment of Formula (IX), each Ra is independently hydrogen, halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl. In one embodiment of Formula (IX), each Ra is independently hydrogen, halogen, or alkyl. In one embodiment of Formula (IX), each Ra is independently hydrogen or alkyl.
[0226] In one embodiment of Formula (IX), two Ra on the same carbon form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
[0227] In one embodiment of Formula (IX), R is
Figure imgf000078_0001
Figure imgf000078_0002
[0228] In one embodiment of Formula (IX), R and R are independently hydrogen or optionally substituted alkyl. In one embodiment of Formula (IX), R67 and R68 are hydrogen. In one embodiment of Formula (IX), R69 is optionally substituted alkyl.
[0229] In one embodiment, the compound is selected from the following compounds:
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0002
In one embodiment, the compound is selected from the following compounds:
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Pharmaceutical Compositions
[0231] As used herein the term "pharmaceutical 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.
[0232] The term "excipient" refers to an inert or inactive substance added to a pharmaceutical composition to further facilitate administration of a compound. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
[0233] The present teachings further comprise pharmaceutical compositions comprising one or more of the compounds of the present disclosure. In one embodiment, a pharmaceutical composition comprises one or more of the compounds of the present disclosure and at least one pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of disclosed herein and at least one pharmaceutically acceptable carrier.
[0234] In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase "active ingredient" generally refers to a compound to be delivered as a compound described herein.
[0235] In some embodiments, 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.
[0236] Although the descriptions of pharmaceutical compositions provided herein 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.
[0237] In some embodiments, the compounds described herein, are formulated into pharmaceutical compositions. In specific embodiments, 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
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).
[0238] Provided herein are pharmaceutical compositions comprising a compound described herein, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds described herein, are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds described herein.
[0239] In one embodiment, one or more compounds described herein, is formulated in an aqueous solutions. In specific embodiments, 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. In other embodiments, one or more compound described herein, is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.
[0240] In another embodiment, 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. In various embodiments, 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.
[0241] In certain embodiments, 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. In specific embodiments, 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.
[0242] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, 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.
[0243] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein, are formulated into other oral dosage forms. 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. In specific embodiments, 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. In other embodiments, 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. In addition, stabilizers are optionally added.
[0244] In other embodiments, 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. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, 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. In still other embodiments, 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. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, 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. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.
[0245] In still other embodiments, 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.
[0246] In yet other embodiments, the compounds described herein, are formulated for transdermal administration. In specific embodiments, 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. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds described herein, is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds described herein. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, 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.
[0247] In other embodiments, 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,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, 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.
[0248] In still other embodiments, 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. In suppository forms of the compositions, 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. [0249] In certain embodiments, 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
pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients is optionally used as suitable and as understood in the art. Pharmaceutical 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.
[0250] Pharmaceutical 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. In addition, 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. Additionally, 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. In addition, the pharmaceutical 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.
[0251] Methods for the preparation of 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. The form of the pharmaceutical 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.
[0252] In some embodiments, pharmaceutical 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. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. [0253] In certain embodiments, 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.
[0254] 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.
[0255] Furthermore, 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.
[0256] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such 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.
[0257] Other useful pharmaceutical 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.
[0258] Still other useful 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.
[0259] Still other useful 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.
[0260] In certain embodiments, aqueous suspension compositions are packaged in single-dose non- reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
[0261] In alternative embodiments, other delivery systems for 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.
[0262] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such 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.
Dosing
[0263] 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).
[0264] 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.
Methods of Use
[0265] In one aspect, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, the liver disease is non-alcoholic steatohepatitis (NASH). In one embodiment, the liver disease is acute liver injury. In one embodiment, the liver disease is hepatic steatosis. In another embodiment, 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. In another embodiment, 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). In another embodiment, 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. In another embodiment, 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). In another embodiment, 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. In another embodiment, the neurodegenerative disease is multiple sclerosis. In another embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis. In another embodiment, the neurodegenerative disease is Alzheimer's disease. In another embodiment, the neurodegenerative disease is Parkinson's disease. In another embodiment, 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. In another embodiment, the blood disease is sickle cell disease.
[0266] In one aspect, 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. [0267] In another aspect, 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.
[0268] In one embodiment, the compound modulates platelet activation, platelet granule secretion, thromboxane A2 generation, or thrombosis modulation.
[0269] In another aspect, 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.
[0270] In one embodiment, the oxidative species is a reactive oxygen species. In another embodiment, the oxidative species contains a radical on the oxygen atom.
[0271] In one embodiment, 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.
Further Forms of Compounds
[0272] In certain embodiments, 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, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[0273] By "pharmaceutically acceptable," as used herein, 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.
[0274] The term "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. In some embodiments, 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. Pharmaceutically acceptable 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.
[0275] In other embodiments, 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.
[0276] It should be understood that 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. By way of example only, 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. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[0277] In yet other embodiments, the compounds disclosed herein are prepared in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, 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.
[0278] In some embodiments, 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. An example, without limitation, of a prodrug would be 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. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
[0279] 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.
[0280] In other embodiments, prodrugs are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In specific embodiments, 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. (Fedorak et al, Am. J. Physiol, 269:G210-218 (1995); McLoed et al, Gastroenterol, 106:405-413 (1994); Hochhaus et al, Biomed. Chrom., 6:283-286 (1992); J. Larsen and
H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al, Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al, J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987).
[0281] By way of example only, in one aspect appropriate prodrugs are prepared by reacting a non- derivatized compounds disclosed herein with a suitable carbamylating agent, such as, but not limited to,
I, 1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like. (Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein-described compounds are a prodrug for another derivative or active compound.
[0282] In some embodiments, 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. In specific embodiments, 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.
[0283] In another embodiment, 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.
[0284] In yet another embodiment, 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. In certain embodiments, compounds disclosed herein are prepared as their individual stereoisomers. In certain embodiments, 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. In some embodiments, resolution of enantiomers is carried out using covalent
diastereomeric derivatives of the compounds described herein. In other embodiments, 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. In these embodiments, 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.
[0285] Additionally, in certain embodiments, the compounds provided herein exist as geometric isomers. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In some embodiments, the compounds described herein exist as tautomers. All tautomers are intended to be within the scope of the molecular formulas described herein. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are envisioned.
EXAMPLES
Example 1: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000105_0001
Step 1: Example lb
[0286] A solution of 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
Step 2: Example Id
[0287] To a suspension of Example lb (1.00 g, 3.77 mmol), Example lc (0.51 g, 4.72 mmol) and Cs2C03 (3.69 g, 11.32 mmol) in DMF (12.5 mL) was added Cul (72 mg, 0.37 mmol) and (1R,2S)-N',N2- dimethylcyclohexane-l,2-diamine (107 mg, 0.75 mmol) under N2 at room temperature. 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
Step 3: Example le
[0288] To a suspension of Example Id (1.00 g, containing DMF, 4.1 mmol) and Cs2C03 (5.32 g, 16.3 mmol) in DMF (20 mL) was added Mel (1.74 g, 12.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with DCM/iPrOH (v/v = 3/1, 50 mL*3). The organic layer was concentrated under reduced pressure and purified by silica gel chromatography (DCM MeOH = 20/1-10/1) to afford the desired product Example le (550 mg, yield 49%) as a yellow solid. LC-MS [M+H]+ = 274.0
Step 4: Example If
[0289] To a mixture of Example le (500 mg, 1.8 mmol) in MeOH (10 mL) was added a solution of NaOH (290 mg, 7.3 mmol) in water (2.5 mL) at room temperature, which was stirred for 16 h. The mixture was concentrated under reduced pressure and water was added. The resulting mixture was extracted with EtOAc (20 mL*3). The aqueous layer was adjusted to pH about 4 with 2N HC1 (aq.) and concentrated to afford the crude product Example If (770 mg, crude yield >100%) as a brown solid. LC- MS [M+H]+ = 260.0
Step 5: Example 1
[0290] A mixture of Example If (400 mg, 1.54 mmol), 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. The reaction mixture was poured into water and extracted with DCM iPrOH (v/v = 3/1, 20 mL*3). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography and Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) twice to afford the desired product (33.7 mg, yield 5%) as a white solid. LC-MS [M+H]+ = 445.1 [0291] Ή NMR (400 MHz, DMSO-<¾ δ 12.66 (s, IH), 8.90 (s, IH), 8.65 (d, J= 3.2 Hz, IH), 8.61 (d, J = 2.8 Hz, IH), 8.36 (d, J= 8.0 Hz, IH), 8.04 (t, J= 8.0 Hz, IH), 7.94 (d, J= 1.2 Hz, IH), 7.84 (d, J= 7.8 Hz, IH), 7.38 (d, J= 1.2 Hz, IH), 5.32-5.29 (m, IH), 3.67 (s, 3H), 1.87-1.80 (m, IH), 1.53 (d, J= 6.8 Hz, 6H), 0.82-0.78 (m, 2H), 0.69-0.66 (m, 2H). Example 2: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(5-isopropyl-lH- tetrazol-l-yl)pyridin-2-yl)-4-methylbenzamide
Figure imgf000107_0001
Step 1: Example 2b
[0292] 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. NH4C1, brine, dried over anhydrous Na2SC>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%.
Step 2: Example 2c
[0293] Example 2b (1.85 g, 7.6 mmol) was dissolved in CH3CN (20 mL), and SiCL, (9.2 mL, 80.1 mmol) was added dropwise, followed by NaN3 (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 Na2S04. The solvent was removed under reduced pressure, and the residue was purified by biotage flash to afford 1.46 g of white solid.
Step 3: Example 2d
[0294] To a mixture of 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) in toluene (3 mL) was added
cesiumcarbonate(1 Umg,0.49mmol). The reaction mixture was heated at 90UC overnight.LC-MS showed the reaction was completed. Then the reaction mixture was diluted with EA, washed with water, brine, and dried over anhydrous Na2S04. The solvent was removed under reduced pressure, the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford 52 mg of white solid.LCMS [M+l]+ = 305.0. Step 4: Example 2e
[0295] 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.
Step 5: Example 2
[0296] A suspension of Example 2f (210 mg, 0.81 mmol) in SOCl2 (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. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min), then by prep-TLC to afford 7 mg of the title compound. LCMS [M+l]+ = 447.1
[0297] 1H NMR (400 MHz, Methanol-d4) δ 8.43 (d, J = 8.3 Hz, 1H), 8.15 (t, J = 8.1 Hz, 1H), 7.78 - 7.68 (m, 3H), 7.35 (d, J = 11.2 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 4.06 (p, J = 6.9 Hz, 1H), 2.26 (s, 3H), 1.90 (td, /= 8.4, 4.2 Hz, 1H), 1.40 (d, J= 6.9 Hz, 6H), 0.88 (dt, J= 8.3, 3.0 Hz, 2H), 0.78 - 0.72 (m, 2H).
Example 3: Synthesis of 2-(5-(4-cyclopropyl-lH-imidazol-l-yl)-2,3-dihydrobenzofuran-7- carboxamido)-6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridine 1-oxide
Figure imgf000108_0001
Step 1: Example 3b
[0298] To a solution of methyl-6-arninopicolinate (4.32 g, 28.4 mmol) in MeOH (50 mL) was added NH2NH2.H20 (2.84 g, 56.8 mmol). The reaction mixture was heated under reflux for 3 h and then cooled to room temperature (detected by TLC, PE/EA=1 : 1). The precipitate formed in the mixture was collected by filtration, washed with EA (200 mL*2) and then dried in vacuoto give Example 3b (3 g) as white solid.
Step 2: Example 3c
[0299] A mixture of Example 3b (3 g, 19.7 mmol) in DMF-DMA (40 mL) was heated under reflux for 18 h, (detected by TLC, PE/EA=1/1) cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in EA (70 mL) and heated at 50° C for 20 min. After being cooled to room temperature, the solid was collected by filtration and dried in vacuo to give Example 3c (5g) as white solid.
Step 3: Example 3d
[0300] To a solution of Example 3c (1 g, 3.8 mmol) in a mixture of CH3CN-AcOH (lOmL, 4: 1) was added propan-2-amine (l.lg, 18.6 mmol). The resulting mixture was heated under reflux for 24 h and then cooled to room temperature (detected by TLC PE/EA=1/1), and the solvent was removed under reduced pressure. The residue was dissolved in water (28 mL) and IN aqueous NaOH was adjustde to a pH of 8.0. The precipitate was collected by filtration and the filtrate was extracted with EA (50 mL><3). The combined organic layers were dried over anhydrous Na2S04, and then concentrated to a volume of 15 mL. To this mixture at 0° C was slowly added PE (400 mL) and the resulting suspension was filtered. The combined solid was re-crystallized from EtOAc/Petroleum Ether (v/v =l/2)to give Example 3d (0.5g) as awhile solid
Step 4: Example 3f
[0301] 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 Na2S04, 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.
Step 5: Example 3h
[0302] A solution of cyclopropyl methyl ketone (20.7 mL, 220 mmol) in MeOH (100 mL) was treated with bromine (11.3 mL, 220 mmol) at -5° C for 2 h. 50 mL of water was added and the reaction was warmed up to room temperature overnight. The mixture was diluted with water (150 mL) and extracted with ethyl ether. The organic phases were separated and washed with NaHC03, dried (Na2S04), and concentrated to dryness, affording light yellow oil (35 g).
Step 6: Example 3i
[0303] A mixture of 2-bromo-l-cyclopropylethanone (3.2 g, 20.0 mmol) and formimidamide acetate (10.4 g, 50.0 mmol) in ethylene glycol (100 mL) was heated at 135°C overnight. After cooling, the mixture was diluted with water (100 mL), and extracted several times with ether. The combined organic layers were dried over MgS04, filtered, and concentrated to afford the crude product (lg yellow oil) which was directly used in next step reaction without further purification. LCMS: [M+l] += 109.3.
Step 7: Example 3k
[0304] A mixture of Example 3j (600 mg, 2.4 mmol) and Example 3i (400 mg, 3.6 mmol), Cul (45 mg, 0.24 mmol), K3P04 (1 g, 4.8 mmol), 4,7-Dihydroxy-l , 10-phenanthroline(9 mg, 0.48 mmol), TBAB (386 mg, 1.2 mmol) in H20 (10 mL) under N2 was heated at 100°C overnight. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to give the crude and further purified by silica chromatography to give the product 200 mg as yellow solid.
Step 8: Example 3
[0305] To a solution of Example 3k (210 mg, 0.77 mmol) in DMF (5 mL) wereadded Example 3f (255mg, 1.15 mmol), DIEA (200.6 mg, 1.54 mmol) and HBTU (410 mg, 1.15 mmol), and then heated at 30oC for 16h. Then the mixture was concentrated, and the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the product (150 mg) as white solid.
[0306] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.96 (s, 1H), 8.73 (dd, J = 8.5, 1.9 Hz, 1H),
8.02 (s, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.81 (dd, J = 2.5, 1.3Hz, 1H), 7.64 (t, J = 8.2 Hz, 1H), 7.51 (dd, J =
7.8, 1.9 Hz, 1H), 7.45 (s, 1H), 4.87 (t, J = 8.7 Hz, 2H), 4.30 - 4.20 (m, 1H), 3.37 (t, J = 8.7 Hz, 2H), 1.87
- 1.80 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H), 0.82 - 0.77 (m, 2H), 0.71 - 0.67 (m, 2H).
Example 4: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-2,3-dihydrobenzofuran-7-carboxamide
Figure imgf000110_0001
Step 1:
[0307] To a solution of (100 mg) in AcOH (20 mL) was added Iron (2.84 g). The reaction mixture was heated at 50°C for 18hand then cooled to room temperature(detected by TLC.DCM: MeOH=10: 1). After cooling, filtered and concentrated under reduced pressure to give the crude and further purified by silica gel chromatography to give crude product(65 mg), then crude purified byPrep-HPLC (by Ultimate XB- C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the product (6mg) as white soild.
[0308] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.06 (t, J = 7.9 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.78 (s, 1H), 7.44 (d, J = 1.5 Hz, 1H), 5.42-5.32 (m,lH), 4.89 (t, J = 8.7 Hz, 2H), 3.37 (d, J = 9.3 Hz, 2H), 1.85 -1.80 (m, 1H), 1.54 (d, J = 6.7 Hz, 6H), 0.81- 0.76 (m, 2H), 0.72-0.66 (m,2H). Example 5: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-lH-l,2,3- triazol-l-yl)pyridin-2-yl)-4-methylbenzamide
Figure imgf000111_0001
Step 1: Example 5b
[0309] A solution of Example 5a (12.5 g, 175 mmol) and con.HCl (30 mL) in 100 niL of water and 50 mL of ether was cooled to 0 °C. A solution of NaN02 (9.6 g, 175 mmol) in 10 mL of water was added dropwise, followed by stirring for 2 h while maintained below 5 °C, and then the organic phase was separated. The aqueous phase was extracted whit ether. The ether solution were combined, washed with water, dried and stripped of solvent. The residue was purified by flash chromatography to give product Example 5b (10.0 g, yield: 75%). LCMS [M+l] + = 155.0
Step 2: Example 5d
[0310] A solution of Example 5b (6.0 g, 38.7 mmol) and Example 5c (8.0 g, 1 17 mmol) in 20mL of toluene was stirred at 120 oC for 18h. The organic was stripped of solvent. The residue was purified by flash chromatography to give product Example 5d (650 mg, yield: 7.65%) and Example 5e (600 mg, yield: 7.65%). LCMS [M+l] += 223.0
Step 3: Example 5f
[0311] To a solution of 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), Cs2C03 (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
Step 4: Example 5h
[0312] To a solution of Example 5f (560 mg, 1.85 mmol) in 8mL of DCM was added 2 mL of TFA stirred at 20°C for 4h. The mixture was stripped of solvent without purified for next step Example 5h (450 mg, crude). LCMS [M+l] + = 204.1
Step 5: Example 5
[0313] 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. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, ΙΟμιη, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 5 (8.0 mg, yield: 4.5%). LCMS [M+l] + = 446.1
[0314] 1H NMR (400 MHz, DMSO-dV) δ 11.09 (s, lH), 8.37 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.69(s, 1H), 7.64 (d,J = 6.8 Hz, 1H), 7.45 (d, J = 11.0 Hz, 1H), 7.18 (s, 1H), 3.13 - 3.03 (m,lH), 2.23 (s, 3H), 1.87 - 1.80 (m,lH), 1.28 (d, J = 6.9 Hz, 6H), 0.83 - 0.77 (m, 2H), 0.70 - 0.66 (m,2H).
Example 6: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000112_0001
Step 1: Example 6b
[0315] A solution of 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
Step 2: Example 6d
[0316] To a suspension of Example 6b (1.00 g, 3.58 mmol), Example lc (483 mg, 4.48 mmol) and Cs2C03 (3.50 g, 10.75 mmol) in DMF (12.5 mL) was added Cul (68 mg, 0.36 mmol) and (1R,2S)-N',N2- dimethylcyclohexane-l,2-diamine (112 mg, 0.79mmol) under N2 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. The filter cake was washed with MeOH (30 mL*3) and the filtrate was concentrated to afford the crude product Example 6c (1.48 g, containing DMF, crude yield >100%), which was used for the next step without further purification. LC-MS [M+l]+ = 260
Step 3: Example 6d
[0317] To a suspension of Example 6c (1.48 g, containing DMF, 5.71 mmol) and Cs2C03 (11.20 g, 34.28 mmol) in DMF (40 mL) was added Mel (4.86 g, 34.28 mmol) at room temperature and the suspension was stirred for 1.5 h. The mixture was filtered and the cake was washed with MeOH (20 mL*3). The filtrate was concentrated under reduced pressure and the residue was dissolved in water (50 mL) and extracted with DCM/iPrOH (v/v = 3/1, 50 mL*3). The combined organic layer was concentrated under reduced pressure and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford the desired product Example 6d (70 mg, yield 4%) as a yellow solid. LC-MS [M+l]+ =288
Step 4: Example 6e
[0318] 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
Step 5: Example 6f
[0319] 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. The reaction mixture was concentrated under reduced pressure, which was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (35.1 mg, yield 32%) as a white solid. LC-MS [M+l]+ =459.0
[0320] 1H NMR (400 MHz, DMSO-4,) δ 12.53 (s, 1H), 8.88 (s, 1H), 8.33 (d, J= 8.0 Hz, 1H), 8.26 (s, 1H), 8.02 (t, J= 8.0 Hz, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.60 (s, 1H), 7.06 (s, 1H), 5.27-5.34 (m, 1H), 3.67 (s, 3H), 2.25 (s, 3H), 1.81-1.88 (m, 1H), 1.52 (d, J= 8.0 Hz, 6H), 0.78-0.81 (m, 2H), 0.69-0.71 (m, 2H). Example 7: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(5-isopropyl-lH-l,2,3- lrluzol-l-yl)pyrldln-2-yl)-4-methylbenzamide
Figure imgf000113_0001
Step 1: Example 7b
[0321] A solution of 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 Na2S04 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
Step 2: Example 7e
A solution of Example 7b (6.0 g, 38.7 mmol) and Example 7c (8.0 g, 117 mmol) in 20mL of toluene was stirred at 120°C for 18h. The mixture was concentrated. The residue was purified by flash chromatography (Petroleum Ether/EtOAc =4/1) to give product Example 7d (650 mg, yield: 7.65%)
LCMS [M+l]+= 223.0 and Example 7e (600 mg, yield: 7.07%).LCMS [M+l]+ = 223.0
Example 7d: 1H NMR (400 MHz, Chloroform-^) δ 8.37 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.95-7.87 (m,
1H), 7.39 (d, J = 7.5 Hz, 1H), 3.25 (p, J = 6.8 Hz, 1H), 1.38 (d, J = 6.6 Hz, 6H).
Example 7e: 1H NMR (400 MHz, Chloroform-d) δ 7.97 (dd, J = 8.0, 0.8 Hz, 1H), 7.88 (t, J = 7.9 Hz,
1H), 7.60 - 7.55 (m, 1H), 7.39 (dd, J = 7.8, 0.8 Hz, 1H), 3.85 (p, J = 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz,
6H).
Step 3: Example 7g
[0322] To a solution of Example 7e (444 mg, 2.0 mmol) and tert-butyl carbamate (370 mg, 3.16 mmol) in 6 mL of toluene was added Pd(OAc)2 (23 mg, 0.1 mmol), BINAP (146 mg, 0.2 mmol), Cs2C03(914 mg, 2.8 mmol) stirred at 100 °C overnight. The mixture was diluted by DCM, washed with water, dried and stripped of solvent. The residue was purified byflash chromatography (Petroleum Ether/EtOAc =3/1 ) to give product Example 7g (560 mg, yield: 92%). LCMS [M+l] + = 304.0
Step 4: Example 7i
[0323] To a solution of Example 7g (560 mg, 1.85 mmol) in 8mL of DCM, was added 2 mL of TFA and stirred at 20°C for 4h. The mixture was stripped of solvent without purified for next step Example 7i (450 mg, crude). LCMS [M+l] + = 204.1
Step 5: Example 7
[0324] To a solution of Example 7j (92 mg, 0.35 mmol)in 5mL of DMF was addedisobutyl carbonochloridate (61 mg, 0.44 mmol) and Et3N (101 mg, 1.0 mmol) at 0 °C and stirred for lh. Then Example 7i (102 mg, 0.5 mmol) was added, and the resulting mixture was stirred at 100°C for 4h. The mixture was diluted by DCM, washed with water, dried and stripped of solvent. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 7 (20.1 mg, yield: 9.1%).
[0325] LCMS [M+l] + = 446.1
[0326] Ή NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.28 (d, /= 8.2 Hz, 1H), 8.16 (t, J= 8.0 Hz, 1H), 7.74 (s, 1H), 7.71 -7.59 (m, 3H), 7.45 (d, J= 10.9 Hz, 1H), 7.16 (s, 1H), 3.73 (d, J= 6.9 Hz, 1H), 2.23 (s, 3H), 1.86 - 1.79 (m, 1H), 1.16 (d, J= 6.8 Hz, 6H), 0.82 -0.76 (m, 2H), 0.69 - 0.66 (m, 2H). Example 8: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(3-isopropylisoxazol-4- yl)pyridin-2-yl)-4-methylbenzamide
Figure imgf000115_0001
p
[0327] A mixtureof Example 8a (33 mg.O.l l mmol), Example 8b (30 mg,0.07 mmol), and Pd(dppf)Cl2 (5 mg, 0.01 mmol), Na2C03 (23 mg, 0.90 mmol) in dioxane/H20 (1.5 mL/0.3 mL) was degassed with N2 and stirred at 110°C for 4 h.The mixture was diluted with water (50 mL), and then extracted with EtOAc (30 mL*3). The combined organic layer was washed with brine (20 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (3.4 mg, yield 11 %) as a pale white solid. LC-MS [M+l]+ = 446.0
[0328] 1H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J= 14.8 Hz, 1H), 8.70 (s, 1H), 8.28 (d, J= 8.3 Hz, 1H), 8.06 (d, J= 7.2 Hz, 1H), 7.80 (t, J= 8.0 Hz, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 7.21 (d, J= 12.2 Hz, 1H), 6.80 (s, 1H), 3.61 (p, J= 6.9 Hz, 1H), 2.29 (s, 3H), 1.93 (ddd, J= 13.2, 8.4, 5.1 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H), 0.92 (ddt, J = 8.2, 5.4, 3.1 Hz, 2H), 0.85 (dq, J= 4.8, 3.0 Hz, 2H).
Example 9: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(l-isopropyl-lH-pyrazol- 5-yl)pyridin-2-yl)-4-methylbenzamide
Figure imgf000115_0002
Step 1: Example 9b
The mixture of Example 9a (520 mg, 2.0 mmol) in SOCl2 (10 mL) was degassed with N2 and stirred at 80°C for 1 h. The mixture was cooled to room temperature and concentrated to give the crude desired productExample 9b (600 mg, crude yield >100%) as a yellow solid, which was used in next step directly. Step 2: Example 9d
[0329] To a solutionof Example 9b (600 mg crude, 2.0 mmol theoretically) in DCM (10 mL) were added Example 9c (380 mg, 2.2 mmol) andTEA (404 mg, 4.0 mmol). The reaction mixture was warmed to 25°C and stirred for 30min. The mixture was quenched with sat. NaHC03 (100 mL), and then extracted with DCM (100 mL*3). The combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography
(Petroleum Ether/EtOAc= 3/2) to give the desired product Example 9d (190 mg, yield 23%) as a white solid. LC-MS [M+l]+ = 415.0/417.0
Step 3: Example 9
[0330] A mixtureof Example 9d (83 mg, 0.20 mmol), Example 9e (46 mg, 0.30 mmol), and
Pd(dppf)Cl2(15 mg, 0.02 mmol), Na2C03 (64 mg, 0.6 mmol) in dioxane/H20 (1.6mL/0.4mL) was degassed with N2 and stirred at 110°C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50mL*3). The combined organic layer washed with brine (30mL), dried over Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desire product (24.8 mg, yield 28 %) as a white solid.LC-MS[M+l]+=445.1
1H NMR (400 MHz, Chloroform-d) δ 9.09 (d, J= 15.1 Hz, 1H), 8.31 (d, J= 8.3 Hz, 1H), 8.07 (d, J= 7.3
Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.20 (d,
J= 12.2 Hz, 1H), 6.80 (s, 1H), 6.52 (d, J= 1.9 Hz, 1H), 5.31 (p, J= 6.6 Hz, 1H), 2.29 (s, 3H), 1.95-1.90
(m, 1H), 1.56 (d, J= 6.6 Hz, 6H), 0.92 (ddt, J= 8.3, 5.5, 3.0 Hz, 2H), 0.87-0.81 (m, 2H).
Example 10: Synthesis of 7-(4-cyclopropyl-lH-imidazol-l-yl)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yI)-6-methyl-3,4-dihydroisoquinolin -l(2H)-one
Figure imgf000116_0001
Step 1: Example 10b
[0331] To a solution of Example 10a (31.8 g, 0.22 mol) in con.H2S04 (98%, 200 mL,) was added con.HN03 (>98%, 14.4 g, 0.23 mol) at 0°C. After addition, the reaction mixture was stirred at r.t. for 2 h and then poured into ice water (1 L). The resulting mixture was extracted with EtOAc (300 mL*2). The combined organic layer was washed with water (200 mL*3), followed by brine (200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 5/1) to give the desired product Example 10b (15.0 g, yield 37%) as a yellow solid.
Step 2: Example 10c
[0332] To a solution of Example 10b (10.0 g, 0.05 mol) in MeOH (100 mL) was added 5% Pd-C (1 g), which was stirred under H2 for 48 h at r.t. The mixture was filtered and concentrated to give the desired product Example 10c (6.0 g, yield 71%) as a yellow solid. LCMS [M+l] + = 162.1.
Step 3: Example lOd
[0333] Example 10c (5.0 g, 0.03 mol) was dissolved in con. HC1 (12N, 10 mL) at 0°C. A solution of NaN02 (2.25 g, 0.03 mol) in H20 (15 mL) was added dropwise, maintaining the temperature to be around 0°C for 1 h. Then, a solution of KI (5.67 g, 0.03 mol) in H20 (30 mL) was added and the mixture was stirred for another 1 h. The mixture was extracted with EtOAc and the organic layers were combined, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography (Petroleum ether/EtOAc = 10/1) to give the desired product Example lOd (2.0 g, yield 24%) as a brown solid. LCMS [M+l] + = 272.9.
Step 4: Example lOe
[0334] To a mixture of Example lOd (1.4 g, 5.15 mmol) and methanesulfonic acid (5.5 mL, 84.4 mmol) in DCM (49 mL) was added NaN3 (0.67 g, 10.29 mmol) at 0°C. The mixture was warmed up to it. and stirred for 16 h. The mixture was poured into 10% NaOH (aq., 54 mL) and extracted with DCM (27 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was triturated in MeOH/THF/DMF (4/4/1) under ultrasonic for 15 min and then filtered to give the desired product Example lOe (928 mg, yield 36%) as a white solid. LCMS [M+l] + = 287.9.
Step 5: Example lOg
[0335] A mixture of Example lOe (928 mg, 3.23 mmol), Example lOf (437 mg, 4.04 mmol), Cul (62 mg, 0.32 mmol), Cs2C03 (3.16 g, 9.69 mmol) and N,N'-Dimethyl-l,2-cyclo-hexanediamine (92 mg, 0.65 mmol) in DMF (11.5 mL) was heated at 130°C for 16 h.The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated under reduced pressure to afford crude product (2.64 g) as brown oil (containing DMF). Part of the crude product (0.70 g) was purified by prep-TLC (DCM/MeOH = 100/4) to give the desired product Example lOg (150 mg, yield 17% (64% if the whole crude product was purified)) as a brown solid.
[0336] LCMS [M+l] + =268.1
Step 6: Example 10
[0337] A mixture of Example lOg (150 mg, 0.56 mmol), Example lOh (194 mg, 0.62 mmol), Cul (43 mg, 0.22 mmol), K3P04 (238 mg, 1.12 mmol) and N,N'-Dimethyl-l,2-cyclo-hexanediamine (32 mg, 0.22 mmol) in 1.4,-dioxane (3 mL) was heated at 100°C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (91 mg, yield 36%) as a white solid. LCMS [M+l] + = 454.1. [0338] 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.05 - 7.99 (m, 1H), 7.98 - 7.90 (m, 2H), 7.77 (s,
1H), 7.67 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 5.37 (m, 1H), 4.24 (t, J= 6.4 Hz, 2H), 3.17 (t, J= 6.4 Hz,
2H), 2.23 (s, 3H), 1.84 (m, 1H), 1.49 (d, J= 6.7 Hz, 6H), 0.79 (m, 2H), 0.70 (m, 2H).
Example 11: General Procedure for the synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4- methyl-N-(6-(5-methyl-6,7-dihydro-5H-py [l,2,4]triazol-3-yl)pyridin-2-yl)benzamide
Figure imgf000118_0001
Step 1: Example lib
[0339] A mixture of Example 11a (10.0 g, 100.0 mmol) and POCl3 (32.0 g, 200.0 mmol) in DCM (50 mL) was stirred at 40°C for 1 hour. The mixture concentrated to give the crude desired product Example lib (21.6 g, crude yield >100%) as colorless oil, which was used in the next step without further purification.
Step 2: Example lid
[0340] A mixture of Example lib (21.6 g, crude, 100.0 mmol), Example 11c (10.0 g, 100.0 mmol), and DIPEA (33.0 g, 300.0 mmol) in toluene (50 mL) was stirred at 130°C for 3 hours, which was then cooled to r.t. and treated with NaHC03 (aq.) until pH = 11. Then resulting mixture was stirred at 100°C for overnight, and then cooled to r.t. The mixture was extracted with EtOAc (150 mL*3). The combined organic layer washed with brine (30 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example lid (1.8 g, yield 6%) as yellow oil. LCMS [M+l]+ = 278.9.
Step 3: Example lie
[0341] A mixture of Example lid (1.8 g, 6.4 mmol), BocNH2 (1.13 g, 9.6 mmol), Pd2(dba)3 (585 mg, 0.64 mmol), Xantphos (380 mg, 0.64mmol), and Cs2C03 (4.2 g, 12.8 mmol) in dioxane (20 mL) was stirred at 90°C for overnight. The mixture was diluted with water, extracted with EtOAc (150 mL*3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example lie (1.9 g, yield 94%) as yellow oil. LCMS [M+l]+ =316.0. Step 4: Example llf
[0342] A mixture of Example lie (1.0 g, 3.1 mmol), in HC1/THF (5 mL) was stirred at r.t. for overnight. The mixture was concentrated to give the crude desired product Example llf (800 mg, yield 99%) as yellow oil, which was used in the next step directly without further purification. LCMS [M+l]+ =216.0.
Step 5: Example 11
[0343] To a solution of Example llf (483 mg, 1.86 mmol) and Example llg (400 mg, 1.86 mmol) in pyridine (10 mL) at 0°C was added POCl3 (853 mg, 5.58 mmol). The mixture was stirred at 0°C for 1 hour, and then quenched with water and extracted with EtOAc. The organic layers were combined and concentrated. The residue was purified by prep-HPLC to afford Example 11 (300 mg, yield 35%) as a yellow solid. LC-MS [M+1] + = 458.0.
[0344] 1H NMR (400 MHz, Chloroform-; ) δ 9.05 (d, J= 16.0 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H), 8.09 (t, J= 7.7 Hz, 2H), 7.88 (t, J= 8.0 Hz, 1H), 7.44 (d, J= 1.5 Hz, 1H), 7.19 (d, J = 12.5 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 5.01 (q, J= 6.6 Hz, 1H), 3.14-2.95 (m, 3H), 2.46-2.40 (m, 1H), 2.29 (s, 3H), 1.91 (m, J = 8.3, 5.1 Hz, 1H), 1.55 (d, J= 6.5 Hz, 3H), 0.89 (m, J= 8.2, 2.8 Hz, 2H), 0.83 (m, J= 5.2, 2.7 Hz, 2H).
Example 13: Synthesis of 5-(5-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-2,3-dihydrobenzofuran-7-carboxamide
Figure imgf000119_0001
Step 1: Example 13c
[0345] A mixture of Example 13a (600 mg, 5.55mmol) and Example 13b (400 mg, 1.65 mmol) Cul (45 mg, 0.24 mmol), K3P04 (1 g, 4.7 mmol), 4,7-Dihydroxy-l,10-phenanthroline (cas: 3922-40-5, 90 mg, 0.42 mmol), TBAB (386 mg, 1.2 mmol) in H20 (10 mL) under N2 was heated at 100 oC overnight. After cooling, filtered and concentrated under reduced pressure to give the crude and further purified by silica gelchromatography to give the product 200 mg as yellow solid. LCMS [M+1] + =271.0
Step 2: Example 13
[0346] A solution of Example 13c (200 mg, 0.74 mmol) and Example 13d (150 mg, 0.74 mmol) in 5 mL of pyridine was cooled to 0 °C, then POCl3 (765 mg, 5 mmol) was added dropwise. The reaction mixture was stirred for 1 h at this temperature. LC-MS analysis showed Example 13c was consumed, the mixture was poured into 50 mL of water and stirred for 10 min. Then the mixture was extracted with DCM (50 mL * 3). The combined organic phase was dried over anhydrous Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified with Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 13 (5 mg, yield 2.9%) as a white solid. LCMS [M+l] + =456.1
[0347] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.89 (s, 1H), 8.31 - 8.26 (m, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.78 (d, J= 2.5 Hz, 1H), 7.73 (s, 1H), 7.68 (d, /= 2.2 Hz, 1H), 6.71 (s, 1H), 5.42- 5.32 (m, 1H), 4.91 (t, J= 8.7 Hz,2H), 3.39 (d, J= 8.5 Hz, 2H), 1.58 (d, J= 5.4 Hz, 1H), 1.53 (d, J= 6.7 Hz, 6H), 0.80 - 0.75 (m, 2H), 0.61 (dt, J= 5.2, 2.9 Hz, 2H).
Example 15&16: Synthesis of 6-(4-cyclopropyI-lH-imidazol-l-yl)-2-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)isoindolin-l-one (15) and 6-(5-cyclopropyl-lH-imidazol-l-yl)-2-(6-(4- isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-l-one (16)
Figure imgf000120_0001
Step 1: Example 15c &15d
[0348] Into a 20-mL microwave tube were added Example 15a (500 mg, 1.93 mmol), Example 15b (229 mg, 2.12 mmol), Cul (184 mg, 0.97 mmol), K3PO4 (819 mg, 3.86 mmol) and quinolin-8-ol (50 mg, 0.38 mmol) successively. Then, DMF (6 mL) was added by a syringe. The mixture was degassed by nitrogen for three times and sealed. The reaction was heated to 130°C under microwave for 30 min. The reaction was filtered, washed by MeOH and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford a mixture of Example 15c&15d (80 mg, yield 17 %) as a white solid. LCMS [M+l] + = 240.0
Step 2: Example 15
[0349] To a solution of Example 15c&15d (70 mg, 0.29 mmol) in 1,4-dioxane (2 mL) was added Example 15e (101 mg, 0.32 mmol), Cul (22 mg, 0.12 mmol), K3PO4 (125 mg, 0.59 mmol) and N1.N2- dimethylcyclohexane-l,2-diamine (17 mg, 0.12 mmol) successively. The mixture was degassed by nitrogen for three times and heated at 100°C for 16 h. The reaction was filtered and purified by silica gel chromatography to give a crude product, which was further purified by Prep-HPLC (by Ultimate XB- C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford the desired product Example 15 (17 mg, yield 14 %) & the other isomer Example 16 (7 mg, yield 7%) as a white solid. LCMS [M/2+l]+ = 213.6
Example 15
[0350] 1H NMR (400 MHz, DMSO-d6) 6 8.92 (s, 1H), 8.63 (d, J= 8.3 Hz, 1H), 8.26 (d, J= 1.5 Hz, 1H), 8.08 (t, J= 8.0 Hz, 1H), 8.03 (d, J= 2.2 Hz, 1H), 7.97 (dd, J= 8.2, 2.2 Hz, 1H), 7.91 (d, J= 7.6 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.65 (d, J= 1.5 Hz, 1H), 5.54-5.46 (m, 1H), 5.17 (s, 2H), 1.82 (td, J= 8.4, 4.3 Hz, 1H), 1.56 (d, J= 6.7 Hz, 6H), 0.79 (dd, J= 8.4, 2.5 Hz, 2H), 0.69 (dd, J = 5.1, 2.3 Hz, 2H).
Example 16
[0351] 1H NMR (400 MHz, DMSO-<¾ δ 8.92 (s, 1H), 8.65-8.60 (m, 1H), 8.26 (s, 1H), 8.08 (t, J= 8.0 Hz, 1H), 8.04 (d, J= 2.1 Hz, 1H), 7.97 (dd, J= 8.2, 2.2 Hz, 1H), 7.91 (dd, J= 7.6, 0.9 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.66 (s, 1H), 5.50 (p, J= 6.7 Hz, 1H), 5.17 (s, 2H), 1.83 (td, J= 8.4, 4.3 Hz, 1H), 1.56 (d, J= 6.7 Hz, 6H), 0.83-0.78 (m, 2H), 0.70 (dt, J= 5.1, 2.8 Hz, 2H).
Example 17: Synthesis of 5-iodo-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6-dimethyl- 2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000121_0001
Step 1: Example 17b
[0352] A mixture of Example 17a (20.0 g, 0.13 mol) and NIS (38.2 g, 0.17 mol) in DMF (500 mL) was stirred at 50°C with stirring under N2 overnight. Then, the reaction solution was poured into water (1000 mL) and filtrated. The filtrate was washed with water, and then concentrated under reduced pressure to give the crude desired product Example 17b (37.2 g, crude yield 100%) as a brown solid. LCMS [M+l]+ = 280.
Step 2: Example 17c
[0353] A mixture of Example 17b (36.9 g, 0.13 mol), Mel (30.7 mL, 0.49 mol), and K2C03 (54.8 g, 0.40 mol) in DMF (600 mL) was stirred at r.t. with stirring for 4 h. Then, the reaction solution was poured into water (1000 mL). After extraction with EtOAc (200 mL*3), the combined organic layer was dried over Na2S04)filtered, and concentrated under reduced pressureto give the crude desired product Example 17c (29.2 g, crude yield 100%) as yellow liquid. LCMS [M+l]+ = 308. Step 3: Example 17d
[0354] To a mixture of Example 17c (29.2 g, 0.10 mol) in EtOH/H20 (300 mL/150 mL) was added LiOH'H20 (20.0 g, 0.48 mol). The resulting mixture was stirred at r.t. for 2.5 h. After being concentrated under reduced pressure to remove most of EtOH, the residue was acidified with IN HCl solution to a pH of 3. The aqueous solution was washed with EtOAc, and then concentrated under reduced pressure to give the desired product Example 17d (6.0 g, yield 22%) as a yellow solid. LCMS [M+l]+ = 294 Step 4: Example 17
[0355] To a mixture of Example 17d (100 mg, 0.341 mmol) and Example 17e (76 mg, 0.375 mmol) in POClj (287 mg, 1.871mmol) was added pyridine (2 mL) at 0°C, which was stirred at 0°C for 1 h. The reaction solution was poured into water (5 mL) and filtrated. The filtrate was washed with water, followed by EtOAc twice, to give the desired product (54 mg, yield 33%) as a yellow solid. LCMS [M+l]+ = 479.0
[0356] 1H NMR (400 MHz, DMSO-d6 ) δ 12.55 (s, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.31 (dd, J= 8.3, 0.9 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 7.7, 0.9 Hz, 1H), 5.24-5.31 (m, 1H), 3.69 (s, 3H), 2.72 (s, 3H), 1.51 (d, J= 6.7 Hz, 6H).
Example 18: Synthesis of 6-(4-cyclopropyl-lH-imidazol-l-yl)-3-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)quinazolin-4(3H)-one
Figure imgf000122_0001
Step 1: Example 18c
[0357] To a solution of Example 18a (1.00 g, 3.67 mmol) in DMF (10 mL) were added Cul (351 mg, 1.83 mmol), Cs2C03 (2.38 g, 7.30mmol), Example 18b(476 mg, 4.41 mmol), andN1,N2-dimethyl- cyclohexane-l,2-diamine (105 mg, 0.74 mmol). The resulting mixture was degassed with N2 and stirred at 130°C under microwave for 2 h. The mixture was diluted with MeOH and filtered. The filtrate was concentrated under vacuum and the residue was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product Example 18c (110 mg, yield 12%) as a yellow solid. LC-MS: [M+H]+ = 253.0
Step 2: Example 18
[0358] To a mixture of Example 18c (70 mg, 0.28 mmol) and Example 18d (174 mg, 0.56 mmol) in DMSO (2 mL) were added Cul (5 mg, 0.026mmol) and K2C03 (38 mg, 0.28 mmol). The resulting suspension was degassed with N2and stirred at 150°Cunder microwave for 3 h. The mixture was allowed to cool to r.t., diluted with MeOH, and then filtered. The filtrate was concentrated under vacuum and the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product (10 mg, yield 8%) as a brown solid. LCMS [M+l]+ = 439.0
[0359] NMR (400 MHz, Methanol-^) δ 8.93 (s, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 8.27 (q, J= 7.6 Hz, 3H), 8.09 (s, 1H),8.04 (d, J= 7.4 Hz, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.54 (d, J= 17.1 Hz, 1H), 5.57 - 5.42 (m, 1H), 1.93 (s, 1H), 1.58 (s, 6H), 0.90 (s, 2H), 0.78 (s, 2H).
Example 19: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6-dimethyl-2-oxo- 5-phenyl-l,2-dihydropyridine-3-carboxamide
Figure imgf000123_0001
[0360] A mixture of Example 19a (120 mg, 0.25mmol), Example 19b (37 mg, 0.30 mmol),
Pd(dppf)Cl2 (18 mg, 0.02 mmol ) and Na2C03 (66 mg, 0.63 mmol) in dioxane/H20 (v/v=5: l, 6 mL) was stirred at 80°C 18 hunder N2. LC-MS showed most of Example 19a was consumed and the desired product was detected. The mixture was filtered and the filtrate was concentrated.The crude product was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 19 (11.8 mg, yield 11%) as a white solid. LCMS [M+l] + = 429.0
1H NMR (400 MHz δ 12.74 (s, 1H), 8.90 (s, 1H), 8.39 - 8.27 (m, 2H), 8.02 (t, J= 8.0 Hz,
Figure imgf000123_0002
1H), 7.85 - 7.78 (m, 1H), 7.54 - 7.33 (m, 5H), 5.36 - 5.26 (m, 1H), 3.71 (s, 3H), 2.45 (s, 3H), 1.54 (d, J= 6.7 Hz, 6H).
Example 20: Synthesis of 5-(cyclopropylethynyl)-N-(6-(4-isopropyl-4H^l,2,4-triazol-3-yl)pyridin-2- yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000123_0003
[0361] A mixture of Example 20a (120 mg, 0.25 mmol), Example 20b (33 mg, 0.50 mmol),
Pd(PPh3)2Cl2 ( 18 mg, 0.03 mmol ) and Cul (5 mg, 0.03 mmol) in DIPEA (4 mL) was stirred at 80 °C for 18 hunder N2. LC-MS showed most of Example 20a was consumed and the desired product was detected. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 20 (16.6 mg, yield 15.9%) as a white solid.
LCMS [M+1] + = 417.0
[0362] NMR (400 MHz,
Figure imgf000124_0004
δ 12.52 (s, 1H), 8.88 (s, 1H), 8.41 - 8.23 (m, 2H), 8.02 (t, J =
8.0 Hz, 1H), 7.81 (dd, J = 7.7, 0.9 Hz, 1H), 5.34 - 5.25 (m, 1H), 3.62 (s, 3H), 2.63 (s, 3H), 1.62 - 1.38 (m, 6H), 1.22 (s, 1H), 0.96 - 0.83 (m, 2H), 0.81 - 0.69 (m, 2H).
Example 21: Synthesis of 2'-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)spiro[cyclopropane- '-isoindolin] -3'-one
Figure imgf000124_0001
1: Example 21b
[0363] To a slurry of Example 21a (2.0 g, 11.4 mmol) and Ti(OiPr)4 (3.7 mL) in Et20 (60 mL) was added EtMgBr (8 mL, 1 mol/L) with stirring at 20°C. After lh, the reaction mixture was poured into ice water, which was adjusted with aqueous HC1 solution to pH about 5. After extraction with EtOAc (50 mL*2), the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 2/1) to give the desired product Example 21b (500 mg, yield 26 %) as a yellow solid. LC-MS [M+1] + =160.1 Step 2: Example 21
[0364] A mixture of Example 21b (100 mg, 0.62 mmol), Example 21c (210 mg, 0.68 mmol), K3P04 (263 mg, 1.24 mmol), Cul (48 mg, 0.25 mmol) and (lR,2S)-N -dimethylcyclo- hexane-l,2-diamine
Figure imgf000124_0002
(36 mg, 0.25 mmol) in dioxane (1.5 mL) was stirred at 100°C for 16 h. The mixture was then cooled and filtered. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 1/2) to give the desired product (18 mg, yield 8%) as a white solid. LC-MS [M+l]+ = 346.0.
1H NMR (400 MHz, δ 8.94 (s, 1H), 8.13 (t, J= 7.9 Hz, 1H), 7.95 (d, J= 7.6 Hz, 1H), 7.92 -
Figure imgf000124_0003
7.83 (m, 2H), 7.71 (t, J= 7.5 Hz, 1H), 7.54 (t, J= 7.5 Hz, 1H), 7.39 (d, J= 7.7 Hz, 1H), 5.14-5.22 (m, IH), 1.98 (q, /= 5.2 Hz, 2H), 1.51 (q, J= 5.3 Hz, 2H), 1.44 (d, J= 6.7 Hz, 6H). Example 22: Synthesis of 6'-cyclopropyl-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2- dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000125_0001
Example 22a Step 1 Example 22
[0365] Under an inert atmosphere, a mixture of Example 22a (200 mg, 0.42 mmol), Example 22b (77 mg, 0.47 mmol), Pd(dppf)Cl2 (31 mg, 0.042 mmol) and Na2C03 (116 mg, 1.09 mmol) in ethanol/H20 (v/v = 10/1, 11 mL) was stirred at 80°C for 2 h. The mixture was diluted with water, and extracted with EtOAc. The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to afford the desired product Example 22 (16 mg, yield 8%) as a white solid. LC-MS [M+l]+= 470.0
1H NMR (400 MHz, δ 12.70 (s, 1H), 8.89 (s, 1H), 8.39 (d, J= 2.1 Hz, 1H), 8.35 (d, J= 8.2
Figure imgf000125_0004
Hz, 1H), 8.28 (s, 1H), 8.02 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.5 Hz, 1H), 7.66 (dd, J= 8.0, 2.3 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 5.36-5.25 (m, 1H), 3.70 (s, 3H), 2.43 (s, 3H), 2.21- 2.11 (m, 1H), 1.54 (d, J = 6.7 Hz, 6H), 1.00-0.95 (m, 4H).
Example 23: Synthesis of 5-(3,4-difluorophenyl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000125_0002
Example 23a p p
[0366] A mixture of example23a (200mg, 0.42mmol), example23b (80 mg, 0.51 mmol), and Pd(PPh3)4 (45 mg, 0.04 mmol), Na2C03 (98 mg,0.9 mmol) in dioxane/H20 (1.6 mL/0.4 mL) was degassed with N2 and stirred at 100°C for 20 min by M.W. The mixture was diluted with 50 mL of water, extracted with EA (50mL*3). The combined organic layer washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desire product (4.0 mg, yield: 2.2 %) as a white solid. LCMS [M+l] + = 465.0
[0367] 1H NMR (400 MHz, D δ 12.69 (s, 1H), 8.90 (s, 1H), 8.35 (dd, J= 8.3, 0.9 Hz, 1H), 8.29
Figure imgf000125_0003
(s, 1H), 8.02 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6Hz, 1H), 7.59 - 7.49 (m, 2H), 7.24-7.21 (m,3.8 Hz, 1H), 5.35-5.25 (m, 1H), 3.70 (s, 3H), 2.44 (s, 3H), 1.54 (d, J= 6.7 Hz, 6H). Example 24: Synthesis of 5-(3,5-difluorophenyl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000126_0001
[0368] A mixture of Example24a (200 mg, 0.42 mmol), example 24b (80 mg, 0.51 mmol), and Pd(PPh3)4 (45 mg, 0.04 mmol), Na2C03 (98 mg, 0.92 mmol) in dioxane/H20 (1.6 mL/0.4 mL) was degassed with N2 and stirred at 100°C for 20 min by M.W. The mixture was diluted with 50 mLwater, extracted with EA (50 mL *3). The combined organic layer washed with brine (30 mL), dried over Na2SC>4 and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desire product (77.8 mg, yield: 39.3 %) as a white solid. LCMS [M+l]+ = 465.0
[0369] 1H NMR (400 MHz δ 12.66 (s, 1H), 8.90 (s, 1H), 8.35 (d, J= 8.3 Hz, 1H), 8.30 (s,
Figure imgf000126_0003
1H), 8.02 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.32 (tt, J= 9.4, 2.3 Hz, 1H), 7.22 - 7.13 (m, 2H), 5.37 - 5.25 (m, 1H), 3.69 (s, 3H), 2.46 (s, 3H), 1.54 (d, J= 6.7 Hz, 6H).
Example 26: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6-dimethyl-2-oxo- -(thiophen-3-yl)-l,2-dihydropyridine-3-carboxamide
Figure imgf000126_0002
p
[0370] A mixture of Example 26a (200 mg, 0.42 mmol), Example 26b (53 mg, 0.42 mmol),
Pd(dppf)Cl2 (31 mg, 0.04 mmol) and Na2C03 (133 mg, 1.26 mmol) in EtOH/H20 (1.6 mL/0.4 mL) was stirred at 80°C with stirring for 1 h under N2. Then, water (5 mL) was added into the reaction solution, which was filtrated. The filtrate was washed with water and the organic layer was concentrated and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (7 mg, yield 4%) as a white solid.LCMS [M+l]+ = 435.0
[0371] 1H NMR (400 MHz,
Figure imgf000126_0004
) δ 12.73 (s, 1H), 8.90 (s, 1H), 8.39-8.31 (m, 2H), 8.02 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.70 (dd, J= 4.9, 2.9 Hz, 1H), 7.61 (s, 1H), 7.21 (d, J= 4.9 Hz, 1H), 5.28-5.34 (m, 1H), 3.70 (s, 3H), 2.50 (s, 3H), 1.54 (d, J= 6.7 Hz, 6H). Example 27: Synthesis of 5-(furan-3-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazoI-3-yl)pyridin-2-yl)-l,6- dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000127_0001
[0372] A mixture of Example 27a (200 mg, 0.42 mmol), Example 27b (97 mg, 0.87 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and Na2C03 (133 mg, 1.26 mmol) in EtOH/H20 (1.6 mL/0.4 mL) was stirred at 80°C with stirring for 2 h under N2. Then, water (5 mL) was added into the reaction solution, which was filtrated. The filtrate was washed with water and the organic layer was concentrated and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 27 (121 mg, yield 69%) as a yellow solid.LCMS [M+l]+ = 419.0
[0373] 1H NMR (400 MHz, DMSO-4) δ 12.72 (s, 1H), 8.89 (s, 1H), 8.42-8.28 (m, 2H), 8.02 (t, J= 8.0 Hz, 1H), 7.91 (s, 1H), 7.87-7.77 (m, 2H), 6.70 (d, J= 1.8 Hz, 1H), 5.28-5.34 (m, 1H), 3.69 (d, J= 2.3 Hz, 3H), 2.54 (s, 3H), 1.54 (d, /= 6.7 Hz, 6H).
Example 28: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2-dimethyl-6-oxo- l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000127_0002
[0374] A mixture of Example 28a (200 mg, 0.42 mmol), Example 28b (54 mg, 0.42 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and Na2C03 (133 mg, 1.26 mmol) in EtOH/H20 (1.6 mL/0.4 mL) was stirred at 80°C for 1 h under N2. Then, water (5 mL) was added into the reaction solution, which was filtrated. The filtrate was washed with water, and concentrated, which was then purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (12 mg, yield 7%) as a white solid.LCMS [M+l]+ = 430.0 [0375] 1H NMR (400 MHz, 12.69 (s, 1H), 8.90 (s, 1H), 8.66-8.56 (m, 2H), 8.40-8.28 (m,
Figure imgf000127_0003
2H), 8.02 (t, J= 8.0 Hz, 1H), 7.83 (dd, J= 7.8, 5.6 Hz, 2H), 7.52 (dd, J= 7.9, 4.8 Hz, 1H), 5.31 (p, J= 6.7 Hz, 1H), 3.72 (s, 3H), 2.45 (s, 3H), 1.54 (d, J= 6.7 Hz, 6H). Example 30: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6-dimethyl-2-oxo- 5-(phenylethynyl)-l,2-dihydropyridine-3-carboxamide
Figure imgf000128_0001
[0376] A mixture of Example 30a (150 mg, 0.31 mmol), Example 30b (42 mg, 0.41 mmol),
Pd(PPh3)2Cl2 (22 mg, 0.03 mmol) and Cul (6 mg, 0.03 mmol) in DIPEA (5 mL) was stirred at 80 °C 18 hunder N2. LCMS showed most of Example 30a was consumed and the desired product was detected. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 30 (20.9 mg, yield 14.6%) as a white solid. LCMS [M+l]+ = 453.0
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.89 (s, 1H), 8.46 (s, 1H),8.34 (d, J= 8.3 Hz, 1H), 8.02 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.5 Hz, 1H), 7.60-7.57 (m,2H), 7.43-7.41 (m, 3H), 5.35-5.25 (m,lH), 3.66 (s, 3H), 2.76 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 32: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropylisoxazol-3- yl)pyridin-2-yl)-4-methylbenzamide
Figure imgf000128_0002
p Example 32b
[0377] To a solution of Example 32a (1.86 g, 10 mmol) in ethanol (20 mL) were added
Hydroxylaminehydrochloride (828 mg, 12 mmol) and Sodium acetate (1.64 g, 20 mmol). The mixture was stirred at room temperature for 16 h. Ethanol was removed in vacuo. The mixture was diluted with water, extracted with EtOAc, and the organic layers were combined, dried over Na2S04, and
concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 3/1) to give the desired product Example 32b (1.80 g, yield 90%) as a white solid. LC-MS [M+l]+ = 202.9 Step 2: Example 32c
[0378] To a solution of Example 32b (1.80 g, 8.9 mmol) in DMF (10 mL) was added NCS (1.54 g, 11.6 mmol). The mixture was stirred at room temperature for 16 h. Ice water (20 mL) was added to the mixture, and the precipitate was filtered at suction and dried under vacuum to provide the desired product Example 32c (1.60 g, yield 79%) as a white solid. LC-MS [M+l]+ = 236.9
Step 3: Example 32e
[0379] To a solution of pyrrolidine (447 mg, 6.3 mmol) and TEA (303 mg, 3.0 mmol) in DCM (10 mL) at 0°C was added Example 32d (1.03 g, 12.0 mmol). Immediately afterwards, Example 32c (705 mg, 3.0 mmol) in DCM (1 mL) was added dropwise and the reaction was stirred for 10 minutes at 0°C. After which, it was allowed to warm to room temperature and stirred at room temperature for 1.5 h. The mixture was concentrated and the residue was purified by silica gel chromatography (Petroleum
Ether/EtOAc = 10/1) to give the desired product Example 32e (860 mg, yield 85%) as colorless oil. LC- MS [M+l]+ = 339.9
Step 4: Example 32f
[0380] To a solution of Example 32e (860 mg, 2.50 mmol) in DCM (5 mL) was added m-CPBA (658 mg, 3.75 mmol). The mixture was stirred at room temperature for 4 h. The mixture was diluted with sat. NaHCO3, and then extracted with DCM. The organic layers were combined, dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 5/1) to give the desired product Example 32f (420 mg, yield 63%) as colorless oil. LC-MS [M+l]+ = 268.9 Step 5: Example 32g
[0381] Under an inert atmosphere, amixture of Example 32f (100 mg, 0.37 mmol), tert-butyl carbamate (130 mg, 1.11 mmol), Pd(OAc)2 (8 mg, 0.037 mmol), BINAP (25 mg, 0.074 mmol) and Cs2C03 (241 mg, 0.74 mmol) in toluene was stirred at 90°C for 16 h. The mixture was filtered and filtrate was
concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 5/1) to give the desired product Example 32g (60 mg, yield 54%) as a white solid. LCMS [M-l]" = 302.0 Step 6: Example 32h
[0382] To a solution of Example 32g (60 mg, 0.2 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the crude product Example 32h (50 mg, crude yield >100%) was used for next step directly without further purification. LC-MS [M+l]+ = 204.0
Step 7: Example 32
[0383] To a solution of Example 32h (41 mg, 0.2 mmol, theoretically) and Example 32i (52 mg, 0.2 mmol) in pyridine (4 mL) at 0°C was added POCI3 (153 mg 1.0 mmol). The mixture was stirred at 0°C for 1 h. The mixture was quenched with water, and extracted with EtOAc. The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford the desired productExample 32 (5 mg, yield 6%) as a white solid.LC-MS [M+l]+ = 446.0
1HNMR (400 MHz, DMSO-i/fi) δ 10.87 (s, 1H), 8.84 (s, 1H), 8.23 (d, J= 8.1 Hz, 1H), 8.05-7.96 (m, 1H), 7.66 (d, J= 22.2 Hz, 3H), 7.46 (d, J= 10.7 Hz, 1H), 7.17 (s, 1H), 3.49-3.5 (m,lH),2.23 (s, 3H), 1.84 (s, 1H), 1.13 (d, J= 6.5 Hz, 6H), 0.79 (m, 2H), 0.69 (m, 2H).
Example 34: Synthesis of l-(cyclopropylmethyl)-5-iodo-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000130_0001
Step 1: Example 34b
[0384] A mixture of Example 34a (10.0 g, 0.065 mol) and NIS (19.1 g, 0.085 mol) in DMF (300 raL) was stirred at 50°C under N2 overnight. Then, the reaction solution was poured into water (500 mL) and filtrated. The filtrate was washed with water, and then concentrated under reduced pressure to give the crude desired product Example 34b (14.7 g, yield 81%) as a brown solid.LCMS [M+l]+ = 280.1 Step 2: Example 34d
[0385] A mixture of Example 34b (3.0 g, 0.011 mol), Example 34c (4.4 g, 0.032 mol), and K2C03 (4.5 g, 0.032 mol) in DMF (50 mL) was stirred at 70°C overnight for 30 h. Then, the reaction solution was poured into water (200 mL). After extraction with EtOAc (50 mL*2), the combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 9/1) to give the desired product Example 34d (1.2 g, yield 29%) as pale-yellow liquid. LCMS [M+l]+ = 388
[0386] 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 4.24 (d, J= 6.9 Hz, 2H), 4.12 (d, J= 7.1 Hz, 2H), 2.61 (s, 3H), 1.37-1.17 (m, 2H), 0.58 (ddt, J= 9.1, 5.8, 3.0 Hz, 4H), 0.37 (ddt, J= 9.4, 6.3, 4.7 Hz, 4H).
Step 3: Example 34e
[0387] To a solution of Example 34d (1.2 g, 30.0 mmol) in EtOH/H20 (10 mL/5 mL) was added LiOH'H20 (0.65 g, 16.0 mmol), the resulting mixture was stirred at r.t. for 2.5 h. After concentrated under reduced pressure to remove most of EtOH, the resulting aqueous solution was acidified with IN HC1 to a pH about 3. The mixture was washed with EtOAc, and the remained filtrate was concentrated under reduced pressure to give the desired product Example 34e (546 mg, yield 53%) as a white solid.LCMS [M+l]+ = 334.1
Step 4: Example 34
[0388] A mixture of Example 34e (546 mg, 1.64mmol), Example 34f (366 mg, 1.80 mmol), and POCl3 (1.25 g, 8.20 mmol) were added into a round-bottom flask, to which pyridine (8 mL) was added at 0°C. Then, the reaction was stirred at 0°C for 1 h. The reaction solution was poured into water (30 mL) and filtrated. The filtrate was washed with water, followed by EtOAc twice, to give the desired product (37 mg, yield 4%) as a yellow solid.LCMS [M+l] + = 518.9.
[0389] 1H NMR (400 MHz, DMSO-4;) δ 10.54 (s, 1H), 8.88 (s, 1H), 8.48 (s, 1H), 8.30 (d, J= 8.3 Hz, 1H), 8.04 (t, 7= 8.0 Hz, 1H), 7.88 (d, J= 7.6 Hz, 1H), 5.51 (p, J= 6.7 Hz, 1H), 4.30 (d, J= 7.2 Hz, 2H), 2.61 (s, 3H), 1.43 (d, J= 6.7 Hz, 6H), 0.57-0.46 (m, 2H), 0.44-0.33 (m, 2H).
Example 37: Synthesis of 2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-5- ((l-methyl-lH-imidazol-2-yl)ethynyl)benzamide
Figure imgf000131_0001
[0390] Example 37a Example 37
Under inert atmosphere, a mixture of Example 37a (100 mg, 0.27 mmol), Example 37b (144 mg, 0.69mmol), Pd(PPh3)2Cl2 (19 mg, 0.027 mmol),TEA (272 g, 2.7 mmol) and Cul (5.2 mg, 0.027 mmol) in 10 ml DMF was stirred at 80°C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product (17 mg yield 15%) as a yellow solid.LCMS [M+l] + = 444.0
[0391] 1H NMR (400 MHz, DMSO-d6 ) δ 10.91 (s, 1H), 8.85 (s, 1H), 8.19 (d, J= 8.3 Hz, 1H), 8.03 (t, J
= 8.0 Hz, 1H), 7.93 (d, J= 7.1 Hz, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.44 (d, J= 10.9 Hz, 1H), 7.35 (s, 1H),
7.01 (s, 1H), 5.70 - 5.61 (m, 1H), 3.78 (s, 3H), 2.54 (s, 3H), 1.42 (d, J= 6.7 Hz, 6H).
Example 43: Synthesis of 2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-5-
((l-methyl-1 H-imidazol-4-yl)ethynyl)benzaniide
Figure imgf000132_0001
Step 1: Example 43c
[0392] A solution of Example 43a (1.86 g, 6.64 mmol) and Example 43b (1.3 g, 6.40 mmol) in lOmL ofpyridine was cooled to 0 °C, then POCl3 (5 g, 33 mmol) was added dropwise. The reaction mixture was stirred for 1 h at this temperature; LC-MS analysis showed Example 43a consumed, the mixture was poured into 250 mL of water and stirred for 10 min. The mixture was extracted with DCM (250 mL * 3). The combined organic phase was dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (Example 43c, 1.5g yield: 48.5%) as a yellow solid.LCMS [M+l] + = 467.0.
Step2: Example 43e
[0393] Under inert atmosphere, a mixture of Example 43c (1.2 g, 2.58 mmol), Example 43d (0.7 g, 7.12 mmol), Pd(PPh3)2Cl2 (175 mg, 0.25 mmol), triethylamine (2.5 g, 24.71 mmol) and Cul (47 mg, 0.25 mmol) in 100 mL of DMF was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, and filtered and the filtrate was concentrated.The residue was purified by silica gel chromatography to give the desired product (Example 43e, 250 mg yield: 22.3%) as a yellow solid. LCMS [M+l] + = 436.0 Step3: Example 43f
[0394] A mixture of Example 43e (250 mg, 0.57 mmol) and K2C03 (500 mg, 3.62 mmol) in 50 mL of MeOH was stirred at 25°C for 2 hours. The mixture was filtered and the filtrate was concentrated to give 200 mg ofwhite solid product (Example 43f, 200 mg yield: 96.5%). LCMS [M+l] + = 363.0
Step4: Example 43
[0395] Under inert atmosphere, a mixture of Example 43f (100 mg, 0.27 mmol), Example 43g (144 mg, 0.69 mmol), Pd(PPh3)2Cl2 (19 mg, 0.027 mmol), triethylamine (272 mg, 2.7 mmol) and Cul (5.2 mg, 0.027 mmol) in 10 mL of DMF was stirred at 80°C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product (17mg, yield: 14.2%) as a yellow solid. LCMS [M+l] +=444.0 [0396] 1H NMR (400 MHz, DMSO-d6 ) δ 10.85 (s, 1H), 8.85 (s, 1H), 8.19 (d, J= 8.3 Hz, 1H), 8.02 (t, J
= 8.0 Hz, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.77 (d, J= 7.1 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.38 (d, J=
11.1 Hz, 1H), 5.72 - 5.61 (m, 1H), 3.67 (s, 3H), 3.32 (s, 3H), 1.42 (d, J= 6.6 Hz, 6H).
Examples 47 and 48: Synthesis of (R)-5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methyl-N-(6-
(5-methyl-6,7-dihydro-5H-pyrrolo[2,l-c] [l,2,4]triazol-3-yl)pyridin-2-yl)benzamide (47) and (S)-5-
(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,l- c] [l,2,4]triazol-3-yl)pyridin-2-yl)benzamide (48)
[0397] Example 11 was separated using chiral separation. The chiral separation was done on Gilson GX-281 (CHIRALPAK® AD-H: 5 μm, 20 mm* 250 mm), to give two peaks: peak 1 (RT=15.26), and peak 2 (RT=25.55).
Figure imgf000133_0001
Example 47a: (R)-5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7- dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3-yl)pyridin-2-yl)benzamide.TFA
[0398] Peak 1 (RT= 15.26), 30 mg, yield 32% as a yellow solid. Absolute chirality was assigned arbitrarily.
[0399] LCMS [M+l]+ = 458.0/LCMS [M/2+l]+ = 229.6.
[0400] 1H NMR (400 MHz, Chloroform-cO δ 9.06 (d, J= 15.9 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H), 8.08 (d, J= 7.2 Hz, 2H), 7.89 (t, J= 7.9 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J= 12.3 Hz, 1H), 6.81 (s, 1H), 5.03 (s, 1H), 3.03 (s, 3H), 2.42 (s, 1H), 2.29 (s, 3H), 1.92 (s, 1H), 1.55 (d, J= 6.3 Hz, 3H), 0.92 (s, 2H), 0.85 (s, 2H).
Example 48a: (S)-5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7- dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3-yl)pyridin-2-yl)benzamide.TFA
[0401] Peak 2 (RT= 25.55), 14.4 mg, yield 31% as a yellow solid. Absolute chirality was assigned arbitrarily.
[0402] LCMS [M+l]+ = 458.0/LCMS [M/2+l]+ = 229.6.
[0403] 1H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J= 15.9 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 2H), 7.89 (t, J= 7.8 Hz, 1H), 7.50 (s, 1H), 7.20 (d, J= 12.3 Hz, 1H), 6.81 (s, 1H), 5.03 (s, 1H), 3.03 (s, 4H), 2.43 (s, 1H), 2.29 (s, 3H), 1.91 (s, 1H), 1.55 (d, J= 6.2 Hz, 4H), 0.92 (s, 2H), 0.85 (s, 2H).
Figure imgf000134_0001
[0404] A mixture of Example 47b (114 mg, 0.21 mmol) and K2C03 (138 mg, 1.0 mmol) in CH3CN (3 mL) was stirred at room temperature for 30 min. The resulting mixture was filtered, the organic layers was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 35/65 over 50 min, desired peak @ 30 min, H20/CH3CN = 52/48, table shown below) to give the desired product Example 47 (30 mg, yield 32%) as a yellow solid.
[0405] LCMS [M+l]+ = 458.0/LCMS [M/2+l]+ = 229.6.
[0406] 1H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J= 15.9 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H), 8.08 (d, J= 7.2 Hz, 2H), 7.89 (t, J= 7.9 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J= 12.3 Hz, 1H), 6.81 (s, 1H), 5.03 (s, 1H), 3.03 (brs, 3H), 2.42 (s, 1H), 2.29 (s, 3H), 1.92 (s, 1H), 1.55 (d, J= 6.3 Hz, 3H), 0.92 (s, 2H), 0.85 (s, 2H).
Step 2: Example 48
[0407] A mixture of Example 48a (57 mg, 0.10 mmol) and K2C03 (69 mg, 0.5 mmol) in CH3CN (3 mL) was stirred at room temperature for 30 min. The resulting mixture was filtered, the organic layers was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 35/65 over 50 min, desired peak @ 30 min, H20/CH3CN = 52/48, table shown below) to give the desired product Example 48 (14.4 mg, yield 31%) as a yellow solid.
[0408] LCMS [M+l]+ = 458.0/LCMS [M/2+l]+ = 229.6.
[0409] 1H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J= 15.9 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 2H), 7.89
(t, J= 7.8 Hz, 1H), 7.50 (s, 1H), 7.20 (d, J= 12.3 Hz, 1H), 6.81 (s, 1H), 5.03 (s, 1H), 3.03 (brs, 3H), 2.43
(s, 1H), 2.29 (s, 3H), 1.91 (s, 1H), 1.55 (d, J= 6.2 Hz, 3H), 0.92 (s, 2H), 0.85 (s, 2H).
Example 51: Synthesis of 6'-cyclopropyl-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- mcthyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]a=5rb-c oxamide
Figure imgf000135_0001
[0410] A mixture of Example 51a (50mg, O.l lmmol), Example 51b (21mg, 0.13mmol) in Dioxane/H20 (5mL, 10: l(v/v)) was added Pd(dppf)2Cl2 (5 mg, 0.0068 mmol) and Na2C03(34 mg, 0.33 mmol). Then the mixture was degassed by bubbling argon through the solution for 10 min using a syringe needle. After that, the mixture was heated to 80°C and stirred overnight. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (14.7 mg, Yield 30.0%) as a white solid.LCMS [M+l]+ = 456.0 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.89 (s, 1H), 8.74 (d, J= 2.7 Hz, 1H), 8.68 (d, J= 2.1 Hz, 1H), 8.65 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.92 (dd, J= 8.2, 2.4 Hz, 1H), 7.82 (d, /= 7.6 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 5.34-5.26 (m, 1H), 3.70 (s, 3H), 2.17-2.10 (m, 1H), 1.52 (d, J= 6.7 Hz, 6H), 0.99-0.91 (m, 4H).
Example 52: Synthesis of 5-(4-(2-hydroxypropan-2-yl)phenyl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000135_0002
[0411] A mixture of Example 52a (50 mg, 0.11 mmol), Example 52b (23.35 mg, 0.13 mmol) in 1,4- dioxane/H20 (5mL, 10: 1) was added Pd(dppf)2Cl2 (5 mg, 0.0068 mmol) and Na2C03(34.26 mg, 0.33 mmol). Then the mixture was degassed by bubbling argon through the solution for 10 min using a syringe needle. After that, the mixture was heated to 80°C and stirred for overnight at 80°C. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (14.7 mg, Yield 28.8%) as a white solid.LCMS [M+l]+ = 473.0
[0412] 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.89 (s, 1H), 8.75 (d, J= 2.8 Hz, 1H), 8.60 (d, J = 2.8 Hz, 1H), 8.38 (d, J= 8.3 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.1 Hz, 1H), 7.57 (dd, J = 8.7, 12.8 Hz,4H), 5.30 (m, 1H), 5.06 (s, 1H), 3.71 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H), 1.44 (s, 6H). Example 53: Synthesis of 5-(4-(tert-butyl)phenyI)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000136_0001
[0413] A mixture of Example 53a (50 mg, 0.11 mmol), Example 53b (23.0 mg, 0.13 mmol) in Dioxane/H20 (5mL, 10: 1) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol) and Na2C03(34.26 mg, 0.33 mmol). Then the mixture was degassed by bubbling argon through the solution for 10 min using a syringe needle. After that, the mixture was heated to 80°C and stirred for overnight at 80°C. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (Example 53, 6.7 mg, Yield 13.2%) as a white solid.LCMS [M+l]+ = 472.1 [0414] 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.89 (s, 1H), 8.74 (d, J= 2.8 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.38 (d, J= 8.3 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.2 Hz, 1H), 7.58(d, J= 4.0 Hz, 2H),7.49 (d, J= 4.0 Hz, 2H), 5.34-5.24 (m, 1H), 3.71 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H), 1.30 (s, 9H). Example 55: Synthesis of 7-(4-cyclopropyl-lH-imidazol-l-yl)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin 2 yl)isoquinolin-l(2II)-onc
Figure imgf000136_0002
Step 1: Example 55c
[0415] Into a 20-mL microwave tube was added Example 55a (300 mg, 1.339 mmol), Example 55b (173 mg, 1 ,61 mmol), Cul (100 mg, 0.53mmol), K3P04 (567 mg, 2.68 mmol) and Ν',Ν2- dimethylcyclohexane-l,2-diamine (75 mg, 0.53mmol) successively. DMF (6 mL) was added by syringe. The mixture was degassed by nitrogen for three times and sealed. The reaction was heated up to 150°C by microwave for lh. LC-MS showed reaction completed. The reaction was filtered, washed by MeOH and purified by flash chromatography to afford Example 55c (110 mg, yield: 32.6%, crude) as a yellow solid. LCMS [M+l]+ = 252.0 Step 2: Example 55
[0416] To a solution of Example 55c (110 mg, 0.44 mmol) in toluene (2 mL) was added Example 55d (55 mg, 0.18 mmol), Cul (33 mg, 0.18 mmol), K3P04 (11 1 mg, 0.53 mmol) and Ν',Ν2- dimethylcyclohexane-l,2-diamine (25 mg, 0.18 mmol) successively. The mixture was degassed by nitrogen for three times and heated up to 120°C for 1 hour. LC-MS showed reaction completed. The reaction was filtered and purified by flash chromatography to give a crude product which was re-purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford Example 55 (4.7 mg, yield: 7.58 %) as a yellow solid.
[0417] LCMS [M+l]+ =438
[0418] 1H NMR (400 MHz, DMSO-d 6) δ 8.90 (s, 1H), 8.34 (d, J= 2.4 Hz, 1H), 8.30 - 8.08 (m, 3H), 8.06 (dd, J= 8.6, 2.5 Hz, 1H), 7.97 (dd,J= 7.0, 2.0 Hz, 1H), 7.85 (dd, J= 23.3, 8.1 Hz, 2H), 7.62 (d, J= 1.5 Hz, 1H), 6.86 (d, J= 7.6 Hz, 1H), 5.29 (s, 1H), 1.85 (s, 1H), 1.46 (d, J= 6.6 Hz, 6H), 0.75 (ddt, J = 34.4, 5.2, 2.4 Hz, 4H).
Example 57: Synthesis of 5-(6-cyclopropylpyridin-3-yl)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)isoindoline-l,3-dione
Figure imgf000137_0001
mixture of Example 57a (130 mg, 0.32mmol), Example 57b (62 mg, 0.38 mmol), Pd(dppf)2Cl2 ( 23 mg, 0.032 mmol )and Na2C03 (67 mg, 0.63 mmol) in dioxane/H20 (v/v=4: 1, 5 mL) was stirred at 80 °C 18 hunder N2. LCMS (BD01066-085-1) showed most of Example 57a was consumed. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give Example 57(41.2 mg, yield 29.4%) as a white solid. LCMS [M+18+l]+ = 469.0
1H NMR (400 MHz, DMSO-d 6) δ 8.83 (s, 1H), 8.71 (d, J= 2.4 Hz, 1H), 8.33 (dd, J= 8.3, 0.9 Hz, 1H),
8.13 (s, 1H), 7.94 (ddd, J= 8.1, 5.1, 2.7 Hz, 2H), 7.84 - 7.66 (m, 3H), 7.37 (d, J= 8.1 Hz, 1H), 5.72 (p, J
= 6.7 Hz, 1H), 2.18 - 2.08 (m, 1H), 1.47 (d, J= 6.7 Hz, 6H), 1.02 - 0.88 (m, 4H).
Example 59: Synthesis of 6-(cyclopropylethynyl)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)isoindolin-l-one
Figure imgf000138_0001
Step 1: Example 59c
[0420] To a solution of Example 59a (317 mg, 1.5 mmol), Example 59b (470 mg, 1.5 mmol), K3P04 (636 mg, 3 mmol), Cul (29 mg, 0.15 mmol) in dioxane (7 mL) was added N1,N2-dimethylcyclohexane- 1,2-diamine (43 mg, 0.3 mmol). Then mixture was degassed with N2 three times and sealed, which was stirred at 100°C for 30 min under microwave. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL*l, 50 mL*2) The combined DCM layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH = 100/0 to 94/6) to give the desired productExample 59c (400 mg, yield 67%) as a pale yellow solid. LCMS [M+l]+ = 397.9
Step 2: Example 59
[0421] To a solution of Example 59c (200 mg, 0.5 mmol), Example 59d (66 mg, 1 mmol), Cul (10 mg, 0.05 mmol), and Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) in dry DMF (1 mL) was added N,N- Diisopropylethylamine(l mL). Then the mixture was degassed with N2 three times and sealed, which was heated to 100°C overnight. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL*2). The combined DCM layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 8.0/20 to 20/80 over 50 min) to give the desired product Example 59 (22 mg, yield 11%) as a white solid. LC-MS [M+l]+ = 384.0
[0422] 1H NMR (400 MHz, DMSO-<¾ δ 8.90 (s, 1H), 8.57 (dd, J= 8.4, 0.8 Hz, 1H), 8.04 (t, J= 8.0 Hz, 1H), 7.88 (dd, J= 7.7, 0.9 Hz, 1H), 7.74-7.55 (m, 3H), 5.61-5.35 (m, 1H), 5.11 (s, 2H), 1.54 (d, J= 6.7 Hz, 7H), 0.98-0.82 (m, 2H), 0.81-0.67 (m, 2H).
Example 60: Synthesis of 6-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)isoindolin-l-one
Figure imgf000138_0002
Step 1: Example 60c
To a solution of Example 60a (317 mg, 1.5 mmol), Example 60b (470 mg, 1.5 mmol), K3P04 (636 mg, 3 mmol), and Cul (29 mg, 0.15 mmol) in 1,4-dioxane (7 mL) was added N',N^-dimethylcyclohexane-l,2- diamine (43 mg, 0.3 mmol). Then mixture was degassed with N2 three times and sealed, which was then stirred at 100°C for 30 min under microwave. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL*l, 50 mL*2). The combined DCM layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH = 100/0 to 94/6) to give the desired product Example 60c (400 mg, yield 67%) as a pale yellow solid. LC-MS [M+l]+ = 397.9
Step 2: Example 60
[0423] To a solution of Example 60c (100 mg, 0.25 mmol), Example 60d (44 mg, 0.5 mmol), Cul (5 mg, 0.025 mmol), and Pd(PPh3)2Cl2 (20 mg, 0.025 mmol) in dry DMF (0.5 mL) was added DIEA (0.5 mL). Then the mixture was degassed with N2 three times and sealed, which was heated to 100°C overnight. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL*2). The combined DCM layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 60 (5 mg, yield 5%) as a white solid. LC-MS [M+l]+ = 402.0
[0424] 1H NMR (400 MHz, Chloroform-^ δ 8.67 (d, J= 8.4 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J= 7.6 Hz, 1H), 7.97-7.83 (m, 2H), 7.66 (dd, J= 7.9, 1.5 Hz, 1H), 7.50 (d, J= 7.8 Hz, 1H), 5.68-5.51 (m, 1H), 5.03 (s, 2H), 2.46 (s, 1H), 1.63 (m, 12H).
Example 62: Synthesis of 6-(4-cyclopropyl-lH-imidazol-l-yl)-2-(6-(5-isopropyl-lH-l,2,3-triazol-l- yl)pyridin-2-yl)isoindolin-l-one
Figure imgf000139_0001
Step 1: Example 62b
[0425] A mixture of Example 62a (2500 mg, 17.4 mmol) in ether/H20 (10 mL / 20 mL) was added con.HCl (6 mL). The mixture was stirred at 0°C for 10 min, then NaN02 (1320 mg, 19 mmol) was added into the mixture in batches. The mixture was stirred at 0°C for 2 hTLC showed most of Example 62awas consumed. The mixture was added into sat.NaHC03 and extracted with ether acetate (20 mL *3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was filtered and concentrated. The crude product was purified by flash chromatography to give Example 62b(1700 mg, yield 63%) as a yellow solid.
Step 2: Example 62d
[0426] To a solution of Example 62b (1700 mg, 11 mmol) in toluene (10 mL) was added Example 62c (3741 mg, 55 mmol). The mixture was stirred at 110°C for 16h in microwave reactor. LCMS showed reaction completed. The mixture was concentrated under reduced pressure. The residue was re-purified by silic columnflash to afford Example 62d (650 mg, yield: 26.5%) as a white solid.
LCMS [M+l]+ =222.9
Step 3: Example 62g
[0427] To a solution of Example 62e (1000 mg, 4.003 mmol) in con.H2S04 (10 mL) was added Example 62f (856 mg, 4.83 mmol). The mixture was stirred at 90°C for 3h. The mixture was added into H20 (100mL)andwhite solid was separated out. The suspension was filtered, then the solid was added into NH3.H20/MeOH (15mL/15mL).The mixture was stiired at 80°C for lh. The suspension was filtered to afford Example 62g (620 mg, yield: 59.2%) as a white solid.
Step 4: Example 62i
[0428] To a solution of Example 62g (600 mg, 2.317 mmol) in DMF (10 mL) was added Example 62h (275mg, 2.548 mmol), Cul (221mg, 1.16mmol), K3P04 (981 mg,4.63 mmol) andquinolin-8-ol (67mg, 0.463mmol). The mixture was stirred at 130°C for lh in microwave. The suspension was filtered and the liquid was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to afford Example 62i (30 mg, yield: 2%) as a white solid.
Step 5: Example 62
[0429] To a solution of Example 62i (30 mg, 0.125 mmol) in dioxane (2mL) was added Example 62d (34mg, 0.15 mmol), Pd2(dba)3(12mg, 0.0125mmol), X-Phos (6 mg, 0.0125 mmol) and Cs2C03(82mg, 0.25mmol). The mixture was stirred at 80°C for 5h under N2. The suspension was filtered and the liquid was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to afford Example 62 (5.1 mg, yield: 10%) as a white solid.
LCMS [M+l]+ =426.0
[0430] 1H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J= 8.3 Hz, IH), 8.11 - 7.53 (m, 7H), 7.11 (s, IH), 5.09 (s, 2H), 3.93 - 3.75 (m, IH), 1.91 (d, J= 8.1 Hz, IH), 1.37 (d, J = 6.9 Hz, 6H), 0.93 - 0.82 (m, 4H). Example 64: Synthesis of 6-(6-cyclopropylpyridin-3-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)imidazo[l,2-a]pyridine-8-carboxamide
Figure imgf000141_0001
Step 1: Example 64c
[0431] To a solution of Example 64a (240 mg, l.Ommol,) and Example 64b (203 mg, 1.0 mmol) in 4 mL pyridine at 0°C was added POCI3 (153 mg 1.0 mmol). The mixture was stirred at 0°C for 1 hour. The mixture was quenched with water, extracted with EtOAc, organic layers were combined and
concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford Example 64c (140 mg, yield 33.0%) as a white solid.
[0432] LC-MS [M+l] + = 427.9.
Step 2: Example 64
[0433] A mixture of Example 64c (140 mg, 0.33 mmol), Example 64d (66 mg, 0.40 mmol), Pd(PPh3)4 (38.0 mg, 0.033 mmol) and Na2CO3(70 mg, 0.66 mmol) in dioxane/H20 (2mL/0.4 mL) was stirred at 100 °C for 1 hrs under micro-waved. LCMS (BDO 1061-170-1) showed most of Example 64c was consumed and the desired product was detected. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H2O/CH3CN = from 80/20 to 20/80 over 50 min)to give Example 64 (13.7 mg, yield:9%) as a white solid. LCMS [M+l] + = 465.0.
[0434] 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.25 (d, J= 1.9 Hz, 1H), 8.91 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.41 - 8.39 (m,2H), 8.17 (d, J= 1.3 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.89 (d, J= 8.0 Hz, 1H), 7.82 (d, J= 1.2 Hz, 1H),7.44 (d, J= 1.2 Hz, 1H), 5.51 -5.41 (m, 1H), 2.21 - 2.13 (m, 1H), 1.61 (d, J= 6.7 Hz, 6H), 1.02 - 0.94 (m, 4H).
Example 66: Synthesis of 6'-(2-hydroxypropan-2-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazoI-3- yl)pyridin-2-yl)-l-methyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000141_0002
Step 1: Example 66c
[0435] A mixture of Example 66a (50 mg, 0.11 mmol), Example 66b (43.1 mg, 0.13 mmol) in Dioxane/H20 (2mL, 10: 1) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol) and Na2C03(34.26 mg, 0.33 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 80°Covernight.
LCMS [M+l]+ = 546.1
Step 2: Example 66
[0436] The Example 66c (100 mg, crude) was added HC1 (5 mL, 4M, in dioxane), and then stirred at r.t. for lh. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 66 (21.0 mg, yield: 41.2 % over 2 steps) as white solid. LCMS[M+l]+=474.0
1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.89 (s, 1H), 8.77 (s, 2H), 8.69 (d, J = 2.7 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.08 - 7.98 (m, 2H), 7.82 (d, J= 7.5 Hz, 1H), 7.73 (d, J= 8.3 Hz, 1H), 5.35 - 5.25 (m, 2H),3.71 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H), 1.45 (s, 6H).
Example 67: Synthesis of 8-(6-cyclopropylpyridin-3-yI)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000142_0001
Step 1: Example 67c
[0437] To a mixture of Example 67a (30.0 g, 0.18 mol) and Example 67b (16.7 g, 0.20 mol) in pyridine. (600 mL) at 0°C, was added ΡΟCl3(82.02 g, 0.54 mol) dropwise. Then the mixture was warmed to r.t. and stirred for 3h.After then, the mixture was concentrated under reduced pressure to give a residue. The residue was cooled to 0°C, and H20 (200 mL) was added dropwise. The mixture was extracted with EtOAc (300 mL*3), combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 5/1) to give the desired product (Example 67c, 24.3 g, yield 58%) as a white solid.
LCMS [M+l] + = 236.0.
Step 2: Example 67d
[0438] To amixture of Example 67c(17.0 g, 72.24mmol) in MeOH H20 (300 mL/150 mL) at 0°C, was added Oxone(200 g, 0.33 mol) slowly. The mixture was stirred at 0°Cfor 3 h. After then, the mixture was filtered and concentrated under reduced pressure to give the crude product (Example 67d, 20 g, crude) as a yellow solid. The crude productwas used for next step directly.
[0439] LCMS [M+l] + = 268.9.
Step 3: Example 67f
[0440] To amixture of Example 67d (20 g, crude) and TEA(18.26 g, 0.18 mol) in ACN(400 mL) at 0°C, was added Example 67e (21.7 g, 0.09 mol). The mixture was warmed to r.t. and stirred for overnight. After then, the mixture was added H2O(300mL), and extracted EtOAc (300 mL*3), combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (DCM only) to give product (Example 67f, 14.5 g, two step yield 61.2%) as a yellow solid.
[0441] 1H NMR (400 MHz, Chloroform-d3) δ 8.10 - 8.06 (m, 2H), 7.65 (t, J= 7.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 3.76 (t, J= 7.1 Hz, 2H), 2.56 (t, J= 8.0 Hz, 2H), 2.10 - 2.00 (m, 2H).
Step 4: Example 67h
[0442] To amixture of Example 67f (11.0 g,38 mmol) and Example 67g(25.83 g,300 mmol) in benzene (600 mL), was added Ru2(OAc)4 (5 mg, 11.3 mmol). The mixture was heated at 80°C for 5 h. After then, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (DCM/MeOH = 50/1) to give product (Example 67h, 2.5 g, yield 31.9%) as a yellow solid.LCMS [M+l] + = 210.0.
[0443] 1H NMR (400 MHz, CDC13) δ 7.37 (s, 1H), 4.23 - 4.16 (m, 2H), 3.85 (s, 3H), 3.48 (t, J= 7.8 Hz, 2H), 2.30 - 2.21 (m, 2H).
Step 5: Example 67i
[0444] A mixture of Example 67h (2.5 g, 11.96 mmol) in HBr/H20 (10 mL, 40% in H20) was heated at 130°C for overnight. After then, the mixture was extracted with EtOAc (100 mL*3), combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product (Example 67i, 1.2 g, crude) as a brown solid. The crude was used for next step directly. LCMS [M+l] + = 152.0.
Step 6: Example 67j
[0445] To amixture of Example 67i (1.2 g, 7.95 mmol, crude) and TEA (2.41 g, 23.85 mmol), was added PhN(OTf)2(3.05 g, 9.53 mmol) at 0°C. The mixture was stirred at r.t. for 18 h. After then, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 1/1) to give product (Example 67j, 800 mg, two step yield 23.6%) as a yellow solid.LCMS [M+l] + = 283.9.
Step 7: Example 67k
[0446] To amixture of Example 67j (200 mg, 0.71 mmol), Zn(CN)2 (91.20 mg, 0.78 mmol), Zn (16.16 mg, 0.25 mmol) in DMAC/H20 (5 mL, 10/1), was added Pd(dppf)Cl2 (5 mg). The mixture was degassed with N2 for 3 times. Then the mixture was heated at 120°C for 3 h. After then, the mixture was extracted with EtOAc (50 mL*3), combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product (Example 67k, 200 mg, crude) as a brown solid. The crude was used for next step directly. LCMS [M+l] + = 161.0.
Step 8: Example 671
[0447] To amixture of Example 67k (200 mg, 1.25 mmol) in TFA/DCM (10 mL, 1/1), was added NIS (281 mg, 1.25 mmol). The mixture was degassed with N2 for 3 times. Then the mixture was stirred at r.t. for overnight. After then, the mixture was concentrated under reduced pressure to give residue. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 1/1) to give product (Example 671, 130 mg, two step yield 64.3%) as a white solid.LCMS [M+l] + = 286.8.
Step 9: Example 67m
[0448] A mixture of Example 671 (100 mg, 0.35 mmol) in KOH (2 mL, 50% in water) was added heated at 105°C for 5 h. After then, the mixture was adjusted pH to 7.0 with 12N HC1. The mixture was concentrated under reduced pressure to give residue. The residue was treated with EtOAc (50 mL), filtrated and filtrate was concentrated under reduced pressure to give acrudeproduct (Example 67m, 200 mg, crude) as a brown solid.The crude was used for next step directly. LCMS [M+l] + = 305.8.
Step 10: EAaiuple 67u
[0449] To amixture of Example 67m (200 mg, 0.35 mmol, crude), Example 67n (85.26 mg, 0.42 mmol) in pyridine (5 mL) at 0°C, was added POCl3 (160.65 mg, 1.05 mmol). Then the reaction was started at 0°C with stirring for 1 h. The reaction solution was poured into water (5 mL) and extracted with EtOAc(50 mL*3)and the combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the residue. The residue was purified by Pre-TLC to give
product(Example 67o,30.0 mg, two step yield 9.8%) as a yellow solid.LCMS [M+l] + =490.9.
Step 11: Example 67
[0450] To amixture of Example 67o(30mg,0.06 mmol),Example 67p(91.20mg,0.78mmol), Na2C03 (19.47 mg, 0.18 mmol) in Dioxane/H20 (2 mL, 10/1), was added Pd(dppf)Cl2 (5mg). The mixture was degassed with N2 for 3 times. Then the mixture was heated at 80°C for 12 h. After then, the mixture was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (Example 67,8.8 mg, Yield: 30.0%) as a white solid.
[0451] LCMS [M+l] + = 482.0.
[0452] 1H NMR (400 MHz, DMSO-c/6) δ 12.60 (s, 1H), 8.88 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.36 (d, J= 8.2 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.76 (dd, J= 8.1, 2.3 Hz, 1H), 7.38 (d, .7= 8.1 Hz, 1H), 5.33-5.26 (m,lH) 4.26(t, J= 5.2 Hz, 2H),2.22 - 2.11 (m, 3H), 1.99-1.95 (m, 2H), 1. (d, J= 6.7 Hz, 6H), 0.95 (dd, J= 5.5, 2.3 Hz, 4H).
Example 72: Synthesis of 2,2-difluoro-6-iodo-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2 yl)benzo[d] [1,3] dioxole-4-carboxamide
Figure imgf000145_0001
Step 1: Example 72b
[0453] To a suspension of Example 72a (1 g, 4.95 mmol) in con.H2SC>4 (4 mL) was cooled at 0°C. Then a mixture of con.H2S04 (1 mL) and HN03 (0.5 mL) was added. The resulting mixture was slowly warmed to r.t. and stirred overnight. The mixture was poured into ice water, and stirred for 20 min. The suspension was filtered, and the solid was washed with water (5 mL*2), and dried to give the desired product Example 72b (520 mg, yield 43%) as a yellowsolid. LCMS [M-l]" = 245.9
Step 2: Example 72c
[0454] To a solution of Example 72b (520 mg, 2.1 mmol) in DMF (10 mL) were added Mel (897 mg, 6.3 mmol) and K2C03 (871 mg, 6.3 mmol). The mixture was stirred at r.t. for 2h.The mixture was extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 5/1) togive the desired productExample 72c (250 mg, yield 45%) as a yellow solid. LCMS [M+l]+ = 261.9
Step 3: Example 72d
[0455] To a solution of Example 72c (100 mg, 0.38 mmol) in EtOH/H20 (4 mL/1 mL) were added Fe (214 mg, 3.8 mmol) and NH4C1 (203 mg, 3.8 mmol). The mixture was stirred at 80°C for 2 hs. The mixture was filtered and concentrated. The residue was extracted with EtOAc (10mL*2).The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressureto giveExample 72d (127 mg, crude yield 100%) as a yellowsolid. LCMS [M+l]+ = 231.9
Step 4: Example 72e
[0456] To a suspension of Example 72d (164 mg, 0.71 mmol) in 5% H2S04 (3 mL) was added a solution of NaN02 (73 mg, 1.06 mmol) in H20 (0.3 mL) at 0°C. The mixture was stirred at0°C for 1 h, and then treated with a solution of KI (353 mg, 2.13 mmol) in H20 (0.6 mL), which was stirred at 80°C for 15 min. The mixturewas extracted with DCM (10 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 20/1) togive the desired product Example 72e (200 mg, yield 60%) as a yellow solid. LCMS [M+l]+ = 342.8
Step 5: Example 72f
[0457] To a solution of Example 72e (200 mg, 0.58 mmol) in THF/MeOH/H20 (2 mL/2 mL/1 mL) was added LiOH.H20 (74 mg, 1.75 mmol). The mixture was stirred at r.t. for 2 hs. The mixturewas acidified by IN HC1 to pH = 2~3, and extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure to give the desired product Example 72f (180 mg, yield 94%) as a yellow solid. LCMS [M-l]" = 326.8
Step 6: Example 72
[0458] To a solution of Example 72f (40 mg, 0.12 mmol) in pyridine (1 mL) were added Example 72g (25 mg, 0.12 mmol) and POCl3 (93 mg, 0.61 mmol) at 0°C. The mixture was stirred at0°C for 2 hs. The mixture was poured into the H20 (8 mL). The suspension was filtered, the solid was dried and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 72 (26 mg, yield 42%) as a whitesolid. LCMS [M+l]+ = 513.8
1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.86 (s, 1H), 8.12 (dd, J= 8.3, 1.0 Hz, 1H), 8.07 (d, J =
1.6 Hz, 1H), 8.03 (t, J= 7.9 Hz, 1H), 7.93 (d, J= 1.7 Hz, 1H), 7.88 (dd, /= 7.6, 1.0 Hz, 1H), 5.57 (p, J =
6.7 Hz, 1H), 1.43 (d, J= 6.7 Hz, 6H).
Example 73: Synthesis of 5-(6-cyclopropylpyridin-3-yl)-3-ethynyl-2-fluoro-N-(6-(4-isopropyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)benzamide
Figure imgf000146_0001
Step 1: Example 73b
[0459] A solution of Example 73a (3.0 g, 11.2 mmol) and KBr03 (3.7 g, 22.0 mmol) in 15 mL of cone. H2S04. The reaction mixture was stirred for 2 h at 90°C; LC-MS (BD01052-127) analysis showed Example 73a was consumed; the mixture was poured into 250 mL water and stirred for 10 min. The mixture was extracted with EA (250 mL * 3). The combined organic phase was dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (Example 73b, 3.5 g, yield: 65%) as a yellow solid.LCMS [M+l]+ = 344.0
Step2: Example 73d
[0460] A solution of Example 73b (2 g, 5.8 mmol) and Example 73c (1.3 g, 6.4 mmol) in 200 mL pyridine was cooled to 0 °C, then POCl3 (5 g, 33 mmol) was added dropwise. The reaction mixture was stirred for 1 h at this temperature; LCMS analysis showed Example 73b consumed, the mixture was poured into 250 mL water and stirred for 10 min.The mixture was extracted with DCM (250 mL * 3). The combined organic phase was dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (Example 73d, 2.5 g yield: 81%) as a yellow solid.LCMS [M+l]+ = 531.0
Step 3: Example 73f
[0461] Under inert atmosphere, a mixture of Example 73d (240 mg, 0.45 mmol), Example 73e (44 mg, 0.45 mmol), Pd(PPh3)2Cl2 (31 mg, 0.045 mmol), TEA (0.5 g, 5 mmol) and Cul (8 mg, 0.045 mmol) in 10 mL of DMF was stirred at r.t. for 2 hours. The mixture was filtered and the filtrate was concentrated.The residue was purified by silica gel chromatography to give the desired product (Example 73f, 76 mg yield: 40%) as a yellow oil. LCMS [M+l]+ = 501.0
Step4: Example 73h
[0462] A solution of Example 73f (76 mg, 0.15 mmol), Example 73g (23 mg,0.18 mmol), Pd(dppf)Cl2 (5 mg, 0.02 mmol) and Na2C03 (32 mg,0.30 mmol) in 1,4-Dioxane (1 mL) and H20 was stirred at 80°C for 1.5h at microwave. TLC and LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure, which was purified by silica gelon columnfiash to give Example 73h (60 mg, yield 70%) as a brown solid.
LCMS [M+l]+ =540.0
Step5: Example 73
[0463] A mixture of Example 73h (70 mg) and K2C03 (30 mg) in 5 mL MeOH was stirred at 25°C for 2 hours. The mixture was filtered and the filtrate was concentrated.The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product (6 mg, yield: 9.8%) as a white solid. LCMS [M+ll+ = 467.0
1H NMR (400 MHz, DMSO-4;) δ 1 1.09 (s, 1H), 8.84 (s, 1H), 8.77 (d, J= 2.4 Hz, 1H), 8.22 (d, J= 8.3 Hz, 1H), 8.05 -8.01 (m, 4H), 7.89 (d, J= 7.8Hz, 1H), 7.37 (dd, J= 8.3, 5.3 Hz, 1H), 5.69-5.59 (m, 1H), 4.67 (s, 1H), 2.20-2.12 (m, 1H), 1.40 (d, J= 6.7 Hz, 6H), 0.98-0.93 (m, 4H).
Example 75: Synthesis of 6-(6-cyclopropylpyridin-3-yl)-2,2-difluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)benzo [d] [1 ,3] dioxole-4-carboxamide
Figure imgf000148_0002
[0464] To a solution of Example 75a (50 mg, 0.10 mmol) in l,4-dioxane/H20 (1 mL/0.2 mL) were added Example 75b (24 mg, 0.15 mmol), Na2C03 (31 mg, 0.29 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol). The mixture was stirred at 80°C for 2 hs. The mixture was extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 75 (7 mg, yield 14%) as a white solid. LC-MS [M+l]+ = 505.0
1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.85 (s, 1H), 8.78 (d, J= 2.4 Hz, 1H), 8.17 (d, J= 8.2 Hz, 1H), 8.09-7.98 (m, 3H), 7.93-7.84 (m, 2H), 7.40 (d, J= 8.2 Hz, 1H), 5.59-5.53(m, 1H), 2.17-2.12(m, 1H), 1.42 (d, J= 6.7 Hz, 6H), 0.98-0.93(m, 4H).
Example 76: Synthesis of 6-(6-(4-isopropyl-4H-l,2,4-triazoI-3-yl)pyridin-2-yl)-2,2-dimethyl-2,3,5,6- tetrahydro-7H-furo [2,3-fJ isoindoI-7-one
Figure imgf000148_0001
Step 1: Example 76c
[0465] To a solution of Example 76a (1.166 g, 5.0 mmol) and Example 76b (1.062 g, 6.0 mmol) in con.H2S04 (5 mL) was heated to 80 °C and stirred for 3h. Cooled to r.t. and poured into ice water. Stirred for 15 min and filtered, the yellow solid was washed by water (20 mL*3). Then the solid was added ammonium hydroxide (10 mL) and EtOH (10 mL). Then heated to 80 °C and stirred for 3h. Cooled to r.t. and filtered, the residue was purified by flash chromatography to give product Example 76c (800 mg, yield: 67.7%). LCMS [M+l] + = 243.9
Step 2: Example 76f
[0466] To a solution of Example 76c (800 mg, 3.31 mmol), Example 76d (1.14 g, 3.64 mmol), Example 76e (94 mg, 0.66 mmol), Cul (126 mg, 0.66 mmol), K3P04 (1.41 g, 6.62 mmol) in dioxane was stirred at 100 °C for 16h. 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 76f (1.0 g, yield: 70%). LCMS [M+l] + = 429.9
Step 3: Example 76g
[0467] To a solution of Example 7f (600 mg, 1.41 mmol) in 6 mL of DCM was added BBr3 ( 1.76g, 5.05 mmol) at -78 °C and stirred at -78 °C for 3h. The mixture was quenched by MeOH and stripped of solvent. The residue was purified by flash chromatography to give product Example 76g (250 mg, yield: 42.8%). LCMS [M+l] + = 413.9
Step 4: Example 76h
[0468] To a solution of Example 76g (250 mg, 0.60 mmol) and K2C03 (766 mg, 5.5 mmol) in 8mL of THF was added MOMC1 (81 mg, 0.60 mmol) stirred at 20°C for 4h. The mixture was stripped of solvent without purified for next step Example 76h (200 mg, yield: 73%). LCMS [M+l] + = 457.9
Step 5: Example 76j
[0469] A mixture of Example 76h (200 mg, 0. 44 mmol), Example 76i (173 mg, 0.5 mmol), Pd(PPh3)4 (19.0 mg, 0.016 mmol) and CsF (151 mg, 1.0 mmol)inCH3CN (5 mL) was stirred at 90 °C for overnight under N2 protected. The mixture was quenched by HC1, extracted with EtOAc, organic layers were combined and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford Example 76j (150 mg, yield 79.3%) as a white solid. LC-MS [M+l] + = 434.0
Step 6: Example 76k
[0470] To a solution of Example 76j (150 mg, 0.33 mmol) in 8mL of DCM was added 2 mL of TFA stirred at 20°C for 4h. The mixture was stripped of solvent without purified for next step Example 76k (100 mg, yield: 77.0%). LCMS [M+l] + = 390.0
Step 7: Example 76
[0471] To a solution of Example 76k (100 mg, 0.33 mmol) in 8mL of BF3/ether was stirred at 20°C for overnight. The mixture was stripped of solvent purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 76 (8.7 mg, yield: 8.7%). LCMS [M+l] + = 390.0 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.58 (d, J= 8.1 Hz, 1H), 8.04 (t, J= 8.0 Hz, 1H), 7.86 (d, J= 7.3 Hz, 1H), 7.51 (s, 1H), 7.01 (s, 1H), 5.45-5.5 l(m, 1H), 5.01 (s, 2H), 3.1 1 (s, 2H), 1.54 (d, J= 6.7 Hz, 6H), 1.43 (s, 6H).
Example 78: Synthesis of 7-isopropoxy-2-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)isoquinolin-l(2H)-one
Figure imgf000150_0001
Step 1: Example 78d
[0472] Into a 20-mL microwave tube was added Example 78a (1.0 g, 4.46 mmol), Example 78b (171 mg, 6.43 mmol), Cul (511 mg, 2.68 mmol), K3P04 (2.3 g, 10.71 mmol) and Example 78c (380 mg, 2.68 mmol) successively. DMF ( 10 mL) was added by syringe. The mixture was degassed by nitrogen for three times and sealed. The reaction was heated up to 120°C by microwave for 60 min. LCMS showed reaction completed. The mixture was added into 100 mL of H20 and extracted with ether acetate. The combined organic layers were washed by brine, dried over Na2S04 and concentrated. The residue was purified by flash chromatography to afford Example 78d (950 mg, crude, yield: 51.9%) as a brown solid. Step 2: Example 78e
[0473] To a solution of Example 78d (410 mg, 1 mmol) in DMSO/H20 (8 mL 12 mL) was added Cu(acac)2(52 mg, 0.2 mmol), BHMPO (Reaxys-RN: 28695736,65mg, 0.2 mmol), LiOH.H20 (126 mg, 3 mmol) The mixture was degassed by nitrogen for three times and heated up to 80°C for 1 hour. LCMS showed reaction completed. The mixture was added into 100 mL of H20 and extracted with ether acetate. The pH of the water phase was adjusted to 2 and light red solid was separated out. The suspension was filtered and the filter cake was concentrated to give the product Example 78e (250 mg, yield: 72.05 %) as a red solid. LCMS [M/2+l]+ =348
Step 3: Example 78
[0474] To a solution of Example 78e (200 mg, 0.58 mmol) in DMF (5 mL) was added 60%NaH (46 mg, 1.15mmol). The mixture was stirred at 20 °C for 0.5h, then Example 78f (213 mg, 1.73 mmol) was added. The mixture was stirred at 45 °C until LCMS showed reaction completed. The mixture was added into 50 mL H20 and extracted with ether acetate. The combined organic layers were washed by brine, dried over Na2S04 and concentrated. The residue was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the product Example 78 (98.5 mg, yield: 43.7 %) as a white solid. LCMS [M+l]+ = 390.0
[0475] 1H NMR (400 MHz, Chloroform-i/) δ 8.38 (s, 1H), 8.30 (dd, /= 6.7, 1.9 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.91 (d, J= 2.7 Hz, 1H), 7.51 (dd, J= 18.6, 8.1 Hz, 2H), 7.28 (dd, J= 8.6, 2.7 Hz, 1H), 6.60 (d, 7 = 7.6 Hz, 1H), 5.55-5.45 (m, 1H), 4.80 - 4.71 (m, 1H), 1.53 (d, /= 6.7 Hz, 6H), 1.40 (d, J= 6.0 Hz, 6H).
Example 80: Synthesis of N-(6-(l,3,4-thiadiazol-2-yl)pyridin-2-yl)-5-(4-cyclopropyl-lH-imidazol-l- -2-fluoro-4-methylbenzamide
Figure imgf000151_0001
Step 1: Example 80b
[0476] To a solution of Example 80a (2.0 g, 11.7 mmol) in MeOH (20 mL) was added dropwise N2H4.H2O (0.7 g, 14.0 mmol), with stirring at roomtemperature for 20min. Then the remained MeOH was evaporated. MTBE was added to the solid and stirred for 15 min. The reaction mixture wasfiltered and the filter cake was washed with 10 mL MTBE, dried in vacuum to give the desired product Example 80b (1.3g, yield 65%) as a white solid.
Step 2: Example 80c
[0477] A solution of Example 80b (0.2g, 1.17mmol) in 3mL HCOOH was stirred at rt for 16h. 20 mL of diethyl ether were added and the precipitate formed was filtered off with suction. The filter residue was washed with diethyl ether and dried to give the desired product Example 80c (181 mg, yield 77%) as a white solid.
Step 3: Example 80d
[0478] A solution of Example 80c (0.18 g, 0.9 mmol) and Lawessons reagent (274 mg,0.68 mmol) in 3mL toluene with a few drops of pyridine were stirred at 120°C for 16h.The mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure.The residue was purified by silica gel
chromatography to give Example 80d (109 mg, yield 61%) as a white solid. LCMS [M+l]+ = 198.0 Step 4: Example 80e
[0479] A solution of Example 80d (0.74 g, 3.74 mmol) and tert-butylcarbamate (877 mg, 7.5 mmol) in 5 mL toluene was added Pd(OAc)2 (84 mg, 0.37 mmol), BINAP (466 mg,0.75 mmol) and Cs2C03 (3.05 g, 9.4 mmol), then the reaction mixture was heated at 100°C for 16h. The mixture was extracted with EA (15 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure.The residue was purified by silica gel chromatography to give Example 80f (120 mg, yield 11%) as a white solid. LCMS [M-56+l]+ = 222.9.
Step 5: Example 80f
[0480] A solution of Example 80e (60mg, 0.2mmol) in lmL DCM was cooled to 0°C and THF (0.5 mL) was added dropwise. The reaction mixture was stirred for lh at rt.The mixture was extracted with EA (5 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure.The residue was purified by silica gel chromatography to give Example 80f (42 mg, yield 100%) as a white solid.
Step 6: Example 80
[0481] A solution of Example 80f (89 mg, 0.50 mmol) and Example 80g (143 mg, 0.55 mmol) in 2 mL of pyridine was cooled to 0 °C, then POCl3 (230 mg, 1.50 mmol) was added dropwise. The reaction mixture was stirred for 1 h at this temperature.The mixture was poured into 20 mL water and stirred for 10 min, then extracted with EA (10 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Example 80 (21 mg, yield 10%) as a white solid. LCMS [M+l]+ = 421.0
[0482] 1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 9.09 (d, J= 14.2 Hz, 1H), 8.47 (d, J= 8.3 Hz, 1H), 8.22 - 8.17 (m, 1H), 8.05 (d, J= 7.2 Hz, 1H), 7.95 (t, J= 8.0 Hz, 1H), 7.50 (s, 1H), 7.22 (d, J= 12.0 Hz, 1H), 6.80 (s, 1H), 2.29 (s, 3H), 1.92 (dt, J= 8.0, 3.3 Hz, 1H), 0.91 (dt, J= 8.2, 2.9 Hz, 2H), 0.85 (dt, J= 5.5, 2.7 Hz, 2H).
Example 89: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-3-ethynyl-2-fluoro-N-(6-(4-isopropyl- 4H-l,2,4-triazol-3-yl)pyridin-2-yl)benzamide
Figure imgf000153_0001
Step 1: Example 89b
[0483] A solution of Example 73a (3.0 g, 13.6 mmol) and HN03 (0.94 g, 15.0 mmol) in 15M1 of cone. H2S04. The reaction mixture was stirred for 16 h at 25°C. TLC (EA) showed Example 89a was consumed. Then the mixture was poured into 250 mLof water and stirred for 10 min. The mixture was extracted with EA (250 mL * 3). The combined organic phase was dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (Example 89b, 3.5 g, yield: 65%) as a white solid.
Step2: Example 89c
[0484] A solution of Example 89b (2.7 g, 10.2 mmol) and K2C03 (2.8 g, 20.4 mmol) in 50 mL of MeCN was added Mei (1.3 mL, 20.9 mmol). The reaction mixture was stirred for 1 h at 80°C. TLC showed Example 89b wasconsumed, the mixture was poured into 250 mLof water and stirred for 10 min.The mixture was extracted with EA (250 mL * 3). The combined organic phase was dried over Na2S04, then filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (Example 89C, 2.5 g yield: 75%) as colorless oil. Step3: Example 89d
[0485] To a solution of Example 89d (2.2g, 7.9 mmol) in AcOH/H20 (10 mL/10 mL) was added Fe powder (6.66 g, 119.0 mmol). The resulting mixture was stirred at 80°C under N2atmosphere with stirring for 1 hours. The reaction solution was poured into water (200 mL). After extraction with EtOAc (50mL*2), the combined organic layer was dried over Na2S0 , and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc (v/v)=l/l) to give the desired product Example 89d (900 mg, yield 45%) LCMS [M+l] + = 249.0
Step4: Example 89f
[0486] A mixture of Example 89d (509 mg, 2 mmol), Example 89e (1.3 g, 8 mmol), K2C03 (303.6 mg, 2.2 mmol), and KI (365 mg, 2.2 mmol) were dissolved in MeCN (8 mL) with stirring at 70°C for 6 h. Thenthe reaction solution was filtrated and washed with EtOAc. The solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc (v/v)=87/13) to give the desired product Example 89f (400 mg, yield 62%) as a yellowsolid. LCMS [M+l] + = 331.0
Step5: Example 89g (BD01052-148)
[0487] To a solution of Example 89f (100 mg, 0.3 mmol) in HCOOH (2 mL) was added Ac20 (244 mg, 2.39 mmol) with stirring at r.t. for 2h. Then, the reaction solution was poured into water (5 mL), and the pH was adjusted to nearly 9 by using aq.Na2C03. After extraction with EtOAc (5 mL), the organic layer was dried over Na2S04, and concentrated under reduced pressure to give the crude of desired product Example 89g (120 mg yield 100%) as oil.
LCMS [M+l] + = 359.0
Step 6: Example 89
[0488] To a solution of Example 89g (120 mg, 0.34 mmol) in AcOH (1.2 mL) was added NH4OAc (206 mg, 2.60 mmol) with stirring at 110°C overnight. Thenthe reaction solution was poured into water (5 mL), and the pH was adjusted to nearly 9 by using Na2C03. After extraction with EtOAc (5 mL), the organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by Pre-TLC (Petroleum ether/EtOAc (v/v)=2/l) to give the desired product Example 89h (100 mg, yield 91%) asa yellow oil.
LCMS [M+l] + = 329.0
Step 7: Example 89i
[0489] To a mixed solution of Example 89h (400 mg, 1.2 mmol) in EtOH H20 (3 mL/2 mL) was added LiOHHl20 (115 mg, 2.73 mmol) with stirring at r.t. for 1 h. Then, the reaction solution was evaporated under reduced pressure to remove EtOH, and the pH was adjusted to nearly 3 by using aq.HCl. After extraction with EtOAc (15 mL*4), the combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give the desired product Example 89i (323 mg, yield 84%) asa yellowsolid. LCMS [M+l] + = 325.0. Step 8: Example 89k
[0490] To a solution of Example 89i (323 mg, 0.99 mmol) in pyridine (3 mL) at 0°C was added Example 89j (201mg, 0.99 mmol), and POCl3 (765 mg, 4.95 mmol). Then, the reaction was stirred at 0°C for 1 hour. The reaction solution was poured into water (10 mL) and filtrated. The filtrate was washed with water, followed by EtOAc twice, to give the desired product Example 89k, (300 mg.yield 55%) as a yellow solid.LCMS [M+l] + = 510.0
Step9: Example 89m
[0491] Under inert atmosphere, a mixture of Example 89k (240 mg, 0.47 mmol), Example 891 (1 mL, 7.70 mmol), Pd(PPh3)2Cl2 (20 mg, 0.03 mmol), TEA (1 mL, 7.14 mmol ) and Cul (10 mg, 0.05 mmol) in 2.5mL of DMF was stirred at 70°C for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the desired product (Example 891, 100mg yield55%) as a yellow solid.
[0492] LCMS [M+l] + = 528.0
SteplO: Example 89
[0493] A mixture of Example 89m (100 mg, 0.19 mmol)and K2C03 (1 g, 7.23 mmol) in 50mL of MeOH was stirred at 25°C for 2 hours.Themixture was filtered and the filtrate was concentrated to give 12mg of white solid product (12 mg yield: 20%) as a yellow solid. LCMS [M+l] + = 456.0
1H NMR (400 MHz, OUSO-d6) 6 1 1.16 (s, 1H), 8.85 (s, 1H), 8.22 - 8.17 (m, 2H), 8.05 - 7.99 (m, 3H), 7.90 (d, J= 7.8 Hz, 1H), 7.62 (s, 1H), 5.69 - 5.61 (m, 1H), 4.75 (s, 1H), 1.84 - 1.76 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H), 0.81 - 0.76 (m,2H), 0.68 - 0.64 (m,2H).
Example 90: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl-6-oxo-6'- (trifluoromethyl)-l,6-dihydro- '-bipyridine]-5-carboxamide
Figure imgf000155_0001
[0494] A mixture of compound 90a (200 mg, 0.42 mmol), compound 90b (85 mg, 0.5 mmol), and Pd(dppf)Cl2 (29 mg, 0.04 mmol), K2C03(138mg, l .OOmmol) in dioxane/H20 (1.6 mL/0.4 mL) was degassed with N2 and stirred at 100°C for 2h. The mixture was diluted with 50 ml water, extracted with EA (50 mL *3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desire product Example 90 (10.2 mg, yield: 4.9 %) as a white solid. LCMS [M+l]+ = 484.0 [0495] 1H NMR (400 MHz, DMSO-d6) 5 12.60 (s, IH), 9.11 (s, IH), 8.90 - 8.84 (m, 3H), 8.39 (t, J = 7.5 Hz, 2H), 8.07 - 7.98 (m, 2H), 7.84 (d, J= 7.6 Hz, IH), 5.37 - 5.23 (m, IH), 3.73 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H).
Example 91: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-4-ethynyl-2-fluoro-N-(6-(4-isopropyl- 4H-l,2,4-triazol-3-yl)pyridin-2-yl)benzamide
Figure imgf000156_0001
Step 1: Example 91c
[0496] To a solution of Example 91a (90 mg, 0.16 mmol) in DMF/DIPEA (3 mL/3 mL) were added Example 91b (27 mg, 0.32 mmol), Pd(PPh3)2Cl2 (11 mg, 0.016 mmol) and Cul (3 mg, 0.016 mmol). The mixture was stirred at 100°C overnight. The mixture was extracted with EtOAc (15 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM MeOH = 10/1) to give the desired product (40 mg, crude) as brown oil. LCMS [M+l]+ = 514.0
Step 2: Example 91
[0497] To a solution of Example 91c (40 mg, 0.078 mmol) in toluene/i-PrOH (3 mL/1.5 mL) was added NaOH (9 mg, 0.23 mmol). The mixture was stirred at 90°C for 1.5 h. The mixture was extracted with EtOAc (15 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm,'10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 91(2 mg, yield 6%) as a whitesolid. LCMS [M+l]+ = 456.0
[0498] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, IH), 8.84 (s, IH), 8.17 (d, J= 8.2 Hz, IH), 8.02 (t, J = 8.0 Hz, IH), 7.92-7.84 (m, 2H), 7.82-7.73 (m, 2H), 7.29 (d, J= 1.4 Hz, IH), 5.61 (dt, J= 14.0, 7.1 Hz, IH), 4.69 (s, IH), 1.87-1.79 (m, IH), 1.40 (d, J= 6.7 Hz, 6H), 0.81-0.76 (m, 2H), 0.69-0.65 (m, 2H). Example 93: Synthesis of 6'-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl- 6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000156_0002
[0499] A solution of Example 93a (200 mg, 0.43mmol), Example 93b (60 mg, 0.43 mmol),
Pd(dppf)Cl2 (32 mg, 0.043 mmol) and Na2C03 (140 mg, 1.32 mmol) in Dioxane/H20(2 mL/1 mL) was stirred at 80°C for 16h at N2. TLC and LCMS showed the start material was consumed completely. The reaction mixture was concentrated under reduced pressure, which was purified by silica gel columnflash to give Example 93 (90 mg, and yield 48%) as a brown solid. LCMS [M+l]+ =434.0
[0500] 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.89 (s, 1H), 8.77 (d,J= 2.8 Hz, 1H), 8.70 (dJ= 2.8 Hz, lH),8.54(d)J= 2.3 Hz, 1H), 8.37 (d,J= 8.0 Ηζ,ΙΗ), 8.31 (dt,J = 2.8 , 8.4 Ηζ,ΙΗ), 8.03 (t,J= 8.0 Hz, 1H),7.82 (d, J= 7.2 Hz, 1H), 7.30 (dd, J= 2.8 , 8.4 Hz, 1H), 5.35-5.25 (m, 1H), 3.70 (s, 3H), 1.53 (d, J= 6.7Hz, 6H).
Example 94: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-6'-methoxy-l- methyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000157_0001
[0501] A solution of Example 94a (0.15 g, 0.32 mmol), Example 94b (50 mg, 0.32 mmol), Pd(dppf)Cl2 (24 mg, 0.032 mmol) and Na2C03 (0.1 g, 3 eq) in Dioxane/H20(1.5 mL/0.5 mL) was stirred at 80°C for 16h at N2.TLC and LCMS showed the start material was consumed completely. The reaction mixture was concentrated under reduced pressure, which was purified by silica gel columnflash to give Example 94 (50 mg, and yield35%) as a brown solid. LCMS [M+l]+ =446.0
1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.89 (s, 1H), 8.71 (s,lH), 8.60 (s, 1H),8.45(S,1H), 8.36 (d,lH), 8.03 (m,2H), 7.99(s,lH),6.94 (d, 1H), 5.3 (m, 1H), 3.88 (s, 3H), 3.70 (s, 3H),1.52 (d, J= 8.0 Hz, 6H).
Example 95: Synthesis of 6'-chloro-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl- -oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000157_0002
[0502] A solution of Example 95a (295 mg, 0.64 mmol), Example 95b (100 mg, 0.64 mmol),
Pd(dppf)Cl2 (46 mg, 0.06 mmol), Na2C03 (202 mg, 1.9 mmol) in Dioxane/H20=2 mL/lMl was heated at reflux for 18h. The reactionmixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Example 95 (mg, yield 27%) as a white solid. LCMS [M+l] + =450.0 [0503] 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.89 (s, 1H), 8.80 - 8.77 (m, 2H), 8.74 (d, J = 2.6 Hz, 1H), 8.36 (d, J= 8.4, 0.9 Hz, 1H), 8.18 (dd, J= 8.4, 2.7 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6Hz, 1H), 7.61 (d, J= 8.4 Hz, 1H), 5.35-5.25 (m,lH), 3.71 (s, 3H), 1.52 (d, J= 6.7 Hz, 6H).
Example 96: Synthesis of 6'-bromo-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyI- 6-oxo-l,6-dih dro-[3,3'-bi ridine]-5-carboxamide
Figure imgf000158_0001
[0504] To a solution of Example 96a (230 mg, 0.5 mmol), Example 96b (100 mg, 0.5 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), Na2C03 (158 mg, 1.5 mmol) in Dioxane/H20=2mL/lmL. The reaction mixture was heated at reflux for 18h. The mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Example 96 (54 mg, yield 22%) as a white solid. LCMS [M+l] + =495.9
[0505] 1H NMR (400 MHz, DMSO-40 δ 12.62 (s, 1H), 8.89 (s, 1H), 8.78 (s, 2H), 8.72 (d, J= 2.6 Hz,
1H), 8.37 (d, J= 8.3 Hz, 1H), 8.08 (dd, J= 8.4, 2.7 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6Hz,
1H), 7.74 (d, J= 8.3 Hz, 1H), 5.35 - 5.25 (m,lH), 3.71 (s, 3H), 1.52 (d, J= 6.7 Hz, 6H).
Example 97: Synthesis of 6'-(difluoromethyl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-
Figure imgf000158_0002
Step 1: Example97c
[0506] A mixture of Example 97a (150 mg, 0.32 mmol) in dioxane (3mL) was added Example 97b (106 mg, 0.42 mmol), Pd2(dba)3 (15 mg, 0.03 mmol), X-Phos (30 mg, 0.03 mmol) and CH3COOK (95 mg, 0.97mmol). The mixture was stirred at 90°C for 30 min in microwave. The mixture was used in the next step directly.
Step 2: Example 97
[0507] To the mixture from BD01066- 163 was added Example 97d (74 mg, 0.36mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and H20 (0.5 mL) . The mixture was stirred at 90°C for 30 min in microwave. The mixture was added into 50 mLofwater and extracted with ether acetate (20 mL *3). The combined organic phase was washed with brine, dried over Na2SO 4, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to afford Example 97 (13.4 mg, yield: 8.93%) as a white solid. LCMS [M+l] + =466.0
[0508] 1H NMR (400 MHz, DMSO-d 6) δ 12.62 (s, 1H), 9.01 (d, J= 2.2 Hz, 1H), 8.89 (s, 1H), 8.87 - 8.79 (m, 2H), 8.38 (d,J= 8.0 Hz, 1H ), 8.30 (dd, J= 8.0, 2.4 Hz, 2H), 8.04(t,/= 8.0 Ηζ,ΙΗ), 7.87 - 7.72 (m, 2H), 7.00(t, J= 54.8Hz,lH), 5.35 - 5.26 (m, 1H), 3.73 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 99: Synthesis of 5-cyclopropyl-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- methyl-lH-pyrrolo[3,2-b]pyridine-3-carboxamide
Figure imgf000159_0001
[0509] 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1H), 8.89 (s, 1H), 8.75 (t, J= 3.2 Hz, 2H), 8.68 (d, J = 2.9 Hz, 1H), 8.37 (dd, J= 8.3, 0.9 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.96 (dd, J= 8.1, 2.5 Hz, 1H), 7.82 (dd, J= 7.7, 0.9 Hz, 1H), 7.34 (d, J= 8.1 Hz, 1H), 5.35-5.25 (m, 1H), 3.71 (s, 3H), 2.49 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 100: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,l- c] [l,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide
Figure imgf000159_0002
Step 1: Example 100b
[0510] A mixture of Example100a (23g, 100 mmol), NH2NH2 H20 (6.4 g,200 mmol) in MeOH (160 mL) was stirred at 50°C for 2 h. The mixture was diluted with water, extracted with EtOAc (150 mL*3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue waspurified by silica gel chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example 100b (20 g, yield 93%) as a white solid.LCMS [M+l]+ = 217.9. Step 2: Example 100d
A mixture of ExampIe100c (1.7g, 20.0 mmol), P0C13 (3.18 g, 20.0 mmol) in DCM (16 mL) was stirred at 40°C for 1 h. The mixture concentrated and without purification to give the desired product Example 100d ascolorless oil.
Step 3: Example 100e
[0511] A mixture of Example100b (2.16 g, 10.0 mmol), Example 100d (2.06 g, 20.0 mmol), DIPEA (6.45 g, 50.0 mmol) in toluene (16 mL) was stirred at 130°C for 3 h. Then cooled to r.t. and added NaHC03 aq until pH=l 1. Then mixture was stirred at 100°C for 3 h, and then cooled to r.t.. The mixture was diluted with water, extracted with EtOAc (150 mL*3). The combined organic layer washed with' brine (30 mL), dried over Na2S04, and concentrated. The residue was purified by silica gel
chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example 100e (400mg, yield 15% over 2 steps) as yellow oil. LCMS [M+l]+ = 266.9.
Srep4: Example 100f
[0512] A mixture of Example100e (400 mg, 1.50 mmol), tert-butylcarbamate(232 mg, 2.0 mmol), Pd2(dba)3(172 mg, 0.15 mmol), Xantphos (111 mg, 0.15 mmol), Cs2C03 (625 mg, 2.0 mmol) in toluene(5mL) was stirred at 90°C for overnight. The mixture was diluted with water, extracted with EtOAc (150 mL*3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example 100f (100 mg, yield 22%) as yellow oil. LCMS [M+l]+ =302.1. Step5: Example 100g
[0513] A mixture of Example100f (100 mg, 1.50 mmol)in 4M HC1/THF (3 mL) was stirred at r.t. for overnight. The mixture was concentrated to give the desired product Example 100g (100 mg, yield 99%) as yellow oil without further purification. LCMS [M+l]+ =202.1.
Step6: Example 100
[0514] To a solution of Example 100g (100 mg, 0.5 mmol) and Example 100h (156 mg, 0.6 mmol) in pyridine (4 mL) at 0°C was added POCl3 (153 mg 1.0 mmol). The mixture was stirred at 0°C for 1 h. The mixture was quenched with water, and then extracted with EtOAc.The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 85/15 to 40/60 over 40 min, desired peak @ 25 min) to afford Example 100 (15 mg, yield 7%) as a white solid. LC-MS [M+l] + = 444.0.
[0515] 1H NMR (400 MHz, DMSO-d 6) δ 10.88 (s, 1H), 8.14 (d, J= 8.2 Hz, 1H), 7.97 (t, J= 8.0 Hz, 1H), 7.84 (dd, J= 7.6, 0.9 Hz, 1H), 7.67 (d, J = 1.4 Hz, 1H), 7.60 (d, J= 6.6 Hz, 1H), 7.46 (d, J= 10.7 Hz, 1H), 7.16 (d, J= 1.5 Hz, 1H), 4.37 (t, J= 7.1 Hz, 2H), 2.86 (t, J= 7.6 Hz, 2H), 2.67 (q, J= 7.3 Hz, 2H), 2.23 (s, 3H), 1.82 (td, J= 8.3, 4.2 Hz, 1H), 0.81-0.75 (m, 2H), 0.68 (dt, J= 5.2, 2.8 Hz, 2H).
Example 103: Synthesis of 8-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)-5-oxo-l,2,3>5-tetrahydroindolizine-6-carboxamide
Figure imgf000161_0001
Step 1: Example 103c
[0516] To a mixture of Example 103a (200 mg, 0.66 mmol), Example 103b (106 mg, 0.98 mmol) in DMSO (6 mL) was added Cu20 (20.98 mg, 0.13 mmol), 8-quinilinol (19 mg, 0.13 mmol) and K3P04 (695 mg, 3.27mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100°C for 4h. The mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (Example 103c, 20 mg, yield: 10.7%) as white solid. LCMS [M+l]+ = 286.0.
Step 2: Example 103
[0517] Amixture of Example 103c (20 mg, 0.07 mmol) and Example 103d (17.0 mg, 0.08 mmol) in Pyridine (3 mL) was stirred at 0°C for 20 min. Then the mixture was added POCl3 (53.5 mg, 0.35 mmol), and stirred at r.t. for lh. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 103 (2.2 mg, yield: 6.1 %) as white solid. LCMS [M+l] '=471.0.
[0518] 1H NMR (400 MHz, DMSO-d6) 5 12.50 (s, 1H), 8.88 (s, 1H), 8.36 (s, 1H), 8.35 (d, J= 7.6 Hz, 1H),8.02 (d, J= 7.6 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.74 (s, 1H), 7.19 (s, 1H), 5.33 -5.24 (m, 1H), 4.26 (t, J= 7.2 Hz, 2H), 3.21 (t, J = 7.7 Hz, 2H), 2.24-2.15 (m, 2H), 1.85-1.79 (m, 1H), 1.52 (d, J= 6.8 Hz, 6H), 0.86-0.63 (m, 4H).
Example 106: Synthesis of N-(6-(4-cyclopropyl-4H-l,2,4-triazol-3-yI)pyridin-2-yl)-8-(6- cyclopropylpyridin-3-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000161_0002
Step 1: Example 106b
[0519] Toa mixture of Example 106a (100 mg, 0.33 mmol), Example 106b (78.4 mg, 0.39 mmol) in pyridine (5 mL) at 0°C, was added POCl3 (252.45 mg, 1.65 mmol). Then the reaction was started at 0°C with stirring for 1 h. The reaction solution was poured into water (5 mL) and extracted with EtOAc (50 mL*3) and the combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to give the residue. The residue was purified by Pre-TLC to give a crude product (Example 106c, 100 mg) as a yellow solid. The crude was used for next step directly. LCMS [M+l] + = 488.9
Step 2: Example 106
[0520] A mixture of Example 106c (100 mg, crude), Example 106d (39.12 mg, 0.24 mmol), Na2C03 (63.6 mg, 0.6 mmol) in Dioxane/H20 (5 mL, 10/1), was added Pd(dppf)Cl2 (10 mg). The mixture was degassed with N2 for 3 times. Then the mixture was heated at 80°C for 12 h. After then, the mixture was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to give product (8.8 mg, two step yield 14.5%) as a white solid.LCMS [M/2+1] + = 480.0240.5
[0521] 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.66 (s, 1H), 8.50 (d, J= 2.0 Hz, 1H), 8.45 (s, 1H), 8.35 (d, J= 8.1 Hz, 1H), 8.00(t, J= 8.0 Hz, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.76(dd, J = 8.0,2.4Hz,lH), 7.38 (d, J= 8.0 Hz, 1H), 4.29 - 4.20 (m, 2H), 3.78 (dd, J = 9.5, 5.6 Hz, lH),3.27(m, 2H), 2.23 - 2.09 (m, 3H), 1.21 (s, 4H), 1.04 - 0.91 (m, 4H).
Example 107: Synthesis of 6'-cyclopropyl-N-(6-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- methyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000162_0001
Step 1: Example 107c
[0522] A mixture of Example 107a (0.13 g, 0.46 mmol) and Example b (0.112 g, 0.46 mmol) in 2 mL ofPyridine was cooled to 0°C, and was added POCl3 (0.22 mL, 2.3 mmol) at ice bath, the mixture was stirred at 0°C for 1.5h. The mixture was poured into 6mLofwater and stirred for 10 min, filtrated and the filter cake residue was washed with water and to get crude product (0.22 g, yield 102%) as yellow solid.LCMS [M+ 1 ] + = 463.0
Step 2: Example 107
[0523] A mixture of crude Example 107c (0.2 g, 0.43 inrnol), Example 107d (60 mg, 0.43 mmol), Pd(dppf)Cl2 (32 mg, 0.04mmol) and Na2CO3(0.14 g, O. Bmmol) in Dioxane/H20(2mL/lmL) was stirred at 85°C for 16h at N2. The mixture was concentrated under reduced pressure, which was purified by silica gel columnflash to give crude product45 mg as a brown solid,and by further purification, to get desired product Example 107 (23 mg, yield 15%) as a white solid by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) (dissolving in large amount of DMSO), under lyophilization. LCMS [M+l] + = 454.0 [0524] 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.73 (d, J= 2.8 Hz, 1H), 8.66 (s, 2H), 8.64 (d, J = 2.8 Hz, 1H), 8.36 (d, J= 8.3 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.91 (dd, J= 8.1, 2.5 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.37 (d, J= 8.2 Hz, 1H), 3.84 - 3.73 (m, 1H), 3.69 (s, 3H), 2.13 (t, J= 4.9 Hz, lH), 1.15 (d, J= 6.8 Hz, 2H), 1.04 (d, J= 4.4 Hz, 2H), 0.99 - 0.90 (m, 4H).
Example 108: Synthesis of 5-(benzyloxy)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000163_0001
Step 1: Example 108b
[0525] A test-tube was charged with Cul (100 mg, 0.05 mmol),l, 10-phenanthroline (200mg, 0.10 mmol), Cs2C03 (3.2g, 10 mmol), Examplel08a (1.5g,5 mmol) and BnOH(15mL). The test-tube was sealed and the reaction mixture was stirred at 110 °C for 20 h. The resulting suspension was cooled to room temperature. Then the mixture was added aq.HCl to adjust pH=3. The reaction mixture was filtered to give 500mg of Examplel08b as white solid. (Yield: 40%). LCMS [M+l] + = 260.0
Step 2: Example 108
[0526] To a solution of Example 108b (323 mg, 1.15 mmol) in pyridine (10 mL) at 0°C was added Example 108c (236mg, 1.19 mmol), and POCl3 (ImL). Thenthe reaction mixture was stirred at 0°C for 1 h. The reaction solution was poured into water (10 mL) and solid was precipitated. Filtrated, and thesolid cake was washed with water, to give 320mg of crude product. This crude product was purified by Prep- HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give 5mg of white solid. Example 108 (yield: 10%)
1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.87 (s, 1H), 8.33 (d, J= 8.3 Hz, 1H), 8.29 (d, J= 3.4 Hz, 1H), 8.12 (d, J= 3.5 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.45 - 7.32 (m,5H), 5.33 - 5.23 (m, 1H), 5.05 (s, 2H), 3.61 (s, 3H), 1.51 (d, J= 6.7 Hz, 6H).
Example 109: Synthesis of 8-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-cyclopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000163_0002
Step 1: Example 109c
[0527] A slurry of Example 109a (450 mg, 1.48 mmol) and Example 109b (239 mg, 2.21 mmol) in DMSO (20 mL) was added 8-quinilinol (42.92 mg, 0.30 mmol), Cu20 (47.36 mg, 0.30 mmol) and K3P04 (1.57 g, 7.40 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100°Cfor 4h. The mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give product (Example 109c, 80 mg, yield: 19.0%) as white solid. LCMS [M+l] + = 286.0
Step 2: Example 109
[0528] The mixture of Example 105c (80 mg, 0.28 mmol) and Example 109d (68.34 mg, 0.34mmol) in Pyridine (5 mL) was stirred at 0°C for 20 min. Then the mixture was added POCl3 (214.2 mg, 1.4 mmol), and stirred at 0°C for lh. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 109 (9.7 mg, yield: 7.38 %) as white solid. LCMS [M+l] +=469.0
[0529] 1H NMR (400 MHz, DMSO-40 δ 12.50 (s, 1H), 8.66 (s, 1H), 8.38 - 8.32 (m, 2H), 8.01 (t, J= 8.0 Hz, 1H), 7.85 (d, J= 7.4 Hz, 1H), 7.74 (s, 1H), 7.19 (s, 1H), 4.25 (t, J= 7.4 Hz, 2H), 3.81-3.75 (m, 1H), 3.21 (t, J= 7.7 Hz, 2H), 2.24-2.16 (m, 2H), 1.86-1.79 (m, 1H), 1.14 (q, J = 7.2 Hz, 2H),.1.06 - 1.00 (m, 2H), 0.78 (dq, J= 5.6, 3.7, 3.3 Hz, 2H), 0.70 - 0.64 (m, 2H).
Example 110: Synthesis of 6'-ethyl-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl- 6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000164_0001
Step 1: ExamplellOc
[0530] A mixture of Example 110a (200 mg, 1.08 mmol) in dioxane (3mL) was added Example 110b (326 mg, 1.29 mmol), Pd(dppf)Cl2 (78 mg, 0.1 lmmol) and CH3COOK (316 mg, 3.23 mmol).The mixture was stirred at 90°C for 30 min in microwave. The mixture was used in the next step directly. Step 2: Example 110
[0531] To the mixture from BD01066-176 was added Example HOd (199 mg, 0.43 mmol), Pd(dppf)Cl2 (39 mg, 0.05 mmol) and H20 (0.5 mL) . The mixture was stirred at 90°C for 30 min in microwave. The mixture was added into 50 mL of water and extracted with ether acetate (20 mL *3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue waspurified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford Example 110 (16.5 mg, yield: 8.63%) as a gray solid.
[0532] LCMS [M+l] + =444.0
[0533] 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, IH), 8.89 (s, IH), 8.82 - 8.71 (m, 2H), 8.68 (d, J= 2.8 Hz, IH), 8.37 (d,J= 8.3 Hz, IH), 8.03(t, J= 8.0 Hz, IH), 7.98 (dd, J= 8.4,2.4 Hz, IH), 7.82 (d, J= 7.6 Hz, IH), 7.36 (d, J= 8.1 Hz, IH), 5.35 - 5.25 (m, IH), 3.71 (s, 3H), 2.77 (q, J= 7.6 Hz, 2H), 1.53 (d, J= 6.7 Hz, 6H), 1.23 (t, J= 7.6 Hz, 3H).
Example 111: Synthesis of 6'-ethynyI-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- methyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000165_0001
Step 1: Example 111c
[0534] A solution of Example 111a (1.15 g, 2.5 mmol), Example 111b (500 mg, 2.5 mmol),
Pd(dppf)Cl2 (181 mg, 0.25mmol), Na2C03 (787 mg, 7.4 mmol) in Dioxane/H2O=10 mL/5 mLwas heated at reflux for 18h. The mixture was extracted with EA (20 mL * 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04. The solvent was removed under reduced pressure. The residue was purified bysilica gel chromatography to give Example 111c (288 mg, yield 42%) as a white solid. LCMS [M+l] + =494.0
Step 2: Example llle
[0535] A solution of Example 111c (0.2 g, 0.4 mmol), Example llld (794 mg, 8 mmol), Cul (7.7 mg, 0.04 mmol), TEA (205 mg, 2 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol) in 5 mL CH3CN was heated at 100°C for 15h.The mixture was extracted with EA (20 mL * 3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography to give Example llle (80 mg, yield 24%) as a white solid. LCMS [M/2+1] + = 257.0
Step 3: Example 111
[0536] To a solution of Example llle (80 mg, 0.16 mmol) in 5mL THF was added TBAF (102 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for lh. The residue was dissolved in water and extracted with EA (5 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Example 111 (11 mg, yield 16%) as a gray solid. LCMS [M+l] + = 440.0
[0537] 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.90 (d, J= 2.9 Hz, 1H), 8.89 (s, 1H), 8.80 (d, J = 2.9 Hz, 1H), 8.78 (d, J= 2.8 Hz, 1H), 8.37 (d, J= 8.3 Hz, 1H), 8.12 (dd, J= 8.2, 2.5 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.83 (d, J= 7.6 Hz, 1H), 7.65 (d, J= 8.1 Hz, 1H), 5.35 - 5.25 (m, 1H), 4.40 (s, 1H), 3.71 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 113: Synthesis of 5-(cyclopentyloxy)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)- l-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000166_0001
Step 1: Examplell3b
[0538] A mixture of Example 113a (300 mg, 0.68 mmol) in MeOH (15 mL) was added 5% Pd/C (100 mg) themixture was stirred at 68°C for 16h under H2 (2.0 MPa). The mixture was filtered and concentrated. The residue was used in the next step directly.
Step 2: Example 113
[0539] To the Examplell3b (100 mg, 0.28 mmol) in DMF (3 mL) was added Example 113c (105 mg, 0.71 mmol), K2CO3 (1 17 mg, 0.85 mmol). The mixture was stirred at 80°C for 5h. The mixture was added into 50 mL ofwater and extracted with ether acetate (20 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-TLC to afford Example 113 (3.6 mg, yield: 3.43%) as a white solid. LCMS [M+l] + =423.0
[0540] 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J= 8.3, 0.9 Hz, 1H), 8.19 (d, J= 3.4 Hz, 1H), 8.01(t, J= 7.6 Hz , 1H), 7.95(d, J= 3.6 Hz,lH),7.80 (dd, J= 7.7, 0.9 Hz, 1H), 5.32 - 5.23 (m, 1H), 4.70 - 4.65 (m, 1H), 3.60 (s, 3H), 1.89- 1.77 (m, 4H),1.76- 1.65 (m, 4H), 1.50 (d, J= 6.8 Hz, 6H).
Example 115: Synthesis of 5-bromo-6-(difluoromethoxy)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)isoindolin-l-one
Figure imgf000167_0001
[0541] A mixture of Example 115a (620 mg, 1.5 mmol), Example 115b (610 mg, 3.0 mmol) and K2C03 (620 mg, 4.5 mmol) in DMF (15 mL) was stirred at ambient temperature for 16 h. The reaction was diluted with water (20 mL), stirred for 10 min, and then extracted with EtOAc (20 mL*3). The combined organic layers were washed by brine, separated and concentrated to give a residue, which was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford Example 115 (35 mg, yield 5 %) as a white solid. LCMS [M+l]+ =465.9
[0542] 1H NMR (400 MHz, DMSO-d6) 8 8.91 (s, 1H), 8.58 (d, J= 8.4 Hz, 1H), 8.22 (s, 1H), 8.07 (t, J= 8.0 Hz, 1H), 7.92 (d, J= 7.6 Hz, 1H), 7.71 (s, 1H),7.49 (t, J= 73.0 Hz, 1H), 5.49 (m, J= 6.6 Hz, 1H), 5.13 (s, 2H), 1.55 (d, J= 6.7 Hz, 6H).
Example 117: Synthesis of 6'-cyclopropyl-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l- methyl-2-oxo-l,2-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000167_0002
Step 1 : Example 1 17b
[0543] A solution of Example 117a (1 g, 4.58 mmol) and K2C03 (1.56 g, 13.76 mmol) in 10 mL of DMF, and was added Mel (0.7 mL, 11.46 mmol), the reaction was stirred at rt for 2.5 h. LCMS
(BD01075-068) showed SM consumed, the mixture was poured into 30 mL water and stirred for 10 min. The mixture was extracted with EA (10 mL * 3). The combined organic phase was dried over MgS04, filtrated and the filtrate was concentrated under reduced pressure to get desired product (0.82 g, yield 73%) as yellow solid. LCMS [M+l] + = 246.0
Step 2: Example 117c
[0544] A solution of Example 117b (0.60 g, 2.44 mmol) and LiOH.H20 (0.45 g, 10.2 mmol) in 5 mL /2.5 mL (EtOH H20), the reaction was stirred at rtfor 2.5h. LCMS (BD01075-070) showed SM consumed, the mixture was concentrated to remove EtOH, and was acidified with aq HC1 solution to PH3, the filter cake residue was washed with H20, concentrated to get desired product (0.6 g, yield 107%) as a brown solid. LCMS [M+l] + = 232.0
Step 3: Example 117e
[0545] A solution of Example 117c (0.35 g, 1.5 mmol) andExample 117d (0.3 g, 1.5 mmol) in 5 mL Pyridine, the mixture was cooled to 0°C , and was added POC13 (0.22mL, 5eq) at ice bath, the reaction was stirred at 0UC for 1.5 h. the mixture was poured into 2mL water and stirred for 10 min, filtrated and the filter cake residue was washed with water and EA for twice , The residue was purified by silica gel chromatography to give the desired product (Example 117e, 0.4 g yield 63%) as a brown solid.LCMS [M+l] + = 417.0
Step 4: Example 117
[0546] A solution of Example 117e (0.22 g, 0.53 mmol), Example 117f (86 mg, 0.53mmol), Pd(dppf)Cl2 (38 mg, 0.053 mmol) and Na2C03 (0.17 g, 1.57 mmol) in Dioxane/H20(3 mL/1 mL) , the mixture was stirred at 80°C for 16 h at N2.The reaction mixture was concentrated under reduced pressure, which was purified by silica gel columnflash to give crude product 0.2 g, and further purification by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min), under lyophilization to get desired product Example 117 (70 mg, yield 38%) as a white solid. LCMS [M+l] + =456.0
[0547] 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.84 (s, 1H), 8.75 (d, J= 2.3 Hz, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.21 (d, J= 2.6 Hz, 1H), 8.10 (d, J= 8.3 Hz, 1H), 8.03 - 7.97 (m, 2H), 7.77 (d, J= 7.5 Hz, 1H), 7.33 (d, J= 8.2 Hz, 1H), 5.55 - 5.45 (m, 1H), 3.61 (s, 3H), 2.15 - 2.08 (m, 1H), 1.41 (d, J= 6.6 Hz, 6H), 0.97 - 0.91 (m, 4H).
Example 120: Synthesis of 6'-cyclopropyl-N-(3-(4-isopropyl-4H-l,2,4-triazol-3-yl)phenyl)-l-methyl- 6-oxo-l,6-dih dro-[3,3'-bi ridine]-5-carboxamide
Figure imgf000168_0001
Step 1: Example 120c
[0548] To a solution of Example 120a (400 mg, 1.44 mmol) in dioxane/H20 (6.0 mL /1.5 mL) were added Na2C03 (305 mg, 2.88 mmol), Example 120b (286 mg, 1.73 mmol) and Pd(dppf)Cl2 (105 mg, 0.144mmol). The mixture was stirred at 90°Cfor lh under N2 by microwave. To the mixture was added H20 (30 mL), which was then extracted with EtOAc (10 mL*3). Then the pH of the aqueous layer was adjusted to 2. The mixture was extracted with EtOAc (10 mL *5). The combined organic layer was concentrated to give the desired product Example 120c (300 mg, yield 77%) as a gray solid. LCMS [M+l]+ = 271.0
Step 2: Example 120
[0549] To a solution of Example 120c (80 mg, 0.30 mmol) and Example 120d (66 mg, 0.33 mmol) in DMF (2 mL) were added HATU (123 mg, 0.33 mmol) and DIPEA (76 mg, 0.59 mmol). The mixture was stirred at r.t. for 16 h. To the mixture was added H20 (30 mL), which was then extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to obtainthe desired product Example 120 (14 mg, yield 11%) as a white solid. LCMS [M+l]+ = 455.0.
[0550] 1H NMR (400 MHz, DMSO-d6 δ 12.32 (s, 1H), 8.85 (s, 1H), 8.72-8.59 (m, 3H), 8.12 (t, J= 1.9 Hz, 1H), 7.91 (dd, J= 8.1, 2.5 Hz, 1H), 7.75 (dt, 7= 8.4, 1.2 Hz, 1H), 7.55 (t, J= 7.9 Hz, 1H), 7.40-7.31 (m, 2H), 4.46 (p, J= 6.7 Hz, 1H), 3.71 (s, 3H), 2.14(m, 1H), 1.43 (d, J= 6.7 Hz, 6H), 1.01-0.92 (m, 4H). Example 121: Synthesis of 6-(4-cyclopropyl-lH-imidazol-l-yl)-2,2-difluoro-N-(6-(4-isopropyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)benzo[d][l,3]dioxole-4-carboxamide
Figure imgf000169_0001
Step 1: Example 121a
[0551] Example 121a (4.4 g, 21.8 mmol) was dissolved in H2S04 (98%, 44 mL) at 0°C. HN03 (95%, 2.2 mL, 24.9 mmol) was dissolved in H2S04 (98%, 9 mL) at 0°C. Then, the HN03 solution was added into Example 121a solution dropwise, and during this procedure, the temperature was kept around 0°C. After complete addition of HNO3 solution, the mixture was stirred at 0°C for 1 h. The reaction mixture was poured into ice water with stirring for about 10 min, and then filtrated. The filtrate was collected as the crude desired product Example 121b (3 g, crude yield 56%) as a pale-yellow solid.LCMS [M+l]+ = 248.0
Step 2: Example 121c
[0552] A mixture of Example 121b (2.93 g, 11.9 mmol) and K2C03 (6.55 g, 47.4 mmol) in DMF (60 mL) was stirred at r.t. with stirring. Then, Mel (5.05 g, 35.6 mmol) was added to the mixture, which was stirred for 1 h. The reaction solution was poured into water (200 mL). After extraction with EtOAc (50 mL*2),the combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give the crude desired product Example 121c (3.20 g, crude yield 100%) asa dark-yellowliquid. LCMS [M+l]+ = 229.9
Step 3: Example 12 Id
[0553] To a solution of Example 121c (3.20 g, crude, 11.9 mmol) in EtOH/H20 (60 mL/15 mL) was added Fe powder (6.66 g, 119.0 mmol) and NH4C1 (6.31 g, 119.0 mmol). The resulting mixture was stirred at 80°C under N2atmosphere with stirring for 1 h. The reaction solution was poured into water (200 mL). After extraction with EtOAc (50 mL*2), the combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 1/1) to give the desired product Example 121d (328 mg, yield 12%) as pale- yellowliquid. Notebly, there was an isomer (437 mg) obtained during the purification (Petroleum ether/EtOAc = 4/1). LCMS [M+l]+ = 231.9
For Example 121d 1H NMR (400 MHz, Chloroform-d) δ 6.91 (d, J= 2.3 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.75 (s, 2H).
For the isomer, 1H NMR (400 MHz, Chloroform-d) δ 6.98 (d, J= 8.8 Hz, 1H), 6.32 (d, J= 8.8 Hz, 1H), 5.63 (s, 2H), 3.93 (s, 3H).
Step 4: Example 121f
[0554] A mixture of Example 121d (328 mg, 1.42 mmol), Example 121e (278 mg, 1.70 mmol), K2C03 (235 mg, 1.70 mmol), and KI (236 mg, 1.42 mmol) were dissolved in CAN (8 mL) with stirring at 70°C for 6 h. Then, the reaction solution was filtrated and washed with EtOAc. The solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 87/13) to give the desired product Example 121f (187 mg, yield 42%) as a yellow solid. LCMS
[M+1]T = 313.9
Step 5: Example 121g
[0555] To a solution of Example 121f (187 mg, 0.60 mmol) in HCOOH (4 mL) was added Ac20 (244 mg, 2.39 mmol) with stirring at r.t. overnight. Then, the reaction solution was poured into water (5 mL), and the pH was adjusted to nearly 9 by using Na2C03(aq.). After extraction with EtOAc (5 mL),the organic layer was dried over Na2S04, and concentrated under reduced pressure to give the crude of desired product Example 121g (200 mg, crude yield 100%) asdark-yellowliquid.LCMS [M+l]+ = 342.0 Step 6: Example 121h
[0556] To a solution of Example 121g (200 mg, crude, 0.60 mmol) in AcOH (6 mL) was added NH4OAc (368 mg, 4.78 mmol) with stirring at 110°C overnight. Then, the reaction solution was poured into water (5 mL), and the pH of which was adjusted to nearly 9 by using Na2C03 (aq.). After extraction with EtOAc (5 mL), the organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether/EtOAc = 2/1) to give the desired product Example 121h (176 mg, yield 91%) as yellow liquid. LCMS [M+l]+ = 322.9
Step 7: Example 121i
[0557] To a mixture of Example 121h (176 mg, 0.55 mmol) in EtOH/H20 (3 mL/2 mL) was added LiOH.H20 (115 mg, 2.73 mmol) with stirring at r.t. for 1 h. Then, the reaction solution was evaporated under reduced pressure to remove EtOH, and the pH of which was adjusted to nearly 3 by using HC1 (IN, aq.). After extraction with EtOAc (5 mL*4),the combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give the desired product Example 121i (142 mg, yield 84%) as a yellow solid.LCMS [M+l]+ = 309.0
Step 8: Example 121
[0558] To a solution of Example 121i (120 mg, 0.39 mmol) in pyridine (3 mL) at 0°C were added Example 121j (87 mg, 0.43 mmol), and POCl3 (298 mg, 1.95 mmol). Then, the reaction was stirred at 0°C for 1 h. The reaction solution was poured into water (10 mL) and filtrated. The filtrate was washed with water, followed by EtOAc twice, to give the desired product Example 121 (48 mg, yield 25%) as a yellow solid. LCMS [M+l]+ = 494.0
[0559] 1H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 8.38 (d, J= 9.0 Hz, 2H), 8.13 (d, J= 7.7 Hz, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.95-7.90 (m, 1H), 7.86 (s, 1H), 7.37 (d, J= 2.3 Hz, 1H), 7.05 (d, J= 1.5 Hz, 1H), 5.58-5.48 (m, 1H), 1.96-1.88 (m, 1H), 1.63 (d, J= 6.7 Hz, 6H), 0.97-0.81 (m, 4H).
Example 122: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-8-(6- methylpyridin-3-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000171_0001
Step 1: Example 122c
[0560] To amixture of Example 122a (0.20 g, 0.65 mmol) and Example 122b (0.14 g, 0.65 mmol) in Pyridine (2 mL) at 0°C was added POCl3 (0.3 mL, 3.27 mmol), which was stirred at 0°C for 1.5 h. The mixture was poured into water (10 mL), and then extracted with DCM (20 mL*2). The combined organic layer was dried over Na2S04, filtered and concentrated to get the crude product Example 122c (0.15 g, yield 47%) as a yellow solid. LCMS [M+l]+ = 490.9
Step 2: Example 122
[0561] A mixture of Example 122c (0.15 g, crude, 0.30 mmol), Example 122d (41 mg, 0.30 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol) and Na2C03 (0.1 g, 0.90 mmol) in Dioxane/H20 (3 mL/1 mL) was exchanged with N2 for 3 times, and then stirred at 85°C for 16 hunder N2. The mixture was concentrated under reduced pressure and purified by silica gelchromatography (DCM/MeOH = 50/1 to 20/1) to give crude product (0.17g),which was further purifiedby Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 122 (40 mg, yield 29%) as a yellow solid. LCMS [M+l]+ = 456.0
[0562] 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.88 (s, 1H), 8.55 (d, J= 2.4 Hz, 1H), 8.46 (s, 1H), 8.36 (dd, /= 8.3, 0.9 Hz, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.81 (dt, J= 8.0, 2.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 5.27-5.33 ( m, 1H), 4.26 (t, J= 7.4 Hz, 2H), 3.37-3.31 (m, 2H), 2.51(s, 3H), 2.15-2.23(m, 2H), 1.52 (d, J= 6.7 Hz, 6H).
Example 123 and Example 124: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(3-(4- isopropyl-lH-l,2,3-triazol-l-yl)phenyl)-4-methylbenzamide (123) and 5-(4-cyclopropyl-lH- imidazol-l-yl)-2-fluoro-N-(3-(5-isopropyl-lH-l,2,3-triazol-l-yl)phenyl)-4-methylbenzamide (124)
Figure imgf000172_0001
Step 1: Example 123c
[0563] To a solution of Example 123a (12.0 g, 69.0 mmol), Example 123b (900 mg, 10.3 mmol), Cul (1.3 g, 6.9 mmol), NaN3 (7.5 g, 111.6 mmol) and sodium ascorbate (600 mg, 3.0 mmol) in water (100 mL) and EtOH (200 mL) was heated to 80°C overnight under N2 protection. The mixture was concentrated and the residue was purified by silica gel chromatography (Petroleum Ether/EtOAc=3/l) to give the desired product Example 203c (9.0 g, yield 97%) as brown oil. LCMS [M+l] + = 135.0 Step 2: Example 123e and 123f
[0564] To a solution of Example 123c (2.0 g, 14.9 mmol) and Example 123d (2.0 g, 29.8 mmol) in xylene (20 mL) was stirred at 125 °C for overnight. The mixture was concentrated and the residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc= 6/1) to give the desired product Example 123e (1.4 g, 46.8%) as brown oil LCMS [M+l] += 203.0 and Example 123f (700 mg, yield 23.4%) as brown oil.LCMS [M+l] += 203.0
Step 3: Example 124
[0565] To a solution of Example 123e (202 mg, 1.0 mmol) and Example 123g (261 mg, 1.0 mmol) in pyridine (5 mL) at 0°C was added POCl3 (460 mg, 3.0 mmol). The reaction was stirred at 0°C for 1.5 h. The reaction solution was poured into water (5 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product Example 124 (10 mg, yield 2%) as a white solid. LCMS [M+l]= 445.0
[0566] 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.95 (s, 1H), 7.84 (d, J= 8.2 Hz, 1H), 7.75 (s 1H), 7.68(s, 1H), 7.64 (d, J= 6.6 Hz, 1H), 7.60 (t, J= 8.1Hz,lH), 7.46 (d, J= 10.8 Hz, 1H), 7.33-7.29 (m, 1H), 7.17 (s, 1H), 3.06 (m, 1H), 2.23 (s, 3H), 1.84 (m,lH), 1.15 (d, J= 6.8 Hz, 6H), 0.78 (m, 2H), 0.68 (m, 2H).
Step 4: Example 123
[0567] To a solution of Example 123f (202 mg, 1.0 mmol) and Example 123g (261 mg, 1.0 mmol) in pyridine (5 mL) at 0°C was added POCl3 (460 mg, 3.0 mmol). The reaction was stirred at 0°C for 1.5 h. The reaction solution was poured into water (5 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 m, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 123 (20 m¾, yield 5%) as a yellow solid. LCMS [M+l]= 445.0
[0568] 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 7.75 (d, J= 7.6 Hz, 1H), 7.69 (s, 1H), 7.64 (d, /= 6.5 Hz, 1H), 7.61-7.52 (m, 2H), 7.47 (d, J= 10.8 Hz, 1H), 7.18 (s, 1H), 3.06 (m, J= 7.0 Hz, 1H), 2.23 (s, 3H), 1.84 (m, J= 8.4, 4.9 Hz, 1H), 1.30 (d, J= 7.0 Hz, 6H), 0.83-0.76 (m, 2H), 0.69 (m, J= 6.5, 3.7 Hz, 2H).
Example 126: Synthesis of 8-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000173_0001
Step 1: Example 126c [0569] A mixture of Example 126a (1.0 g, 3.3mmol) and Examplel26b (0.67 g, 3.3 mmol) in 10 mL of pyridinewas cooled to 0°C, and was added POCI3 (1.5 ml, 16 mmol) dropwise.The mixture was stirred at 0°C for 1.5h. The mixture was poured into 10 mL of water, then extracted withCH2Cl2 (20 mL*2), the combined organic layers were dried over anhydrous Na2S04, concentrated to get pure desired product 0.3g and crude product 0.5g. LCMS [M+l] + = 491.0
Step 2: Example 126
[0570] A mixture of crude Example 122c (150 mg, 0.3 mmol), Example d (100 mg, 0.3 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol) and Na2C03 (100 mg, 0.9 mmol) in Dioxane/H20(3 mL/1 mL) was exchange N2 for 3 times. After stirred at 85°C for 16 h at N2, the mixture was concentrated under reduced pressure, which was purified by Pre-TLC (Petroleum DCM/MeOH = 10/1) to give Example 126 38 mg, yield 25%) as a yellow solid. LCMS [M+l] + = 500.
[0571] 1H NMR (400 MHz, DMSO-d 6) δ 12.59 (s, 1H), 8.88 (s, 1H), 8.60 (d, J= 2.4 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J= 8.3 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.90 (dd, J= 8.2, 2.4 Hz, 1H), 7.81 (d, J= 7.5 Hz, 1H), 7.74 (d, J= 8.2 Hz, 1H), 5.35-5.28(m,lH), 5.27 (s, 1H), 4.26 (t,J= 7.4 Hz, 2H), 3.34 (d, J= 2.7 Hz, 2H), 2.29 - 2.03 (m, 2H), 1.52 (d, J= 6.7 Hz, 6H), 1.46 (s, 6H).
Example 129: Synthesis of (R)-6'-cyclopropyl-N-(3-(4-(l-hydroxypropan-2-yl)-4H-l,2,4-triazol-3-
Figure imgf000174_0001
Example 129a Example 129c Example 129
Step 1: Examplel29c
[0572] To a solution of Example 129a (400 mg, 1.44 mmol) in dioxane/H20 (6.0 mL /1.5 mL) were added Na2C03 (305 mg, 2.88 mmol), Example 129b (286 mg, 1.73 mmol) and Pd(dppf)(¾ (105 mg, 0.144 mmol). The mixture was stirred at 90°Cfor lh under N2 by microwave. To the mixture was added H20 (30 mL), which was then extracted with EtOAc (10 mL*3). Then the pH of the aqueous layer was adjusted to 2.The mixture was extracted with EtOAc (lOmL *5). The combined organic layer was concentrated to give the desired productExample 129c (300 mg, yield 77%) as a gray solid. LCMS
[M+l]+ = 271.0
Step 2: Example 129
[0573] To a solution of Example 129c (80 mg, 0.30 mmol) andExample 129d (66 mg, 0.33 mmol) in DMF (2 mL) were added HATU (123 mg, 0.33 mmol) and DIPEA (76 mg, 0.59 mmol). The mixture was stirred at r.t. for 16 h.To the mixture was added H20 (30 mL), which was then extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μηι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to obtainthe desired product Example 129 (43.8 mg, yield 31%) as a white solid. LCMS [M+l]+ = 471.0.
[0574] 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.79 (s, 1H), 8.69 (dd, J= 5.5, 2.6 Hz, 2H), 8.65 (d, J= 2.7 Hz, 1H), 8.08 (t, J= 1.9 Hz, 1H), 7.92 (dd, J= 8.2, 2.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.54 (t, J= 7.9 Hz, 1H), 7.38 (d, J= 8.0 Hz, 2H), 5.17 (t, J= 5.3 Hz, 1H), 4.33 (q, J= 6.5 Hz, 1H), 3.72 (s, 3H), 3.61 (p, J= 5.7 Hz, 2H), 2.14 (dt, J= 7.9, 3.1 Hz, 1H), 1.38 (d, J= 6.9 Hz, 3H), 0.99-0.92 (m, 4H). Example 130: Synthesis of N-(3-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)phenyl)-l,6'-dimethyl-6-oxo- l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000175_0001
To a solution of Example 130a (122 mg, 0.5 mmol) in DMF (2 mL) were addedExample 130b (100 mg, 0.5 mmol), DIPEA (258 mg, 2.0 mmol) andHATU (285 mg, 0.75 mmol), which was stirred atr.t.for 2 h. The mixture was extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent:
H20/CH3CN = from 80/20 to 20/80 over 50 min) to giveExample 130 (6 mg, yield 3%) as a yellowsolid.LCMS [M+l]+ = 427.0
[0575] 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.75 (d, J= 2.5 Hz, 1H), 8.73 (d, J= 2.8 Hz,
1H), 8.66 (d, J= 2.9 Hz, 1H), 8.61 (s, 1H), 8.41 (t, J= 1.9 Hz, 1H), 7.97 (dd, J= 8.1, 2.6 Hz, 1H), 7.78
(dt, J= 8.2, 1.6 Hz, 1H), 7.69 (dt, J= 7.9, 1.3 Hz, 1H), 7.54 (t, J= 7.9 Hz, 1H), 7.35 (d, J= 8.2 Hz, 1H),
3.73 (s, 3H), 3.67-3.61 (m, 1H), 2.50 (s, 3H), 1.09-1.04 (m, 2H), 1.01-0.92 (m, 2H).
Example 131: Synthesis of 6-(2,3-dihydroxypropoxy)-2-(6-(4-isopropyl-4H-l,2,4-triazol-3- yl)pyridin-2-yl)isoindolin-l-one
Figure imgf000176_0001
Step 1: Example 131b
[0576] Example 131a (2.0 g, 15.2 mmol) and TEA (2.5 mL, 18.2 mmol) were dissolved in dry DCM (60 mL), followed by addition of MsCl (1.4 mL, 17.4 mmol) at 0°C. The mixture was warmed to ambient temperature and stirred for 16 h. Water was added, the mixture was extracted by DCM (30 mL*2). The combined organic layers were washed by water, dried over Na2S04 and filtered. The solvent was removed in vacuo to give the desired product Example 131b(2.3 g, yield72 %) as brown oil.
Step 2: Example 131d
[0577] To a solution of Example 131c(2.0 g, 4.68 mmol) in dry DCM (40 mL) was added BBr3 (1.5 mL, 14.1 mmol) slowly at 0°C under nitrogen atmosphere. After addition, the mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by adding MeOH slowly at 0°C, stirred for 10 min and filtered. The solid was washed by MeOH, collected and dried to give Example 131d(1.3 g, yield 67 %) as a white solid.
LCMS [M+l]+ =413.9,415.9
Step 3: Example 131e
[0578] A mixture of Example 131d (150 mg, 0.36 mmol), Example 131b (1 15 mg, 0.54 mmol) and K2C03 (100 mg, 0.73 mmol) in DMSO (2 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, diluted with water (10 mL),andextracted with DCM/MeOH (v/v = 10/1, 20 mL*3). The combined organic layers were washed by brine, and concentrated to give a residue, which was purified by silica gel chromatography (DCM/MeOH = 82/18) to afford Example 131e(175 mg, yield91 %) as a white solid.LCMS [M+l]+ =528.0,529.9 Step 4: Example 131f
To a solution of Example 131e(175 mg, 0.33 mmol)in MeOH/THF (10 mL/10 mL) was added 5% Pd/C (20 mg), the mixture was degassed by hydrogen for three times and stirred under a hydrogen balloon for 2 h. The reaction was filtered, concentrated to give Example 131f(147 mg, yield 98 %) as yellow oil.LCMS [M+l]+ =449.9
Step 5: Example 131
[0579] Example 131f (147 mg, 0.33 mmol) was dissolved in MeOH (4 mL), followed by addition of a solution of 2N HC1 (aq.) slowly at ambient temperature. The reaction was stirred at this temperature for 30 min. The reaction was concentrated to dryness and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) directly to give desired product Example 131 (16 mg, yield 12 %) as a white solid.LCMS [M+l]+ =410.0
[0580] 1H NMR (400 MHz, DMSO-d6 ) δ 8.90 (s, 1H), 8.60 (d, J= 8.4 Hz, 1H), 8.05 (t, J= 8.0 Hz, 1H), 7.88 (d, J= 7.5 Hz, 1H), 7.61 (d, J= 8.2 Hz, 1H), 7.28 (d, J= 7.8 Hz, 2H), 5.47-5.51(m, 1H), 5.06 (s, 2H), 4.98 (s, 1H), 4.68 (s, 1H), 4.10 (dd, J= 10.1, 3.9 Hz, 1H), 3.95 (dd, J= 10.0, 6.2 Hz, 1H), 3.81 (s, lH), 3.45 (s, 2H), 1.54 (d, J= 6.6 Hz, 6H).
Example 137: Synthesis of 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(3-(4-isopropyl-4H-l,2,4-triazol-3- yl)phenyl)-l,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carboxamide
Figure imgf000177_0001
Step 1: Example 137b
[0581] To a slurry of Example 137a (10 g, 65.36 mmol) in DMF (100 mL), was added NIS (17 g, 75.16 mmol). The mixture was heated to 50°C and stirred for 2 h.The solution was used for next step directly without wnrlcnp.LCMS [M+l]+ = 279.8
Step 2: Example 137c
[0582] To thecrude Example 137b (33 mL, 1/3 vol. from Step 1) were added Cs2C03 (20.5 g, 63 mmol) and CH3I (15.3 g, 108 mmol). The mixture was stirred at r.t. overnight. The mixture was filtered and filtrate was concentrated under reduced pressure to give the crude product Example 137c(2.0 g, crude yield 30% over two steps) as brown oil, which was used for next step without purification. LCMS
[M+l]+ = 307.8 Step 3: Example 137d
[0583] To a mixture of Example 137c (1.0 g, crude) in MeOH (4 mL) was added aq. NaOH (4 mL, 2N), which was stirred at r.t. for 30 min. The mixture was adjusted pH to 4.0 and concentrated under reduced pressure to remove MeOH. Then the mixture was filtered and the solid was washed by MeOH (3 mL) to give the crude product Example 137d (1.2 g, crude yield >100%) as a yellow solid.LCMS [M+l] + = 293.9
Step 4: Example 137f
[0584] A mixture of Example 137d (200 mg, 0.68 mmol), Example 137e (1 11 mg, 1.02 mmol), 8- quinilinol (19 mg, 0.136 mmol), Cu20 (22 mg, 0.136 mmol) and K3P04 (720 mg, 3.40 mmol) in DMSO (10 mL) was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 100°C for 2h. The mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) givethe desired product Example 137f (40 mg, yield 22%) as a white solid. LCMS [M+l]+ = 274.0 Step 5: Example 137
[0585] To a mixture of Example 137f (40 mg, 0.15 mmol), Example 137g (36 mg, 0.18 mmol) and HATU (63 mg, 0.16 mmol) in DMF (3 mL) was added DIEA (58 mg, 0.45 mmol). The mixture was stirred at r.t. for 1 h. Then the mixture was directly purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 137 (4.7 mg, yield 7%) as a white solid. LCMS [M/2+l]+ = 229.5
1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.85 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.74 (d, J= 9.3 Hz, 1H), 7.60 (s, 1H), 7.55 (t, J= 7.9 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 7.06 (s, 1H), 4.45 (dt, J= 13.4, 6.7 Hz, 1H), 3.68 (s, 3H), 2.25 (s, 3H), 1.84 (dt, J= 8.2, 3.4 Hz, 1H), 1.42 (d, J= 6.7 Hz, 6H), 0.79 (dq, J = 5.6, 3.7, 3.2 Hz, 2H), 0.69 (dt, J= 5.0, 2.7 Hz, 2H).
Example 139: Synthesis of N-(6-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6'-dimethyl-6- oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000178_0001
Step 1: Example 139c
[0586] To amixture of Example 139a (0.2 g, 0.71 mmol) andExample 139b (0.15 g, 0.71 mmol) in Pyridine (3 mL)at 0°C was added POCl3 (0.35 ml, 3.6 mmol), which was stirred at 0°C for 1.5 h. The mixture was poured into water (10 mL), which was then extracted withDCM (20 mL*2). The combined organic layer was dried over Na2S04, filtered and concentrated to give the crude product Example 139c (0.30 g, yield 95%) as a yellow solid. LCMS [M+l]+ = 462.9
Step 2: Example 139
[0587] A mixture ofExample 139c (0.3 g, crude, 0.65 mmol), Example 139d (88 mg, 0.65 mmol), Pd(dppf)Cl2(48 mg, 0.06 mmol) and Na2CO3(0.2 g, 1.9 mmol) in dioxane/H20 (3 mL/0.3 mL) was exchanged with N2 for 3 times, and then stirred at 85°C for 16 h under N2.The mixture was concentrated under reduced pressure, which was purified by silica gel chromatography (DCM/MeOH = 50/1 to 20/1) , followed by prep-TLC (DCM/MeOH = 20/1) purificationto afford the desired productExample 139 (50 mg, yield 18%) as a yellow solid. LCMS [M+l]+ = 428.0
[0588] 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.78 (d, J= 2.8 Hz, 1H), 8.77 (d, J= 2.5 Hz, 1H), 8.70 (d, J= 2.9 Hz, 1H), 8.68 (s, 1H), 8.39 (d, J= 8.2 Hz, 1H), 8.04 (t, J= 8.0 Hz, 1H), 7.99 (dd, J = 8.1, 2.6 Hz, 1H), 7.92-7.83 (m, 1H), 7.37 (d, J= 8.1 Hz, 1H), 3.82 (tt, J= 7.5, 4.1 Hz, 1H), 3.72 (s, 3H), 2.52 (s, 3H), 1.21-1.14 (m, 2H), 1.11-1.03 (m, 2H).
Example 140: N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl-2-oxo-5- ((tetrahydrofuran-3-yl)oxy)-l,2-dihydropyridine-3-carboxamide
Figure imgf000179_0001
Step 1: Examplel40b
[0589] A mixture ofExample 140a (1.50 g, 0.68 mmol) in phenylmethanol (15 mL) were added 4,7- dihydroxy-l ,10-phenanthroline (228 mg, 1.08 mmol), Cul (103 mg, 0.54 mmol) and Cs2C03 (3.50 g, 10.75 mmol). The mixture was stirred at 110°C for 16 h under N2 and thenconcentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/l) to afford the desired product Example 140b (500 mg, yield 36%) as a yellow solid. LCMS [M+l]+ =260
Step 2: Example 140d
[0590] To a solution of Examplel40b (500 mg, 1.92 mmol)in pyridine (15mL) were added Example 140c (468 mg, 2.307 mmol) and POCl3 (882 mg, 5.769 mmol) at 0°C. The mixture was stirred at 0°C for 20 min. To the mixture was added water (50 mL) and yellow solid was filtered and collectedto afford the desired product Example 140d (520 mg, yield 61%) as a yellow solid. LCMS [M+l]+ =445 Step 3: Example 140e
[0591] To a solution of Example 140d (300 mg, 0.68 mmol)in DCM (15mL) was added BBr3 (2 mL, IN, 2 mmol) at -60°C. The mixture was warmed up to r.t. for 2 h. MeOH (50 mL) was carefully added into the mixture, whichwas then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/l) to afford the desired product Example 140e (150 mg, yield 63%) as a yellow solid. LCMS [M+l]+ =355
Step 4: Example 140g
[0592] To a solution of Examplel40f (500 mg, 4.90 mmol)in DCM (15mL) were added Et3N (980 mg, 9.80 mmol) and MsCl (670 mg, 5.88 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. Water (50 mL) was added into the mixture, which was then extracted with DCM (15mL*3). The combined organic layerwas concentrated under reduced pressure to afford the crude product Example 140f (950 mg, crude yield 100%) as yellow oil.
Step 5: Example 140
[0593] To a mixture of Example 140e (150 mg, 0.42 mmol)in DMF (4mL)were added Examplel40g (140 mg, 0.85 mmol) and K2C03 (117 mg, 0.85 mmol). The mixture was stirred at 90°C for 2 h. Water (50 mL) was added into the mixture, which was then extracted with DCM (15mL*3). The combined organic layerwas concentrated under reduced pressure and the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to afford the desired product Example 140 (39 mg, yield 22%) as a white solid. LCMS [M+l]+ =425.0
[0594] 1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.91 (s, 1H), 8.36 (dd, J= 8.4, 0.9 Hz, 1H), 8.25 (d, J= 3.4 Hz, 1H), 8.06-8.02 (m, 2H), 7.84 (dd, J= 7.6, 0.9 Hz, 1H), 5.33-5.27 (m, 1H), 4.93 (td, J= 4.1, 2.1 Hz, 1H), 3.89-3.75 (m, 4H), 3.63 (s, 3H), 2.17 (dd, J= 13.7, 5.7 Hz, 1H), 2.03 (d, J= 6.6 Hz, 1H), 1.54 (d, J= 6.7 Hz, 6H).
Example 141: Synthesis of 2-(6-(5,6-dihydro-8H-[l,2,4]triazolo[3,4-c][l,4]oxazin-3-yl)pyridin-2-yl)- 6-methoxyisoindoIin-l-one
Figure imgf000181_0001
Step 1: Example 141b
[0595] A mixture of Example 141a (1.22 g, 12.0 mmol) and POCl3 (1.85 g, 12.0 mmol) in dry DCM (20 mL) was stirred at 40°C for 1 h. The reaction was concentrated dryness to afford Example 141b (1.43 g, yield 100%) as yellow oil, which was used for next step directly without any further purification. Step 2: Example 141d
[0596] A mixture of Example 141c (2.16 g, 10.0 mmol), Example 141b(1.43 g, 12.0 mmol) and DIPEA(6.45 g, 50.0 mmol) in toluene (50 mL) was stirred at 130°C for 5 h. The reaction was cooled to r.t, diluted with water, and extracted with EtOAc (150 mL *3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by silica gel
chromatography (Petroleum Ether/EtOAc = 0/100) to give the desired product Example 141d (760 mg, yield 27%) as a yellow solid.
LCMS [M+l]+ = 281.0 , 283.0
Step 3: Example 141
[0597] To a solution of Example 141e (85 mg, 0.52 mmol), Example 141d (160 mg, 0.57 mmol) in 1 ,4-dioxane (4 mL) were added Pd2(dba)3 (48 mg, 0.052 mmol), Xant-phos (60 mg, 0.104 mmol) and Cs2C03 (340 mg, 1.04 mmol) successively. The mixture was sealed, degassed by nitrogen for three times and heated at 90°C for 3 h. The reaction mixture was diluted with EtOAc, washed with water and extracted by EtOAc (20 mL*2). The combined organic layers were concentrated and purified by Prep- HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 141 (28 mg, yield 15%) as a white solid.LCMS [M+lf =364.0 [0598] 1H NMR (400 MHz,CDC13) δ 8.70 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 7.6 Hz, 1H), 7.90 (t, J= 8.0 Hz, 1H), 7.45 (d, J= 8.3 Hz, 1H), 7.41 (d, J= 2.5 Hz, 1H), 7.21 (dd, J= 8.4, 2.5 Hz, 1H), 5.09 (s, 2H), 4.99 (s, 2H), 4.65 (t, J= 5.3 Hz, 2H), 4.14 (t, J= 5.3 Hz, 2H), 3.90 (s, 3H).
Example 143: Synthesis of N-(6-(5,6-dihydro-8H-[l,2,4]triazolo[3,4-c][l,4]oxazin-3-yl)pyridin-2-yl)- l,6'-dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000182_0001
Step 1: Example 143b
[0599] To a solution of Example 143a(450 mg, 1.01 mmol), tert-butylcarbamate(376 mg, 3.21 mmol) in 1,4-dioxane (10 mL) were added Pd2(dba)3 (150 mg, 0.16 mmol), Xant-phos (186 mg, 0.32 mmol) and CS2CO3 (1.05 g, 3.21 mmol) successively. The mixture was degassed by nitrogen for three times and heated at 100°C for 3 h. The reaction mixture was diluted with EtOAc, washed with water and extracted by EtOAc (30 mL*2). The combined organic layers were concentrated and purified by silica gel chromatography (EtOAc/MeOH = 91/9) to give Example 143b(300 mg, yield 59%) as a yellow solid.LCMS [M+l]+ =318.0
Step 2: Example 143c
[0600] To a solution of Example 143b (150 mg, 0.47 mmol) in DCM (2 mL) was added 4M
HCl/dioxane (1 mL) at room temperature. The reaction was stirred at this temperature for 2 h. The mixture was concentrated to dryness to give the desired product Example 143c (102 mg, yield 100%) as a yellow solid.LCMS [M+l]+ =218.0
Step 3: Example 143
[0601] Example 143d (1 15mg, 0.47 mmol) and Example 143c (102mg, 0.47 mmol) were dissolved in pyridine (3 mL) and cooled to 0°C. POCl3 (217 mg, 1.42 mmol) was added slowly at 0°C and the mixture was stirred at 0°C for 0.5 h. The reaction was quenched by adding water slowly at 0°C. The solid was filtered and suspended by MeOH (5 mL) for 15 min. After filtration, the solid was dried to give
Examplel43 (16 mg, yield 8%) as a gray solid. LCMS [M+l]+ = 444.0 [0602] 1H NMR (400 MHz, Chloroform-d) δ 12.43 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.42 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 7.7 Hz, 1H), 7.91-7.81 (m, 2H), 7.74 (d, J= 8.0 Hz, 1H), 7.29 (s, 1H), 5.07 (s, 2H), 4.72 (t, J= 5.3 Hz, 2H), 4.13 (d, J= 6.8 Hz, 2H), 3.81 (s, 3H), 2.63 (s, 3H).
Example 146: Synthesis of N-(6-([l,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-l,6'-dimethyl-6- oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000183_0001
Example 146a Step 1 Example 146b Step 2 Example 146c Step 3 Example 146
Step 1: Example 146b
[0603] A solution of Example 146a (500 mg, 1.8 mmol), tert-butylcarbamate(421 mg, 3.6 mmol), Pd2(dba)3 (183 mg, 0.2 mmol) Xant-phos (231 mg, 0.4 mmol) and Cs2C03 (1.5 g, 4.5 mmol) in 1,4- dioxane (10 mL) was stirred under N2 at 110°C for 16 h. The mixture was diluted with water and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated andconcentrated under reduced pressure.The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 3/1) to give the desired product Example 146b (500 mg, yield 89%) as a yellow solid. LCMS [M+l]+= 312.0
Step 2: Example 146c
[0604] To a solution of Example 146b (500 mg, 1.6 mmol) in DCM (10 mL) was added HCl.dioxane (2 mL, 8 mmol), which was stirred at r.t. for 2 h. The mixture was diluted with NaHC03 solution and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated andconcentrated to give the desired product Example 146c (600 mg, crude yield >100%) as a white solid. LCMS [M+l]+= 212.0
Step 3: Example 146
[0605] To a solution of Example 146c (100 mg, 0.47 mmol) and Example 146d (114 mg, 0.47 mmol) in pyridine (3 mL) was added POCl3 (215 mg, 1.41 mmol) at 0°C, which was stirred at 0°C for 1 h. The mixture was diluted with water and filtered. The cake was washed by DCM/MeOH (5 mL/5 mL), filtered and dried to give Example 146 (31 mg, yield 15%) as a white solid. LCMS [M+l]+= 438.0
[0606] 'HNMR (400 MHz, Chloroform-;/) δ 12.57 (s, 1H), 9.88-9.84 (m, 1H), 8.91 (d, J= 2.8 Hz, 1H), 8.68 (d, J= 2.4 Hz, 1H), 8.40 (d, J= 8.3 Hz, 1H), 8.34-8.30 (m, 1H), 7.94 (t, J= 8.0 Hz, 1H), 7.90-7.85 (m, 2H), 7.78 (dd, J= 8.1, 2.5 Hz, 1H), 7.40-7.35 (m, 1H), 7.30 (d, J= 8.2 Hz, 1H), 7.07 (t, J= 6.6 Hz, 1H), 3.85 (s, 3H), 2.65 (s, 3H).
Example 147: Synthesis of N-(6-(6,7-dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3-yl)pyridin-2-yl)-l,6'- dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000184_0001
Step 1: Example 147b
[0607] A mixture of Example 147a (1.6 g, 18.0 mmol) and POCl3 (2.9 g, 18.0 mmol) in dry DCM (30 mL) was stirred at 40°C for 1 h. The reaction was concentrated to dryness to afford Example 147b (1.85 g, yield 100%) as yellow oil, which was used for the next step directly without further purification. Step 2: Example 147d
[0608] A mixture of Example 147c (3.24g, 15.0 mmol), Example 147b(1.85g, 18.0 mmol) and DIPEA(9.68g, 75.0 mmol) in toluene (50 mL) was stirred at 130°C for 3h, and then cooled to r.t., to which was added NaHC03(aq.) until pH = 11. Theresulting mixture was stirred at 100°C for 16 h, and then cooled to r.t., which was diluted with water, and extracted with EtOAc (100 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO 4 and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 0/100) to give the desired product Example 147d (400 mg, yield 10%) as yellow oil.LCMS [M+l]+ = 264.9,266.9.
Step 3: Example 147e
[0609] To a solution of Example 147d(400 mg, 1.52 mmol), BocNH2(354 mg, 3.02 mmol) in 1,4- dioxane (10 mL) were added Pd2(dba)3 (140 mg, 0.152 mmol), Xant-phos (176 mg, 0.30 mmol) and CS2CO3 (980 mg, 3.02 mmol) successively. The mixture was degassed by nitrogen for three times and heated at 90°C for 3 h. The reaction mixture was diluted with EtOAc, washed with water and extracted by EtOAc (50 mL*3). The combined organic layers were concentrated and purified by silica gel chromatography (EtOAc/MeOH = 75/25) to give Example 147e(376 mg, yield 83%) as a yellow solid.LCMS [M+l]+ =302.0
Step 4: Example 147f
[0610] To a solution of Example 147e(180 mg, 0.60 mmol) in DCM (5 mL) was added 4M HCl dioxane (2 mL) at room temperature. The reaction was stirred at this temperature for 2 h. The mixture was concentrated to dryness to give the desired product Example 147f (120 mg, yield 100%) as a yellow solid.LCMS [M+l]+ =202.0 Step 5: Example 147
[0611] Example 147f (120mg, 0.60 mmol) and Example 147g (145mg, 0.60 mmol) were dissolved in pyridine (3 mL) and cooled to 0°C. POCl3 (274 mg, 1.79 mmol) was added slowly at 0°C and the mixture was stirred at 0°C for 0.5 h. The reaction was quenched by adding water slowly at 0°C. The solid was filtered and suspended by MeOH (6 mL) for 15 min. After filtration, the solid was dried to give Example 147 (31 mg, yieldl2 %) as a gray solid. LCMS [M+l]+ = 428.0
[0612] 1H NMR (400 MHz, Chloroform-d) δ 12.38 (s, 1H), 8.89 (d, J= 2.8 Hz, 1H), 8.66 (d, J= 2.4 Hz, 1H), 8.39 (d, J= 8.2 Hz, 1H), 8.05 (d, J= 7.7 Hz, 1H), 7.90-7.82 (m, 2H), 7.77 (d, J= 8.5 Hz, 1H), 7.30 (d, J= 8.2 Hz, 1H), 4.55 (t, J= 7.2 Hz, 2H), 3.82 (s, 3H), 3.04 (t, J= 7.6 Hz, 2H), 2.80-2.88(m, 2H), 2.64 (s, 3H).
Example 149: Synthesis of N-(6-(4-ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6'-dimethyl-6-oxo-l,6- dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000185_0001
Step 1: Example 149b
[0613] A mixture of Example 149a (0.2 g, 0.76 mmol) andNH2Et.HCl (0.31 g, 3.80 mmol) in
CH3CN/AcOH (8 mL, v/v = 4/1) was stirred at 90°C for 4 h. The mixture was concentrated and dissolved in MeOH (3 mL). Then con. HC1 (0.5 mL) was added into the mixture, which was stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was slurried with EtO Ac/Petroleum Ether (10 mL, v/v = 1/5), filtered and dried to give the desired product Example 149b(150 mg, yield 100%) as a white solid. LCMS [M+l]+ = 190.0
Step 2: Example 149c
[0614] A mixture of Example 149c (2.0 g, 7.2 mmol), Example 149d (1.0 g, 7.2 mmol),
Pd(dppf)Cl2(520 mg, 0.72 mmol) and Cs2C03 (7.0 g, 21.5 mmol) in dioxane/H20 (30 mL/2.5 mL) was exchanged with N2 for 3 times, and then stirred at 85°C for 16 h at N2.The mixture was concentrated under reduced pressure, and purified by silica gel chromatography (DCM/MeOH = 50/1 to 20/1) to give the desired product Example 149e (1.8 g, yield 100%) as a brown solid.LCMS [M+l]+ = 244.9
Step 3: Example 149 [0615] To amixture of Example 149b (0.15 g, 0.81 mmol) and Example 149e (0.2 g, 0.81 mmol) in pyridine (5 mL) at 0°C was added P0C13 (0.4 mL, 4.0 mmol), which wasstirred at 0°C for 1.5 h. The mixture was poured into water (10 mL), and the precipitate was filtered. The solid was slurried by MeOH/DCM (6 mL, v/v = 3: 1), filtered and dried to get the desired product Example 149 (35 mg, yield 10%). LCMS [M+l]+ = 416
[0616] 1H NMR (400 MHz, DMSO-d6 δ 12.71 (s, 1H), 8.75 (dd, J= 5.2, 2.7 Hz, 2H), 8.71-8.65 (m, 2H), 8.39-8.33 (m, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.97 (dd, J= 8.1, 2.5 Hz, 1H), 7.89 (dd, J= 7.6, 0.9 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 4.53 (q, J= 7.1 Hz, 2H), 3.71 (s, 3H), 2.49 (s, 3H), 1.43 (t, J= 7.1 Hz, 3H).
Example 153: Synthesis of N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-3- yl)pyridin-2-yl)-l,6'-dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000186_0001
Step 1: Example 153b
[0617] To a solution of Example 153a (1.0 g, 8.85 mmol) in DCM (10 mL) was added POCl3 (1.5 g, 9.73 mmol) at r.t., the mixture was stirred at 40°C for 1 h. Then, the reaction mixture was concentrated and used in next step without further purification.
Step 2: Example 153d
[0618] A mixture of Example 153b (crude from step 1), Example 153c (1.9 g, 8.85 mmol) and DIPEA (5.7 g, 7 mL, 44 mmol) in toluene (20 mL) was stirred at 130°C for 3 h. After cooling to r.t., the mixture was adjusted to pH = 9 withNaHC03 aqueous, then stirred at 100°C for 3 h. The mixture was diluted with water, extracted with EtOAc and purified by silica gel chromatography (EtOAc/MeOH = 85/15) to give Example 153d (300 mg, yield 12%)as a yellow solid. LCMS [M+l ]+=293
Step 3: Example 153e
[0619] A mixture of Example 153d (300 mg, 1.0 mmol), BocNH2 (240 mg, 2.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (116 mg, 0.2 mmol) and Cs2C03 (670 mg, 2.0 mmol) in dioxane (5 mL) was stirred at 100°C for 16 h under N2. The mixture was diluted with EtOAc, and filtered. The filtrate was concentrated, and then purified by silica gel chromatography (EtOAc/MeOH = 85/15) directly
(EtOAc/MeOH = 85/15) to give Example 153e (270 mg, yield 80%) as yellow oil. LCMS [M+l]+=330. Step 4: Example 153f
[0620] To a solution of Example 153e (270 mg, 0.82 mmol) in dioxane (2 mL) was added HCl/dioxane (4 mL, 6.2 M), and stirred at r.t. for 2 h. The mixture was concentrated to give Example 153f (300 mg crude, crude yield >100%) as a white solid. LCMS [M+l]+=230.
Step 5: Example 153
[0621] To a mixture of Example 153f (300 mg, 1.12 mmol) and Example 153g (200 mg, 0.82 mmol) in pyridine (3 mL) was added POCl3 (0.5 mL, 780 mg, 5.1 mmol) at 0°C, which was stirred at 0°C for 1 h. The mixture was quenched with water and extracted with DCM, purified by prep-TLC plate
(DCM/MeOH = 10/1) to give Example 153 (11 mg, yield 6%) as a yellow solid. LCMS [M+l]+=456.0.
[0622] 1H NMR (400 MHz, Chloroform-d ) δ 12.58 (s, 1H), 8.86 (d, J= 2.8 Hz, 1H), 8.64 (s, 1H), 8.39 (d, J= 8.2 Hz, 1H), 8.02 (d, J= 7.7 Hz, 1H), 7.87-7.79 (m, 2H), 7.73 (dd, J= 8.1, 2.5 Hz, 1H), 7.27 (s, 1H), 3.79 (s, 3H), 3.10 (s, 2H), 2.65 (d, J= 7.6 Hz, 2H), 2.62 (s, 3H), 1.86 (s, 6H).
Example 154: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2,6'-trimethyl-6-
Figure imgf000187_0001
Example 154a Step 1 Example 154b Step 2 Example 154c Step 3
Figure imgf000187_0002
Example 154e Step 4 Example 154
Step 1: Example 154b
[0623] A solution of Example 154a (0.8 g, 2.86 mmol) andK2C03 (1.2 g, 8.6 mmol) in DMF (10 mL) was added Mel (0.4 mL, 7.1 mmol). The reaction was stirred at r.t. for 2.5 h, which was then poured into water (30 mL) and stirred for 10 min. The mixture was extracted with EtOAc (10 mL*3) and the combined organic phase was dried over MgS04, and filtrated. The filtrate was concentrated under reduced pressure to give the desired product Example 154b (0.46 g, yield 53%) as a yellow solid. LCMS [M+l] + = 308.0
Step 2: Example 154c
[0624] A solution of Example 154b (0.4 g, 0.33 mmol) andLiOH.H20 (0.28 g, 1.63 mmol) in
EtOH/H20(4 mL/2 mL) was stirred at r.t. for 2.5 h. The mixture was concentrated to remove EtOH, and then acidified with aq. HC1 to pH 3. The precipitate was filtered and the cake was washed with H20 and then dried to get the crude product Example 154c (0.44 g, yield 100%) as a brown solid. LCMS [M+1] + = 294.0
Step 3: Example 154e
[0625] To a solution of Example 154c (0.15 g, crude, 0.51 mmol) andExample 154d (0.11 g, 0.51 mmol) in Pyridine (5 mL) at 0°C was added POCl3 (0.25 mL, 2.55 mmol). The reaction was stirred at 0°C for 1.5 h, poured into water and stirred for another 10 min. The precipitate was filtrated and the solid was washed with water and EtOAc twice to give the desired product Example 154e(0.14 g, yield 55%) as a brown solid.LCMS [M+1] + = 479.0
Step 4: Example 154
[0626] A solution ofExample 154e (0.14 g, 0.29 mmol),Example 154f (40 mg, 0.29 mmol),
Pd(dppf)Cl2 (22 mg, 0.029 mmol) and Na2C03(93 mg, 0.87 mmol) in Dioxane/H20 (3 mL/1 mL) was stirred at 80°C for 16 h under N2. The reaction mixture was concentrated under reduced pressure, which was purified by silica gel chromatography (DCM/MeOH = 50: 1 to 20: 1), followed by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)purification to get the desired product Example 154 (50 mg, yield 45%) as a white solid.LCMS [M+1] + =444.1
1H NMR (400 MHz, DMSO-d6) 6 δ 12.69 (s, 1H), 8.88 (s, 1H), 8.43 (d, J= 2.4 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H), 8.28 (s, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.80 (d, J= 7.6 Hz, 1H), 7.69 (dd, J= 8.0, 2.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.30 (p, J= 6.7 Hz, 1H), 3.7 (s, 3H), 2.52 (s, 3H), 2.43 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 155: Synthesis of N-(6-(4-cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2,6'-trimethyI- 6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxami
Figure imgf000188_0001
Step 1: Example 155b [0627] A solution of Example 155a (0.8 g, 2.86 mmol) andK2C03 (1.2 g, 8.6 mmol) in DMF (10 mL) was added Mel (0.4 mL, 7.1 mmol). The reaction was stirred at r.t. for 2.5 h, which was then poured into water (30 mL) and stirred for 10 min. The mixture was extracted with EtOAc (10 mL*3) and the combined organic phase was dried over MgS04, and filtrated. The filtrate was concentrated under reduced pressure to give the desired product Example 155b (0.46 g, yield 53%) as a yellow solid. LCMS [M+l] + = 308.0
Step 2: Example 155c
[0628] A solution of Example 155b (0.4 g, 0.33 mmol) andLiOH.H20 (0.28 g, 1.63 mmol) in
EtOH H20(4 mL/2 mL) was stirred at r.t. for 2.5 h. The mixture was concentrated to remove EtOH, and then acidified with aq. HC1 to pH 3. The precipitate was filtered and the cake was washed with H20 and then dried to get the crude product Example 155c (0.44 g, yield 100%) as a brown solid. LCMS [M+l] + = 294.0
Step 3: Example 155e
[0629] To a solution of Example 155c (0.15 g, crude, 0.51 mmol) andExample 155d (0.11 g, 0.51 mmol) in Pyridine (5 mL) at 0°C was added POCl3 (0.25 mL, 2.55 mmol). The reaction was stirred at 0°C for 1.5 h, poured into water and stirred for another 10 min. The precipitate was filtrated and the solid was washed with water and EtOAc twice to give the desired product Example 155e(0.13 g, yield 53%) as a brown solid.LCMS [M+l] + = 477.0
Step 4: Example 155
[0630] A solution ofExample 155e (0.13 g, 0.27 mmol), Example 155f (40 mg, 0.27 mmol),
Pd(dppf)Cl2 (20 mg, 0.03 mmol) and Na2C03(87 mg, 0.82 mmol) in Dioxane/H20 (3 mL/1 mL) was stirred at 80°C for 16 h under N2. The reaction mixture was concentrated under reduced pressure, which was purified by silica gel chromatography (DCM MeOH = 50: 1 to 20: 1), followed by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) purification to give the desired product Example 155 (54 mg, yield 45%) as a white solid.LCMS [M+l] + = 442.0
[0631] 'HNMR (400 MHz, DMSO-d6δ 12.68 (s, 1H), 8.66 (s, 1H),8.43 (d, J= 2.4 Hz, 1H), 8.36-8.32 (m, 1H), 8.28 (s, 1H), 8.00 (t, J= 8.0 Hz, 1H), 7.83 (dd, J= 7.6, 0.9 Hz, 1H), 7.69 (dd, J= 7.9, 2.4 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 3.80 (tt, J= 7.5, 4.0 Hz, 1H), 3.69 (s, 3H), 2.52 (s, 3H), 2.43 (s, 3H), 1.18- 1.12 (m, 2H), 1.06-1.01 (m, 2H).
Example 156: Synthesis of l,6,-dimethyI-N-(6-(4-methyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-6-oxo- l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000190_0001
Step 1: Example 156b
[0632] A mixture of Example 149a (0.50 g, 1.9 mmol) andNH2Me.HCl (0.65 g, 9.5 mmol) in
CH3CN/AcOH (8 mL, v/v = 4/1) was stirred at 90°C for 4 h. The mixture was concentrated and dissolved in MeOH (5 mL). Then con. HC1 (1 mL) was added into the mixture, which was stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was slurried with EtO Ac/Petroleum Ether (10 mL, v/v = 1/5), filtered and dried to give the desired product Example 156b (195 mg, yield 59%) as a white solid.
LCMS [M+l]+ = 176.0
Step 2: Example 156e
[0633] A mixture of Example 156c (2.0 g, 7.2 mmol), Example 156d (1.0 g, 7.2 mmol),
Pd(dppf)Cl2(520 mg, 0.72 mmol) and Cs2CO3(7.0 g, 21.5 mmol) in dioxane/H20 (30 mL/2.5 mL) was exchanged with N2 for 3 times, and then stirred at 85°C for 16 h under N2.The mixture was concentrated under reduced pressure, and purified by silica gel chromatography to give the desired product Example 156e (1.8 g, yield 100%) as a brown solid.LCMS [M+l]+ = 244.9
Step 3: Example 156
[0634] To amixture of Example 156b (0.14 g, 0.80mmol) andExample 156e (0.20 g, 0.82 mmol) in pyridine (5 mL)at 0°C was added POCl3 (0.4 mL, 4.0 mmol), which was stirred at 0°C for 1.5 h. The mixture was poured into water (10 mL), and the precipitate was filtered. The solid was slurried by MeOH/DCM (6 mL, v/v = 3/1), filtered and dried to get the desired product Example 156 (80 mg,yield24%).LCMS [M+l]+ = 402.0
[0635] 1H NJVLK. (400 MHz, DMSO-d 6) δ 12.69 (s, 1H), 8.75 (dd, J= 4.7, 2.6 Hz, 2H), 8.68 (d, J= 2.8
Hz, 1H), 8.61 (s, 1H), 8.35 (d, J= 8.2 Hz, 1H), 8.02 (t, J= 8.0 Hz, 1H), 7.97 (dd, J= 8.1, 2.5 Hz, 1H),
7.89 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 4.04 (s, 3H), 3.71 (s, 3H), 2.49 (s, 3H).
Example 157: Synthesis of (R)-8-(6-cyclopropylpyridin-3-yl)-N-(6-(4-(l-hydroxypropan-2-yl)-4H- l,2,4-triazol-3-yl)pyridin-2-yl)-5-oxo-l,2,3,5-tetrahydroindolizine-6-carboxamide
Figure imgf000191_0001
Step 1: Example 157c
[0636] Example 157a (600 mg, 3.93 mmol) and Example 157b (1.2 g, 3.93 mmol) were dissolved in pyridine (20 mL) and cooled to 0°C. POCl3 (1.8 g, 11.8 mmol) was added slowly at 0°C and the mixture was stirred at 0°C for 0.5 h. The reaction was quenched by adding water slowly at 0°C. The solid was filtered, washed by water for 3 times. The solid was dried to give Example 157c (870 mg, yield51 %) as a brown solid.LCMS [M+l]+ =439.9
Step 2: Example 157d
[0637] To a solution of Example 157c (870 mg, 1.98 mmol) in a mixed solvent (DCM MeOH=2/3, 50 mL) was added N2H .H2O (250 mg, 3.96 mmol). The mixture was refluxed at 60°C for 48 h. After cooling to r.t., the reaction mixture was filtered. The solid was washed by MeOH (50 mL) and dried to give the desired product Example 157d (752 mg, yield86 %) as a light orange solid. LCMS [M+l]+ =439.9
Step 3: Example 157e
[0638] Example 157d (752 mg, 1.72 mmol) was dissolved in DMF-DMA (75 mL) and the mixture was refluxed at 90°C for 1.5 h. The mixture was concentrated to dryness, and then suspended by MeOH (10 mL) and filtered. The solid was collected and dried to give the desired product Example 157e (650 mg, yield77 %) as a yellowish solid. LCMS [M+l]+ =494.9
Step 4: Example 157g
[0639] To a solution of Example 157e (650 mg, 1.32 mmol) in MeCN (8 mL) were added AcOH (2 mL) and Example 157f (197 mg, 2.63 mmol). The mixture was stirred at 90°C for 1.5 h. The mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by silica gelchromatography (Petroluem Ether/EtOAc=0/100 then EtOAc/MeOH=75/25) to give the desired product Example 157g (92 mg, yield 14%) as a yellowish solid. LCMS [M+l]+ =506.9
Step 5: Example 157
[0640] To a solution of Example 157g (92 mg, 0.18 mmol), Example 157h (35 mg, 0.21 mmol) in 1,4- dioxane/H20 (4 mL/1 mL) were added Pd(dppf)Cl2 (13 mg, 0.018 mmol) and Na2C03 (40 mg, 0.36 mmol). The mixture was degassed by nitrogen for three times and heated at 90°C for 2 h. The reaction mixture was filtered, washed with EtOAc and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 157 (4 mg, yield 4%) as a white solid. LCMS [M+l]+ = 498.0 [0641] 1H NMR (400 MHz, Chloroform-d) δ 12.57 (s, 1H), 8.59 (s, 1H), 8.42 (d, J= 13.4 Hz, 2H), 8.21 (d, J= 8.2 Hz, 1H), 7.97 (d, J= 7.7 Hz, 1H), 7.83 (t, J= 8.0 Hz, 1H), 7.55 (d, J= 8.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.43 (q, J= 6.7 Hz, 1H), 4.29 (dd, J= 14.1, 6.3 Hz, 4H), 3.88-3.74 (m, 1H), 3.29 (q, J = 8.3 Hz, 2H), 2.29 (s, 2H), 2.07 (q, J= 6.7 Hz, 1H), 1.67 (d, J= 7.0 Hz, 3H), 1.05 (d, J= 6.9 Hz, 4H). Example 158: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl-6-oxo-l,6- dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000192_0001
[0642] To a solution of Example 158a (462 mg, 1 mmol), Example 158b (122 mg, 1 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Na2C03 (272 mg, 2 mmol). The mixture was degassed with N2 three times, then heated to 95°C and stirred for 20 h. The mixture was concentrated under reduced pressure. The residue was purified with Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm,, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 158 (12 mg, yield 3%) as a pale brown solid. LCMS [M+l]+ =416.0
[0643] 1H NMR (400 MHz, DMSO-<¾ δ 12.65 (s, 1H), 8.89 (d, J= 2.5 Hz, 2H), 8.78 (d, J= 2.9 Hz, 1H), 8.72 (d, J= 2.8 Hz, 1H), 8.56 (dd, J= 4.7, 1.6 Hz, 1H), 8.37 (d, J= 8.3 Hz, 1H), 8.08 (dt, J= 8.1, 2.0 Hz, 1H), 8.03 (t, J= 8.0 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.49 (dd, J= 8.0, 4.7 Hz, 1H), 5.30 (p, J = 6.7 Hz, 1H), 3.71 (s, 3H), 1.53 (d, J= 6.7 Hz, 6H).
Example 159: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2'-dimethyl-6- oxo-l,6-dihydro-[3,3'-hipyridine]-5-carboxamide
Figure imgf000192_0002
[0644] To a solution of Example 159a (462 mg, 1 mmol), Example 159b (219 mg, 1 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Na2C03 (272 mg, 2 mmol). The mixture was degassed with N2 three times, then heated to 95°C and stirred for 20 h. The mixture was concentrated under reduced pressure. The residue was purified with Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μm , speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give the desired product Example 159 (10 mg, yield 2%) as a pale brown solid. LCMS [M+l]+ =430.0
[0645] 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.89 (s, 1H), 8.48 (d, J= 3.0 Hz, 2H), 8.39-8.30 (m, 2H), 8.02 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.32 (dd, J = 7.7, 4.8 Hz, 1H), 5.29 (p, J= 6.7 Hz, 1H), 3.68 (s, 3H), 2.48 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).
Example 160: Synthesis of l,6'-dimethyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,l- c] [l,2,4]triazol-3-yl)pyridin-2-yl)-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000193_0001
Step 1: Example 160b
[0646] To a solution of Example 160a (1.0 g, 10.1 mmol) in DCM (10 mL) was added POCl3 (1.7 g, 11.1 mmol) at ambient temperature, which was then stirred at 40°C for 1 h. The reaction mixture was concentrated to afford Example 160b (1.1 g, crude yield >100%) as brown oil, which was used in next step without further purification.
Step 2: Example 160d
[0647] A mixture of Example 160b (1.1 g, crude from step 1, theoretically 10.1 mmol), Example 160c (2.1 g, 9.7 mmol) and DIPEA (8 mL) in toluene (10 mL) was stirred at 130°C for 3 h. After cooling to r.t, NaHCO3 aqueous was added to the mixture to adjust pH to 9, which was then stirred at 100°C for another 3 h. The mixture was diluted with water, extracted with EtOAc and purified by silica gel chromatography (EtOAc/McOII - 85/15) to give Example 160d (180 mg, 9% yield) as a yellow solid. LC-MS [M+l]+=280.9
Step 3: Example 160e
[0648] A mixture of Example 160d (180 mg, 0.65 mmol), BocNH2 (152 mg, 1.30 mmol), Pd2(dba)3 (60 mg, 0.065 mmol), Xantphos (75 mg, 0.13 mmol) and Cs2CC>3 (420 mg, 1.30 mmol) in dioxane (5 mL) was stirred at 100°C for 16 h under N2. The mixture was diluted with EtOAc, filtered and the filtrate was concentrated, purified by silica gel chromatography directly (EtOAc/MeOH = 85/15) to give Example 160e (200 mg, 95% yield) as yellow oil. LC-MS [M+l]+= 316.0
Step 4: Example 160f
[0649] To a solution of Example 160e (200 mg, 0.635 mmol) in dioxane (2 mL) was added HCl/dioxane (4 mL, 6.2 M), the mixture was stirred at r.t. for 2 h. The mixture was concentrated to give Example 160f (160 mg, crude yield 100%) as a white solid. LC-MS [M+l]+=216.0
Step 5: Example 160
[0650] To a mixture of Example 160f (160 mg, 0.744 mmol) and Example 160g (182 mg, 0.744 mmol) in pyridine (5 mL) was added POCI3 (350 mg, 2.23 mmol) at 0°C. The mixture was stirred at 0°C for 1 h, quenched with water and extracted with EtOAc. The organic phases were combined, concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give Example 160 (27 mg, 8% yield) as a yellow solid. LC-MS [M+l]+= 442.0
[0651] 1H NMR (400 MHz, Chloroform-^ δ 12.47 (s, 1H), 8.88 (d, J= 2.8 Hz, 1H), 8.64 (d, J= 2.5 Hz, 1H), 8.38 (d, J= 8.2 Hz, 1H), 8.05 (d, J= 7.6 Hz, 1H), 7.88-7.81 (m, 2H), 7.72 (dd, J= 8.1, 2.5 Hz, 1H), 7.27 (s, 1H), 5.15 (m,lH), 3.81 (s, 3H), 3.13-2.98 (m, 3H), 2.62 (s, 3H), 2.43 (m,lH), 1.60 (d, J= 6.5 Hz, 3H).
Example 161: Synthesis of 2-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yI)-5,6- dimethoxyisoindolin-l-one
Figure imgf000194_0001
Step 1: Examplel61c
[0652] Con. H2S04 (15 mL) was cooled to 5°C. Example 161a (5.08 g, 27.89 mmol) and Example 161b (5.55 g, 31.32mmol) were pre-mixed and added to the cooled con. H2SO4 in portions.Then the mixture was stirred for 3 hs at 5-15°C. The mixture was poured into ice-water (80 mL) with good stirring. After stirring for 30 min, the suspension was filtrated, and the solid was washed with water (50 mL*2), and dried under reduced pressure to give the desired product Example 161c (14.3 g, yield >100%) as a white solid. The crude product was used the next step without further purification. LCMS [M+l]+ = 342.0. Step 2: Examplel61d
[0653] To a solution of Example 161c (14.3 g, 27.88 mmol) and Cs2C03 (12.7 g, 38.82 mmol) in DMF (100 mL) was added Mel (2.3 mL, 35.84 mmol). Then the mixture was stirred overnight at room temperature. The mixture was diluted with water (200 mL), and extracted with EtOAc (150 mL*4). The combined organics were washed with brine (100 mL), dried over Na2S04, and concentrated under reduced pressure to give the desired product Example 161d (14.0 g, yield >100%) as a white solid. The crude product was used the next step without further purification. LCMS [M+l]+ = 356.0.
Step 3: Examplel61e
[0654] A solution of Example 161d (14.0 g, 27.88 mmol) and hydrazine hydrate (3 mL, 59.73 mmol) in methanol (100 mL) was heated to 80°C and stirred for 3 h. The mixture was cooled to room temperature and stirred overnight, which was then filtrated. The solid was washed with methanol (10 mL*2). The filtrate was concentrated under reduced pressure to 1/5 volume, and then filtered. The solid was washed with methanol (5 mL), combined with previous solid, and dried under reduced pressure to give the desired product Example 161e (3.1g, yield 41%) as a white solid. LCMS [M+l]+ = 193.9.
Step 4: Example 161
[0655] To a solution of Example 161e (72 mg, 0.373 mmol), Example 161f (100 mg, 0.373 mmol), Pd2(dba)3 (34 mg, 0.373 mmol) and Cs2C03 (243 mg, 0.746 mmol) in 1,4-dioxane (10 mL) was added Xantphos (43 mg, 0.0746 mmol). The mixture was degassed with N2 three times, then heated to 100°C and stirred overnight for 20 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL), and extracted with DCM (50 mL*2). Combined organic layer was concentrated under reduced pressure to give crude product as a brown solid, which was then purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product (59 mg, yield 42%) as a white solid. LCMS [M+l]+ =380.0
1H NMR (400 MHz, DMSO-d6) 5 8.90 (s, 1H), 8.58 (d, J= 8.4 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.85 (d, J= 7.5 Hz, 1H), 7.28 (d, J= 21.8 Hz, 2H), 5.48-5.54(m, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H).
Example 162: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l-methyl-2-oxo-5- phenoxy-l,2-dihydropyridine-3-carboxamide
Figure imgf000196_0001
Step 1: Example 162b
[0656] To a solution of Example 162a (500 mg, 1.79 mmol) in DMSO (5 mL) were added phenol (253 mg, 2.69 mmol), Cul (34 mg, 0.18 mmol), K2C03 (742 mg, 5.38 mmol) and (1S,2S)-N',N2- dimethylcyclohexane-l ,2-diamine(25 mg, 0.18 mmol). The mixture was stirred underM.W. at 100°C for 2.5h. The mixture was extracted with EtOAc (20 mL*2). The aqueous layer was acidified by IN HCl to pH = 3-4 and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc) to give the desired product Example 162b (38 mg, yield 8%) as a yellow solid. LCMS [M+l]+ = 245.9
Step 2: Example 162
[0657] To a solution of Example 162b (38 mg, 0.15 mmol) in pyridine (1 mL) were added Example 162c (38 mg, 0.19 mmol) and POCl3 (119 mg, 0.77 mmol) at 0°C under N2. The mixture was stirred at 0°C for 2 h, which was then poured into the H20 (6 mL). The suspension was filtered and the solid was dried to give Example 162 (34 mg, yield 53%) as a yellowsolid.LCMS [M+l]+ = 431.0
[0658] 1H NMR (400 MHz, DMSO-d6) 5 12.76 (s, 1H), 8.89 (s, 1H), 8.35 (d, J= 3.3 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 3.3 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.42-7.33 (m, 2H), 7.15-7.09 (m, 1H), 7.08-7.01 (m, 2H), 5.23-5.33(m, J= 6.7 Hz, 1H), 3.63 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).
Example 163: Synthesis of (R)-N-(6-(4-(l-hydroxypropan-2-yl)-4H-l,2,4-triazoI-3-yl)pyridin-2-yl)- l,6'-dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000197_0001
Step 1: Example 163c
[0659] Example 163a (1.9 g, 12.54 mmol) and Example 163b (3.5 g, 12.54 mmol) were dissolved in pyridine (40 mL) and cooled to 0uC. POCl3 (5.8 g, 37.63 mmol) was added slowly at 0°C and the mixture was stirred at 0°C for 1 h. The reaction was quenched by adding water slowly at 0°C. The solid was filtered and suspended by MeOH (15 mL) for 15 min. After filtration, the solid was dried to give Example 163c (2.15 g, yield 42%) as a white solid. LCMS [M+l]+ =413.9
Step 2: Example 163d
[0660] To a solution of Example 163c (2.15 g, 5.21 mmol) in a mixed solvent (DCM/MeOH=2/l, 150 mL) was added N2H4.H20 (650 mg, 10.4 mmol). The mixture was refluxed at 60°C for 48 h. After cooling to r.t., the reaction mixture was filtered. The solid was washed by MeOH (50 mL) and dried to give the desired product Example 163d (2.0 g, yield93 %) as a white solid. LCMS [M+l]+ =413.8 Step 3: Example 163e
[0661] Example 163d (400 mg, 0.97 mmol) was dissolved in DMF-DMA (40 mL) and the mixture was refluxed at 90°C for 16 h. The mixture was concentrated to dryness, suspended by EtOAc (10 mL) and filtered. The solid was collected and dried to give the desired product Example 163e (453 mg, yield100 %) as a white solid. LCMS [M+l]+ =468.9
Step 4: Example 163g
[0662] To a solution of Example 163e (453 mg, 0.97 mmol) in MeCN (8 mL) were added AcOH (2 mL) and Example 163f (150 mg, 1.94 mmol). The mixture was stirred at 90°C for 16 h. The mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by silica gelchromatography (Petroluem Ether/EtOAc=0/100, then EtOAc/MeOH=90/10) to give the desired product Example 163g (70 mg, yield 15%) as a yellowish solid. LCMS [M+l]+ =480.9
Step 5: Example 163
[0663] To a solution of Example 163g (70 mg, 0.15 mmol), Example 163h (24 mg, 0.17 mmol) in 1 ,4- dioxane/H20 (4 mL/1 mL) were added Pd(dppf)Cl2 (11 mg, 0.015 mmol) and Na2C03 (31 mg, 0.30 mmol). The mixture was degassed by nitrogen for three times and heated at 95°C for 2 h. The reaction mixture was filtered, washed with EtOAc and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) to give Example 163 (5 mg, yield 8%) as a gray solid.LCMS [M+l]+ = 446.0
[0664] 1H NMR (400 MHz, Chloroform-d) δ 12.66 (s, 1H), 8.88 (d, J= 2.8 Hz, 1H), 8.64 (d, J= 2.5 Hz, 1H), 8.39 (s, 1H), 8.24 (d, J= 8.2 Hz, 1H), 8.05 (d, J= 7.7 Hz, 1H), 7.89 (t, J= 7.9 Hz, 1H), 7.83 (t, J= 3.9 Hz, 1H), 7.72 (dd, J = 8.1, 2.6 Hz, 1H), 7.29 (d, J= 10.6 Hz, 1H), 5.44 (q, J= 6.6 Hz, 1H), 4.31 (dd, J= 10.9, 5.1 Hz, 1H), 4.19 (s, 1H), 3.84 (s, 1H), 3.80 (d, J= 3.2 Hz, 3H), 2.62 (s, 3H), 1.70 (d, J= 7.0 Hz, 3H).
Example 164: Synthesis of N-(6-(4-(2,2-difluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,6'- dimethyl-6-oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000198_0001
Step 1: Example 164c
[0665] A mixture of Example 164a (3 g, 11.5 mmol) and Example 164b (1.39 g, 17.2 mmol) in a mixed solution of ACN/AcOH (40 mL/10 mL) was heated at 90°C for 1.5 h. After the temperature was cooled down to r.t., it was filtrated. The filtrated solution was concentrated. To the residue was added MeOH (10 mL) and HC1 (3 M, 5 mL), which was stirred for 2 h. Then, the pH was adjusted to ~7 by KOH (solid). After extraction with EtOAc (10 mL*2), thecombined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (pure EtOAc) to give the desired product Example 164c (1.25 g, yield 48%) as a yellow solid. LCMS [M+l]+ = 226
Step 2: Example 164
[0666] To a solution of Example 164d (200 mg, 0.82 mmol) in pyridine (4 mL) at 0°C were added Example 164c (240 mg, 0.90 mmol), and POCl3 (628 mg, 4.10 mmol). The reaction was stirred at 0°C for 40 min. Then, water (3 mL) was added to quench the reaction. The resulting solution was filtrated and the filtrate was washed by water twice to give the desired product Example 164 (105 mg, yield 28%) as a gray solid.LCMS [M+l]+ = 226.5/452.0 [0667] 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.78-8.62 (m, 4H), 8.34 (d, J= 8.2 Hz, 1H), 8.07-7.85 (m, 3H), 7.38-7.29 (m, 1H), 6.49 (t, J= 55.2 Hz, 1H), 5.13 (t, J= 15.2 Hz, 2H), 3.70 (s, 3H), 2.48 (s, 3H)
Example 165: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,4',6'-trimethyl-6- oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000199_0001
Step 1: Examplel65b
[0668] To a mixture of Example 165a (186 mg, 1.00 mmol) in dioxane (3 mL) were added (BPin)2 (305 mg, 1.29 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and KOAc (294 mg, 3.00 mmol). The mixture was stirred at 100°C for 45 min under N2 by microwave. The crude mixture Example 165b was used in the next step directly.
Step 2: Example 165
[0669] To the mixture Example 165b were added Example 165c (278 mg, 0.60 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol) and H20 (0.5 mL). The mixture was stirred at 100°C for 45 min under N2 by microwave. To the mixture was added water (50 mL), and the resulting mixture was extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2SC>4, filtrated and the filtratewas concentrated under reduced pressure. The residue was purified by prep-TLC
(DCM/MeOH=15/l) to afford the desired product Example 165 (7 mg, yield 3%, over two steps) as a white solid. LCMS [M/2+l]+ =444.0
[0670] 1H NMR (400 MHz, Chloroform-d ) δ 12.50 (s, 1H), 8.63 (d, J= 2.7 Hz, 1H), 8.44-8.34 (m, 2H), 8.28 (s, 1H), 8.03 (d; J= 7.6 Hz, 1H), 7.87 (t, J= 8.0 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.10 (s, 1H), 5.64 (q, J= 6.7 Hz, 1H), 3.77 (s, 3H), 2.56 (s, 3H), 2.29 (s, 3H), 1.62 (d, 6H).
Example 167: Structure of N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-l,2',6'-trimethyl-6- oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000199_0002
Step 1: Example 167c
[0671] To a solution of Example 167a (4.0 g, 14.3 mmol) andExample 167b (2.9 g, 14.3 mmol) in Pyridine (25 mL) at 0°C was added POCl3 (6.7 mL, 71.7 mmol). The reaction was stirred at 0°C for 1.5 h, poured into water (35 mL) and stirred for 10 min. The resulting mixture was filtrated and the solid was washed with water and EtOAc to give the desired product Example 167c (3.47 g, yield 52%) as a brown solid.LCMS [M+l]+ = 465.0
Step 2: Example 167
[0672] A solution of Example 167c (0.2 g, 0.43 mmol), Example 167d (65 mg, 0.43 mmol),
Pd(dppf)Cl2 (32 mg, 0.043 mmol) and Na2CO3(140 mg, 1.3 mmol) in Dioxane/H20 (3 mL/1 mL) was stirred at 80°C for 16 h under N2. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel chromatography (DCM/MeOH = 50/1 to 20/1), followed by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min) purification to get the desired product Example 167 (35 mg, yield 18%) as a brown solid.LCMS [M+l]+ = 444.0
[0673] 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.89 (s, 1H), 8.44 (d, J= 2.8 Hz, 1H), 8.37-8.30
(m, 2H), 8.01 (t, J= 8.0 Hz, 1H), 7.81 (dd, J= 7.6, 0.9 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.17 (d, J= 7.8
Hz, 1H), 5.29 (m, 1H), 3.68 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).
Example 168: Synthesis of N-(6-(4-isopropyl-4H-l,2,4-tria2ol-3-yl)pyridin-2-yl)-l,5'-dimethyI-6- oxo-l,6-dihydro-[3,3'-bipyridine]-5-carboxamide
Figure imgf000200_0001
Step 1: Example 168c
[0674] To a solution of Example 168a (4.0 g, 14.3 mmol) and Example 168b (2.9 g, 14.3 mmol) in Pyridine (25 mL) at 0°C was added POCl3 (6.7 mL, 71.7 mmol). The reaction was stirred at 0°C for 1.5 h, poured into water (35 mL) and stirred for another 10 min. The resulting mixture was filtrated and the solid was washed with water and EtOAc to give the desired product Example 168c (3.47 g, yield 52%) as a brown solid. LCMS [M+l]+ = 465.0
Step 2: Example 168
[0675] A solution of Example 168c (0.2 g, 0.43 mmol). Example 168d (60 mg, 0.43 mmol),
Pd(dppf)Cl2 (32 mg, 0.04 mmol) and Na2C03 (140 mg, 1.3 mmol) in Dioxane/H20 (3 mL/1 mL) was stirred at 80°C for 16 h under N2. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel chromatography (DCM/MeOH = 50/1 to 20/1), followed by prep-TLC purification (DCM/MeOH = 20/1) to get the desired product Example 168 (37 mg, yield 20%) as a brown solid.LCMS [M+l]+= 430.0 [0676] 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (s, IH), 8.89 (s, IH), 8.78 (d, J= 2.9 Hz, IH), 8.73 (d, J = 2.8 Hz, IH), 8.69 (s, IH), 8.43-8.33 (m, 2H), 8.03 (t, J= 8.0 Hz, IH), 7.93 (s, IH), 7.82 (d, J= 7.5 Hz, IH), 5.30 (m, IH), 3.71 (s, 3H), 2.36 (s, 3H), 1.52 (d, J= 6.7 Hz, 6H).
Example A: Binding assay: Kd determination by DiscoveRx, KINOMEscan™ Profiling
Compound Handling
[0677] An 11 -point 3-fold serial dilution of each test compound was prepared in 100% DMSO at 100x final test concentration and subsequently diluted to lx in the assay (final DMSO concentration = 1%). Most Kds were determined using a compound top concentration = 30,000 nM. If the final Kd determined was < 0.5 nM (the lowest concentration tested), the measurmenet was repeated with a serial dilution starting at a lower top concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be > 30,000 nM.
Binding Constants (Kds)
[0678] Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation:
Figure imgf000201_0001
[0679] The Hill slope was set to -1
[0680] Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm [0681] The binding data is shown in the table below:
Figure imgf000201_0002
Figure imgf000202_0001
A≤ 1 nM; 1 < B≤5 nM; 5 < C≤10 nM; D > 10 nM
Example B: Cell assay: Phospho-p38 MAPK ELISA
[0682] The assay was using the following parameters:
• Cell line: HK-2. P12
• Seeding density: HK-2: 20,000 cells/well in 96-well plate
• Treatment starting time: 24 hours after cell seeding
• Compound treatment: 1 μΜ top dose, 1 :3 dilution (10-point)
o Agonist: H202, 1 mM treatment
o Control: GS-4997
• Elisa kit: Cell Signaling Technology PathScan® Phospho-p38 MAPK (Thrl80/Tyrl82)
Sandwich ELISA kit (Cal. No. 7946C)
• Timeline: cell seeding followed by compound treatment 24h later followed by agonist treatment 1.5h later followed by Lysis and collection 30 minutes later.
[0683] The IC50 are shown in the table below:
Figure imgf000202_0002
Figure imgf000203_0001
Example C: Pharmacokinetics:
[0684] Subjects: SD rat, 180-220 g, male, n=6
[0685] Food Status: Fasted overnight with free access to water, and the animals were fed four hours after dosing.
[0686] Formulation: 0.5%MC
[0687] Sample Collection: The animals were restrained manually at the designated time points, approximately 150 μL . of blood sample was collected via orbit into EDTAK2 tubes.
[0688] Sample Processing: Blood samples were centrifuged at 5000 rpm for 10 min to obtain plasma sample
[0689] Sample Storage: Store plasma samples at below -60°C until analysis.
[0690] The pharmacokinetic data is shown in the table below:
Figure imgf000203_0002
Example FhERG Channel QPatchHTX
Figure imgf000204_0001
Example F: In Vitro ASK-1 Inhibition Study
[0691] ASK 1 T7 phage strains will be prepared in an E. coli host derived from the BL21 strain. E. colt will be grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates will be centrifuged and filtered to remove cell debris. The remaining kinases will be produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads will be treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads will be blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
Example G: In Vivo Study of Compounds for NASH Inhibition
[0692] In this multicenter, randomized, open-label trial, 72 subjects with biopsy-confirmed NASH (NAFLD Activity Score [NAS] >5) and F2-3 fibrosis will receive a pharmaceutical composition comprising a compound described herein for 24 weeks (W24). Liver biopsies will be performed at baseline and W24. Hepatic proton density fat fraction (PDFF) and stiffness will be measured by Magnetic Resonance Imaging (MRI) and Magnetic Resonance Elastography (MRE), respectively, at baseline, W12, and W24.
Example H: In vivo Study
[0693] 50 subjects with NAFLD will be randomized to either drug or placebo for 24-weeks. To examine the efficacy of a compound described herein, 10 mg orally daily versus placebo in improving hepatic steatosis assessed by lipid turnover (triglyceride kinetics, palmitate kinetics, indirect calorimetry), liver fat content (magnetic resonance live spectroscopy), insulin sensitivity (glucose kinetics during hyperinsulinaemic euglycaemic clamp), body composition (DXA and MRI), lipase activity and fat cell size (fat biopsy from abdominal and femoral adipose tissue).
Example I: Pharmaceutical Compositions
Example la: Parenteral Composition
[0694] To prepare a parenteral pharmaceutical composition suitable for administration by injection. 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
Example lb: Oral Composition
[0695] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral admimstration. Example Ic: Sublingual (Hard Lozenge) Composition
[0696] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound described herein, with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound of Formula (IX), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof:
(Formula IX),
Figure imgf000206_0002
wherein:
Figure imgf000206_0001
wherein:
Y2 is N or CRY2;
R63 is hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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; and
RY2 is hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -0C(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - optionally substituted
Figure imgf000206_0004
alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or
Figure imgf000206_0003
Y2 is NRY3;
R63 is O or S; and
RY3 is hydrogen or optionally substituted alkyl;
R60, R61, and R62 are independently hydrogen, halogen, CN, OR67, -SR67, -S(=0)R69, -N02, - NR67R68) .S(=0)2R69 ; -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -0C(=0)R69, -C02R67, -0C02R67, - C(=0)NR67R68, -0C(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)0R67, 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; R64 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;
or R63 and R64 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R65 is optionally substituted fused bicyclic heterocycloalkyl or optionally substituted fused bicyclic heteroaryl;
each R66 is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
each R67 and R68 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 R67 and R68, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R69 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; and
s3 is 0-3.
2. The compound of claim 1, wherein
Figure imgf000207_0001
3. The compound of claim 1 or 2, wherein Y2 is CR .
4. The compound of any one of claims 1 -3, wherein R is hydrogen, halogen, or alkyl.
5. The compound of any one of claims 1-4, wherein R is hydrogen.
6. The compound of any one of claims 1 -5, wherein R63 is hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
7. The compound of any one of claims 1 -6, wherein RbJ is hydrogen, halogen, or alkyl.
8. The compound of any one of claims 1 -7, wherein R63 is hydrogen or halogen.
9. The compound of any one of claims 1 -8, wherein R63 is halogen.
10. The compound of claim 1 , wherein
Figure imgf000207_0002
1 1. The compound of claim 1 or 10, wherein Y2 is NRY3 and RY3 is optionally substituted alkyl.
12. The compound of claim 1 or 10 or 11, wherein R63 is O.
13. The compound of any one of claims 1-12, wherein R61 is -OR67, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
14. The compound of any one of claims 1-13, wherein R61 is an optionally substituted aryl.
15. The compound of any one of claims 1-14, wherein R61 is an optionally substituted phenyl.
16. The compound of any one of claims 1-13, wherein R61 is an optionally substituted heteroaryl.
17. The compound of any one of claims 1-13 or 16, wherein R61 is an optionally substituted
5- membered heteroaryl selected from imidazole, pyrazole, pyrrole, triazole, tetrazole, thiophene, furan, thiazole, isothiazole, oxazole, or isoxazole.
18. The compound of any one of claims 1-13 or 16 or 17, wherein R61 is an optionally substituted 5-membered heteroaryl selected from imidazole, pyrazole, triazole, and thiophene.
19. The compound of any one of claims 1-13 or 16-18, wherein R61 is an optionally substituted imidazole.
20. The compound of any one of claims 1-13 or 16, wherein R61 is an optionally substituted
6- membered heteroaryl selected from pyridine, pyrimidine, pyrazine, and pyridazine.
21. The compound of of any one of claims 1-13 or 16 or 20, wherein R61 is an optionally substituted pyridine.
22. The compound of any one of claims 1-21 , wherein R61 is optionally substituted with 1, 2, or 3 Rb; and each Rb is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, - S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, - C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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.
23. The compound of any one of claims 1-22, wherein R61 is optionally substituted with 1 or 2 Rb; and each Rb is independently halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted
heterocycloalkyl.
24. The compound of any one of claims 1-23, wherein R61 is optionally substituted with 1 or 2 Rb; and each Rb is independently halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
25. The compound of any one of claims 1-24, wherein R61 is optionally substituted with 1 Rb; and Rb is cycloalkyl.
26. The compound of any one of claims 1-25, wherein R is hydrogen, halogen, -CN, -OR , -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
27. The compound of any one of claims 1-26, wherein R60 is hydrogen, halogen, or alkyl.
28. The compound of any one of claims 1-27, wherein R60 is hydrogen.
29. The compound of any one of claims 1-28, wherein R62 is hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
30. The compound of any one of claims 1-29, wherein R62 is hydrogen, halogen, or alkyl.
31. The compound of any one of claims 1 -30, wherein R62 is hydrogen or alkyl.
32. The compound of any one of claims 1-31, wherein R62 is alkyl.
33. The compound of any one of claims 1-32, wherein R64 is hydrogen or alkyl.
34. The compound of claim 21 , wherein R63 and R64 are taken together with the atom to which they are attached to form an optionally substituted 5- or 6-membered heterocycloalkyl.
35. The compound of any one of claims 1-8 or 13-32, wherein R63 and R64 are taken together with the atom to which they are attached to form a 5- or 6-membered heterocycloalkyl, each optionally substituted with oxo, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, - NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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.
36. The compound of any one of claims 1 -8 or 13-32 or 35, wherein R63 and R64 are taken together with the atom to which they are attached to form a 5-membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR67, -NR67R68, -C02R67, optionally substituted alkyl, or optionally substituted heteroalkyl.
37. The compound of any one of claims 1-8 or 13-32 or 35 or 36, wherein R63 and R64 are taken together with the atom to which they are attached to form a 6-membered heterocycloalkyl optionally substituted with oxo, halogen, -CN, -OR67, -NR67R68, -C02R67, optionally substituted alkyl, or optionally substituted heteroalkyl.
38. The compound of any one of claims 1-8 or 13-32, wherein R63 and R64 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, - C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, - NR67C(=0)R69, -NR67C(=0)OR67, 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.
39. The compound of any one of claims 1-8 or 13-32 or 38, wherein R63 and R64 are taken together with the atom to which they are attached to form a 6-membered heteroaryl optionally substituted with halogen, -CN, -OR67, -NR67R68, -C02R67, optionally substituted alkyl, or optionally substituted heteroalkyl.
40. The compound of any one of claims 1-39, wherein s3 is 0 or 1.
41. The compound of any one of claims 1-40, wherein R66 is hydrogen, halogen, or alkyl.
42. The compound of any one of claims 1-41, wherein R65 is an optionally substituted 5/5 fused bicyclic heteroaryl.
43. The compound of any one of claims 1-41, wherein R65 is an optionally substituted 5/6 fused bicyclic heteroaryl.
44. The compound of any one of claims 1-43, wherein R65 is optionally substituted with 1, 2, or 3 Ra; and each Ra is independently halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, - S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, - C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
45. The compound of any one of claims 1-44, wherein R65 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted
heterocycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
46. The compound of any one of claims 1-45, wherein R65 is optionally substituted with 1 or 2 Ra; and each Ra is independently halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl; or two Ra form an optionally substituted cycloalkyl or an optionally substituted
heterocycloalkyl.
47. The compound of any one of claims 1-46, wherein R65 is optionally substituted with 1 Ra; and Ra is alkyl.
48. The compound of any one of claims 1 -47, wherein R65 is wherein: each X is independently N or CRa;
Figure imgf000210_0001
Ring E is a 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl;
each Ra is independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-4.
49. The compound of claim 48, wherein Ring E is a 5- to 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
50. The compound of claim 48, wherein Ring E is a 5-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
51. The compound of claim 48, wherein Ring E is a 5-membered heterocycloalkyl.
52. The compound of claim 48, wherein Ring E is a 6-membered heterocycloalkyl comprising 0-2 additional heteroatoms selected from N, O, and S.
53. The compound of claim 48, wherein Ring E is a 6-membered heterocycloalkyl.
54. The compound of claim 48, wherein Ring E is a 5- to 6-membered heteroaryl comprising 0-2 additional heteroatoms selected from N, O, and S.
55. The compound of claim 48, wherein Ring E is a 5-membered heteroaryl comprising 0-2 additional heteroatoms selected from N, O, and S.
56. The compound of claim 48, wherein Ring E is a 6-membered heteroaryl comprising 0-2 additional heteroatoms selected from N.
57. The compound of claim 48, wherein Ring E is a 6-membered heteroaryl.
58. The compound of any one of claims 1-57, wherein R is
Figure imgf000211_0001
Figure imgf000211_0002
each Ra is independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, -C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, - OC(=0)NR67R68, -NR67C(=0)NR67R68, -NR67C(=0)R69, -NR67C(=0)OR67, 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 two Ra form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; and s4 is 0-2.
59. The compound of any one of claims 48-58, wherein s4 is 0 or 1.
60. The compound of any one of claims 48-59, wherein s4 is 1.
61. The compound of any one of claims 48-58, wherein s4 is 2.
62. The compound of any one of claims 48-61, wherein X are both N.
63. The compound of any one of claims 48-61, wherein one X is N and the other is CRa.
64. The compound of any one of claims 48-61, wherein X are both CRa.
65. The compound of any one of claims 48-64, wherein each Ra is independently hydrogen, halogen, -CN, -OR67, -SR67, -S(=0)R69, -N02, -NR67R68, -S(=0)2R69, -NR67S(=0)2R69, -S(=0)2NR67R68, - C(=0)R69, -OC(=0)R69, -C02R67, -OC02R67, -C(=0)NR67R68, -OC(=0)NR67R68, -NR67C(=0)NR67R68, - NR67C(=0)R69, -NR67C(=0)OR67, 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.
66. The compound of any one of claims 48-65, wherein each Ra is independently hydrogen, halogen, -CN, -OR67, -NR67R68, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
67. The compound of any one of claims 48-66, wherein each Ra is independently hydrogen, halogen, -CN, -OH, -NH2, alkyl, haloalkyl, hydroxyalkyl, or cycloalkyl.
68. The compound of any one of claims 48-67, wherein each Ra is independently hydrogen, halogen, or alkyl.
69. The compound of any one of claims 48-68, wherein each Ra is independently hydrogen or alkyl.
70. The compound of any one of claims 48-64, wherein two Ra on the same carbon form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
71. The compound of any one of claims 1 -70, wherein R is
Figure imgf000212_0001
Figure imgf000212_0002
Figure imgf000213_0001
72. The compound of any one of claims 1-71, wherein R and R are independently hydrogen or optionally substituted alkyl.
73. The compound of any one of claims 1-72, wherein R67 and R68 are hydrogen.
74. The compound of any one of claims 1-73, wherein R69 is optionally substituted alkyl.
75. A compound selected from the group consisting of:
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
76. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-75, and at least one pharmaceutically acceptable excipient.
77. The pharmaceutical composition of claim 76, wherein the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration or ophthalmic administration.
78. The pharmaceutical composition of claim 76 or 77, wherein 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.
79. A method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-75, or a pharmaceutical composition of any one of claims 76-78.
80. The method of claim 79, wherein 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.
81. The method of claim 80, wherein 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.
82. The method of claim 80, wherein 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.
83. The method of claim 80, wherein 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),
84. The method of claim 80, wherein 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.
85. The method of claim 80, wherein 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).
86. The method of claim 80, wherein 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.
87. The method of claim 80, wherein 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.
88. The method of claim 80, wherein the blood disease is sickle cell disease.
89. 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 of any one of claims 1-75, or a pharmaceutical composition of any one of claims 76-78.
90. A method for modulating platelets in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 -75 or a pharmaceutical composition of any one of claims 76-78.
91. The method of claim 90, wherein the compound modulates platelet activation, platelet granule secretion, thromboxane A2 generation, or thrombosis modulation.
92. 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 of any one of claims 1-75, or a pharmaceutical composition of any one of claims 76-78.
93. The method of claim 92, wherein the oxidative species is a reactive oxygen species.
94. The method of claim 93, wherein the oxidative species contains a radical on the oxygen atom.
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