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Definitions

• the present disclosure relates generally to inhibitors of kinase, therapeutic methods of use, and manufacture thereof.
• inflammation can be a protective mechanism in response to harmful stimuli such as invasion of pathogens and tissue damages
• chronic inflammation is an important underlying factor in many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer.
• cell death pathways such as necrosis and apoptosis which are useful in eliminating infected or damaged cells, is also an important underlying mechanism for human diseases, including acute and chronic neurodegenerative diseases.
• Receptor-interacting protein kinase 1 is a key regulator of inflammation, apoptosis and necroptosis.
• Receptor-interacting protein kinase 1 has an important role in modulating inflammatory responses mediated by nuclear-factor kappa-light chain enhancer of activated B cells (NF- ⁇ ). More recent research has shown that its kinase activity controls necroptosis, a form of necrotic cell death, which was traditionally thought to be passive and unregulated, and is characterized by a unique morphology. Further, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex indicating its activity in regulating apoptosis.
• the receptor-interacting protein kinase 1 is subject to complex and intricate regulatory mechanisms, including ubiquitylation, deubiquitylation and phosphorylation. These regulatory events collectively determine whether a cell will survive and activate an inflammatory response or die through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death, and conversely, research has shown that inhibition of receptor- interacting protein kinase 1 can be effective therapies for diseases involving inflammation or cell death.
• compositions including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds.
• the disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated by receptor-interacting protein kinase 1.
• the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by (or mediated, at least in part, by) receptor-interacting protein kinase 1.
• provided is a compound of Formula I. In certain embodiments, provided is a compound of Formula lie. In certain embodiments, provided is a compound of Formula He. In certain embodiments, provided is a compound of Formula Ilf . In certain embodiments, provided is a compound of Formula V. In certain embodiments, provided is a compound of Formula Va. In certain embodiments, provided is a compound of Formula VI. In certain embodiments, provided is a compound as in Table 1, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 2, or a
• composition comprising a compound, including those of any Formula described herein, and an excipient.
• the compounds and compositions are for use in medicine.
• the compounds and compositions are for use in the treatment of a receptor-interacting protein kinase 1- mediated disease or disorder.
• a method of treating a receptor-interacting protein kinase 1 -mediated disease or disorder comprising administering a therapeutically effective amount of a compound or
• the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti -phospholipid syndrome, vasculitis, osteoarthritis, non- alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, my
• the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysomal storage disease, Gaucher's disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age- related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.
• trauma trauma, ischemia, stroke, cardiac infarction, infection, lysomal storage disease, Gaucher's disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age- related macular degeneration,
• the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy.
• the disease or disorder is brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, or a prion disorder.
• a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
• -C(0)NH 2 is attached through the carbon atom.
• a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
• a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
• C u _ v indicates that the following group has from u to v carbon atoms.
• Ci_6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
• references to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
• the term “about” includes the indicated amount ⁇ 10%.
• the term “about” includes the indicated amount ⁇ 5%.
• the term “about” includes the indicated amount ⁇ 1%.
• to the term “about X” includes description of "X”.
• the singular forms "a” and “the” include plural references unless the context clearly dictates otherwise.
• reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
• alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., Ci-20 alkyl), 1 to 8 carbon atoms (i.e., Ci_s alkyl), 1 to 6 carbon atoms (i.e., Ci-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). In certain embodiments, alkyl has 1 to 12 carbon atoms (i.e., Ci-12 alkyl).
• alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methylpentyl.
• alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, "butyl” includes n-butyl (i.e.
• -(CH 2 ) 3 CH 3 sec-butyl (i.e. - CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e. -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e. -C(CH 3 ) 3 ); and "propyl” includes n- propyl (i.e. -(CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH(CH 3 ) 2 ).
• alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2 _ 2 o alkenyl), 2 to 8 carbon atoms (i.e., C 2 _s alkenyl), 2 to 6 carbon atoms (i.e., C 2 _6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2 _4 alkenyl).
• alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
• Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2 _ 2 o alkynyl), 2 to 8 carbon atoms (i.e., C 2 _s alkynyl), 2 to 6 carbon atoms (i.e., C 2 _6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2 _4 alkynyl).
• alkynyl also includes those groups having one triple bond and one double bond.
• Alkoxy refers to the group “alkyl-O”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
• Alkylthio refers to the group “alkyl-S-”.
• acyl refers to a group -C(0)R, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• acyl include formyl, acetyl, cyclcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
• Amido refers to both a "C -amido” group which refers to the group -C(0)NR y R z and an "N- amido” group which refers to the group -NR y C(0)R z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
• Amino refers to the group -NR y R z wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.
• Amino refers to -C(NH)(NH 2 ). In certain embodiments, “Amidino” refers to -C(NR)(NR 2 ), wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
• aryl has 6 to 20 ring carbon atoms (i.e., C 6 -2o aryl), 6 to 12 carbon ring atoms (i.e., C 6 -i2 aryl), or 6 to 10 carbon ring atoms (i.e., C 6 -io aryl). In certain embodiments, aryl has 6 to 18 carbon ring atoms (i.e., C 6 -i8 aryl).
• aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
• Arylalkyl or “Aralkyl” refers to the group “aryl-alkyl-”.
• Carbamoyl refers to both an "0-carbamoyl” group which refers to the group -0-C(0)NR y R z and an "N-carbamoyl” group which refers to the group -NR y C(0)OR z , wherein R y and R z are
• Carboxyl refers to -C(0)OH.
• Carboxyl ester or “ester” refer to both -OC(0)R and -C(0)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• Cyano or “carbonitrile” refers to the group -CN.
• Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
• cycloalkyl includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond).
• cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3 _ 2 o cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3 _i 2 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3 _i 0 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3 _ 8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3 _6 cycloalkyl).
• cycloalkyl has from 3 to 15 ring carbon atoms (i.e., C 3 _i5 cycloalkyl).
• cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
• cycloalkyl also includes "spiro cycloalkyl" when there are two positions for substitution on the same carbon atom.
• Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Poly cyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like.
• “Guanidino” refers to -NHC(NH)(NH 2 ). In certain embodiments, “guanidino” refers to - NRC(NR)(NR 2 ), wherein each R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Cycloalkylalkyl refers to the group “cycloalkyl-alkyl-”.
• Hydrazino refers to -NHNH 2 .
• Imino refers to a group -C(NR)R, wherein each R is independently hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• Imido refers to a group -C(0)NRC(0)R, wherein each R is independently hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• Halogen or "halo” includes fluoro, chloro, bromo, and iodo.
• Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
• Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen.
• Examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ). In certain embodiments, examples of haloalkyl include difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,
• Haloalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
• Hydroalkyl refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxy group.
• Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
• the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
• Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-, - S(O)-, -S(0) 2 -, and the like, where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
• heteroalkyl groups include - OCH 3 , -CH 2 OCH 3 , -SCH 3 , -CH 2 SCH 3 , -NRCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
• R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
• examples of heteroalkyl groups include -CH 2 OCH 3 , -CH 2 SCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
• heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
• the term "heteroalkyl" requires that the point of attachment to the remainder of the molecule is through a carbon atom.
• Heteroaryl refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• heteroaryl includes 1 to 20 ring carbon atoms (i.e., Ci_ 2 o heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3 _i 2 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3 _s heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
• heteroaryl refers to a 5- 14 membered ring system.
• heteroaryl includes 1 to 13 ring carbon atoms (i.e., C 3 _i 2 heteroaryl).
• heteroaryl includes 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
• fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system.
• heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
• Heteroarylalkyl refers to the group “heteroaryl-alkyl-”.
• Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
• the term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bridged- heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
• a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
• heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
• heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
• examples of heterocyclyl groups include 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, quinuclidiny
• spiro-heterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten- membered heterocyclyl.
• spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l- azaspiro[3.3]heptanyl.
• fused-heterocyclyl rings include, but are not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
• Niro refers to the group -N0 2 .
• Heterocyclylalkyl refers to the group “heterocyclyl -alkyl-”.
• Sulfonyl refers to the group -S(0) 2 R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.
• R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.
• sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
• Sulfinyl refers to the group -S(0)R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.
• Sulfonamido refers to the groups -SO 2 NRR and -NRSO 2 R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• Alkylsulfonyl refers to the group -S(0) 2 R, where R is alkyl.
• Alkylsulfinyl refers to the group -S(0)R, where R is alkyl.
• Thiocyanate refers to the group -SCN.
• Thiol refers to the group -SH.
• R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
• a divalent group such as a divalent "alkyl” group, a divalent “aryl” group, etc., may also be referred to as an "alkylene” group or an "alkylenyl” group, an "arylene” group or an “arylenyl” group, respectively.
• combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
• the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
• the term "substituted" used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroary
• heterocyclylalkyl hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N-oxide, or -Si(R 100 )3 wherein each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.
• the term "substituted" used herein means any of the above groups (i.e., alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, hydroxyalkyl and/or alkoxyalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to: an alkyl group, a haloalkyl group, a halogen atom such as F, CI, Br, and I; an alkenyl, a haloalkenyl group, an alkynyl group, a haloalkynyl group, a cyclic group such as an aryl, heteroaryl, cycloalkyl, or heterocyclyl group, an oxygen atom in groups such as hydroxy groups, alkoxy groups, and ester groups; a sulfur atom
• 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, formyl, carboxyl, carbonate, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• a higher-order bond e.g., a double- or triple-bond
• nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• substituted includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more hydrogen atoms are
• substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl group.
• R g and R h and R are the same or different and independently hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h and R 1 are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxy or alkoxy.
• cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl are independently optionally substituted with one or more oxo, alkyl, halo, amino, hydroxy or alkoxy.
• each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
• impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
• impermissible substitution patterns are well known to the skilled artisan.
• substituted may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
• substituted alkyl refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
• the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
• the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
• any compound or formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), U C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 C1 and 125 I.
• isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
• isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• the disclosure also includes "deuterated analogs" of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
• deuterated analogs of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
• Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug
• Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (AD ME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
• An 18 F, 3 H, U C labeled compound may be useful for PET or SPECT or other imaging studies.
• Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
• the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
• any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
• a position is designated specifically as ⁇ " or "hydrogen”
• the position is understood to have hydrogen at its natural abundance isotopic composition.
• any atom specifically designated as a deuterium (D) is meant to represent deuterium.
• the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
• the term "pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
• “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
• Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
• pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkyl amines (i.e., HN(alkyl) 2 ), trialkyl amines (i.e., N(alkyl) 3 ), substituted alkyl amines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl) amines (i.e., N(substituted alkyl) 3 ), alkenyl amines (i.e., NH 2 (alkenyl)), dialkenyl amines (i.e., HN(alkenyl) 2 ), trialkenyl amines (i.e.,
• Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
• hydrate refers to the complex formed by the combining of a compound of Formula I and water.
• a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention.
• solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.
• Tautomers are in equilibrium with one another.
• amide containing compounds may exist in equilibrium with imidic acid tautomers.
• the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers.
• the amide containing compounds are understood to include their imidic acid tautomers.
• the imidic acid containing compounds are understood to include their amide tautomers.
• the compounds disclosed herein, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
• the disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example,
• Steps are isomers that differ only in the way the atoms are arranged in space and include enantiomers and diastereomers.
• a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are
• Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture.
• Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.
• Prodrugs means any compound which releases an active parent drug according to Formula I or any other formula described herein in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of a compound of Formula I or any other formula described herein are prepared by modifying functional groups present in the compound of Formula I or any other formula described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
• Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
• Prodrugs include compounds of Formula I or any other formula described herein wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I or any other formula described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively.
• Examples of prodrugs include, but are not limited to esters (e.g. , acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g. , N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I or any other formula described herein and the like.
• esters e.g. , acetate, formate and benzoate derivatives
• amides e.g. , acetate, formate and benzoate derivatives
• amides e.g. , acetate, formate and benzoate derivatives
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 2. List of Abbreviations and Acronyms
• rovided is a compound of Formula I:
• Y 1 is O or NR 2 ;
• X 1 and X 2 are each independently nitrogen or carbon and either
• X 1 and X 2 together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano or when Y 1 is NR 2 , then R 2 and R 1 together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or
• X 1 and R 1 together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X 2 is -CH 2 -;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(0)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroary
• L is absent or -C(R ) 2 -, and each R is optionally substituted Ci-Ce alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 )2- and at least one R 6 is other than hydrogen;
• Y 2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;
• Y 2 is -S-, -S(O)-, or -S(0)2-; and A is other than isoxazole and phenyl or Y 2 is
• Y 2 is -NR 5 - and A is other than isoxazole, pyrazole and triazole; (6) the carbonyl moiety and L are substituted other than 1,3- on ring A; or
• R is substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, wherein at least one substituent is cyano;
• R 1 is C 2 -C 6 alkyl optionally substituted with halo, hydroxy or cyano; or
• At least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position; and further provided the moiety wherein the nitrogen containing aromatic ring is optionally substituted;
• the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N- (5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)isoxazole-3 -carboxamide ; 2-(4- bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4
• a compound of Formula I or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof
• Y 1 is O or NR 2 ;
• X 1 and X 2 are each independently nitrogen or carbon and either
• X 1 and X 2 together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano or when Y 1 is NR 2 , then R 2 and R 1 together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or
• X 1 and R 1 together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X 2 is -CH 2 -;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• L is absent or -C(R 8 ) 2 -, and each R 8 is optionally substituted Ci-C 6 alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 ) 2 - and at least one R 6 is other than hydrogen;
• Y 2 is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring;
• Y 2 is -S-, -S(O)-, or -S(0) 2 -; and A is other than isoxazole and phenyl or Y 2 is
• Y 2 is -NR 5 - and A is other than isoxazole, pyrazole and triazole; or
• R 1 is C 2 -Ce alkyl optionally substituted with halo, hydroxy or cyano; or hen X 1 and X 2 form an optionally substituted phenyl ring as in the moiety
• At least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position; and further provided the moiety
• nitrogen containing aromatic ring is optionally substituted
• the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N- (5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)isoxazole-3 -carboxamide ; 2-(4- bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• L is absent or -C(R 8 ) 2 -, and each R 8 is optionally substituted Ci-C 6 alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• Y 1 is NR 2 .
• X 1 and X 2 are each independently nitrogen or carbon, and together form a 5 membered optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• X 1 and R 1 together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and X 2 is - CH 2 -.
• Y 2 is -C(R 6 )2-; and one R 6 is hydrogen, halo, or optionally substituted Ci-C 6 alkyl, and the other R 6 is halo or optionally substituted Ci-C 6 alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• Y 2 is -O- and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring.
• Y 2 is -S-, -S(O)-, or -S(0)2-; and A is other than isoxazole and phenyl or Y 2 is -S(0)(NH)-.
• Y 2 is -NR 5 -; X 1 and X 2 together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X 1 and X 2 together form an optionally substituted pyridyl, and A is other than triazole; or X 1 and X 2 are optionally substituted pyrimidyl, and A is other than pyrazole and triazole.
• the carbonyl moiety and L are substituted other than 1,3- on ring A.
• a compound of Formula I or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;
• Y 1 is O or NR 2 ;
• X 1 and X 2 are each independently nitrogen or carbon and either
• X 1 and X 2 together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R 1 is H or Ci-C 6 alkyl optionally substituted with halo, hydroxy or cyano or when Y 1 is NR 2 , then R 2 and R 1 together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or
• X 1 and R 1 together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X 2 is -CH 2 -;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and each R 8 is optionally substituted Ci-Ce alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• X 1 and X 2 are each independently nitrogen or carbon, and together form a 5 membered optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• X 1 and R 1 together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring ; and X 2 is -CH 2 -;
• Y 2 is -C(R 6 ) 2 -; and one R 6 is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R 6 is halo or optionally substituted Ci-Ce alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -0-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring;
• Y 2 is -S-, -S(O)-, or -S(0) 2 -; and A is other than isoxazole and phenyl or Y 2 is
• Y 2 is -NR 5 -; X 1 and X 2 together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X 1 and X 2 together form an optionally substituted pyridyl, and A is other than triazole; or X 1 and X 2 are optionally substituted pyrimidyl, and A is other than pyrazole and triazole;
• Y 2 is -0-; X 1 and X 2 together form an optionally substituted pyridyl, and A is other than isoxazole;
• R 1 is C 2 -C6 alkyl optionally substituted with halo, hydroxy or cyano; or
• At least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;
• the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N- (5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)isoxazole-3 -carboxamide ; 2-(4- bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4
• the compound is not 5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5- tetrahydro-5 -methyl-4-oxo- 1 ,5 -benzoxazepin-3 -yl] -3 -isoxazolecarboxamide or 5- (difluorophenylmethyl)-N-[(3 S)-2,3 ,4,5 -tetrahydro-4-oxo- 1 ,5 -benzoxazepin-3 -yl] -3 - isoxazolecarboxamide.
• compounds that are useful as inhibitors of receptor-interacting protein kinase 1.
• provided is a compound of Formula I wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• X 1 and X 2 are each independently nitrogen or carbon, and together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or
• Y 1 is O or NR 2 , where R 2 and R 1 together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and each R 8 is optionally substituted Ci-Ce alkyl or halo provided that the compound is not 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin- 3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [l,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• X 1 and X 2 are each independently nitrogen or carbon, and together form a 5 membered optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• X 1 and R 1 together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring ; and X 2 is -CH 2 -;
• Y 2 is -C(R 6 ) 2 -; and one R 6 is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R 6 is halo or optionally substituted Ci-Ce alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -0-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4-carboxamide or 2 -benzyl -N-(5-methyl-4-oxo-2,3, 4,5- tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)thiazole-4-carboxamide ;
• Y 2 is -S-, -S(O)-, or -S(0) 2 -; and A is other than 1,3-isoxazole or Y 2 is -S(0)N(H)-;
• Y 2 is -NR 5 -; X 1 and X 2 together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X 1 and X 2 together form an optionally substituted pyridyl, and A is other than triazole; or X 1 and X 2 are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or
• R 1 is Ci-Ce alkyl. In certain embodiments, R 1 is methyl.
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH;
• X 6 , X 7 , X 8 and X 9 are each N or CH;
• q 0, 1 or 2;
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0)2-Ci-C6 alkyl.
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH;
• X 6 , X 7 , X 8 and X 9 are each N or CH;
• q 0, 1 or 2;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH;
• X 6 , X 7 , X 8 and X 9 are each N or CH;
• q 0, 1 or 2;
• each R 10 is independently halo or optionally substituted alkyl.
• Y 1 is O.
• R 1 is methyl. In certain embodiments, R 1 is ethyl.
• Y is
• Y 2 is -0-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered cycloalkyl or 3- or 4-membered heterocycloalkyl ring.
• both R 3 and R 4 are fluoro, or either R 3 or R 4 are fluoro and the other is hydrogen, or R 3 and R 4 form a cyclopropyl or R 3 joins with R 6 to form a cyclopropyl.
• R 3 or R 4 is methyl.
• A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.
• A is isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H- pyrrolo[l,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.
• A is phenyl
• L is absent, -S(0) 2 - or -C(R 8 ) 2 -.
• R 9 is phenyl or 2,3-dihydro-lH-indenyl. In certain embodiments, R 9 phenyl. In certain embodiments, R 9 is 2-F-phenyl. In certain embodiments, R 9 is pyridyl. In certain embodiments, R 9 is optionally substituted pyridyl, phenyl or 2,3-dihydro-lH-indenyl.
• q is 0. In certain embodiments, q is 1. In certain embodiments, R 10 methyl.
• Y 1 is O or NR 2 ;
• X 1 and X 2 are each independently nitrogen or carbon and either
• X 1 and X 2 together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano or when Y 1 is NR 2 , then R 2 and R 1 together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or
• X 1 and R 1 together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X 2 is -CH 2 -;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.
• ring A is a 3-, 4- or 5-membered monocyclic ring.
• the moiety
• q is 0 or R 10 is halo or alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring.
• R 9 is substituted with at least one cyano.
• the compound is of Formula II:
• q 0, 1, or 2;
• X 6 , X 7 , X 8 and X 9 are each N or CH;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 ) 2 -, and each R 8 is optionally substituted Ci-Ce alkyl or halo, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 ) 2 -; and one R 6 is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R 6 is halo or optionally substituted Ci-Ce alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -0-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring;
• Y 2 is -S-, -S(O)-, or -S(0) 2 -; and A is other than isoxazole or Y 2 is -S(0)(NH)-;
• Y is -NR -; X , X , X and X together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X 6 , X 7 , X 8 and X 9 together form an optionally substituted pyridyl, and A is other than triazole; or X 6 , X 7 , X 8 and X 9 are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or
• Y 2 is -0-; X 1 and X 2 together form an optionally substituted pyridyl, and A is other than isoxazole;
• R 1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or
• At least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;
• the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N- (5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)isoxazole-3 -carboxamide ; 2-(4- bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4
• the compound is of Formula II wherein
• q 0, 1, or 2;
• X 6 , X 7 , X 8 and X 9 are each N or CH;
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is - ⁇ -, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently halo or optionally substituted alkyl
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 ) 2 -, and each R 8 is optionally substituted Ci-C 6 alkyl or halo provided that the compound is not 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin- 3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [l,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 ) 2 -; and one R 6 is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R 6 is halo or optionally substituted Ci-Ce alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -0-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b] [l,4]oxazepin-3-yl)thiazole-4-carboxamide or 2 -benzyl -N-(5-methyl-4-oxo-2,3, 4,5- tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)thiazole-4-carboxamide ;
• Y 2 is -S-, -S(O)-, or -S(0) 2 -; and A is other than 1,3-isoxazole or Y 2 is -S(0)N(H)-;
• Y is -NR -; X , X , X and X together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X 6 , X 7 , X 8 and X 9 together form an optionally substituted pyridyl, and A is other than triazole; or X 6 , X 7 , X 8 and X 9 are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or
• the compound is of Formula II and L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• R 1 is H or optionally substituted Ci-Ce alkyl. In any of the embodiments of Formula II (or subformula thereof), R 1 is H or d- Ce alkyl.
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0)2-Ci-C6 alkyl. In any of the embodiments of Formula II (or subformula thereof), q is 0, 1 or 2 and when present, each R 10 is independently cyano, halo or optionally substituted alkyl. In any of the embodiments of Formula II (or subformula thereof), each R 10 is independently halo. In certain embodiments, each R 10 is
• q is 0. In any of the embodiments of Formula II (or subformula thereof), q is 1. In any of the embodiments of Formula II (or subformula thereof), q is 2.
• q 0, 1 or 2;
• R 1 is H or Ci-C 6 alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 ) 2 -, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 1 is C2-C6 alkyl optionally substituted with halo, hydroxy or cyano; or
• At least one substituent is at the 1 or 4 position and is (a) other than fluoro, chloro or methyl at the 1 position, and/or (b) other than fluoro or methyl for the 4 position;
• the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)isoxazole-3-carboxamide; 5-(difluoro(phenyl)methyl)-N- (5 -methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo [b] [ 1 ,4]oxazepin-3 -yl)isoxazole-3 -carboxamide ; 2-(4- bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)thiazole-4
• the compound is of Formula Ila wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl;
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.
• R 11 or R 12 is halo and the other is Ci_ 6 alkyl or Ci_ 6 cycloalkyl and the remaining variables are as defined throughout.
• the compound is of Formula IIa-2:
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-Ce alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IIa-2a. In certain embodiments, the compound is of Formula IIa-2b. In certain embodiments, the compound is of Formula IIa-3. In certain embodiments, the compound is of Formula IIa-4. In certain embodiments, the compound is of Formula -5.
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl
• L is absent or -C(R 8 ) 2 -, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 ) 2 -; and two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• the compound is not 5-(phenylmethyl)-N-[(3S)-l,2,3,4-tetrahydro-7-methyl-2- oxopyrido[2,3-b][l,4]oxazepin-3-yl]-3-isoxazolecarboxamide; N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-l- methyl-2-oxo-lH-pyrido[2,3-b][l,4]diazepin-3-yl]-3-(phenylmethyl)-lH-l,2,4-triazole-5-carboxamide; 5-(phenylmethyl)-N-[(3S)-l,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][l,4]oxazepin-3-yl]-3- isoxazolecarboxamide; or N-[(3S)-8-fluoro-2,3,4,5-te
• the compound is of Formula lib wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 ) 2 -, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of
• the compound is of Formula lib- 1 :
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-Ce alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IIb-2. In certain embodiments, the compound is of Formula IIb-3. In certain embodiments, the compound is of Formula IIb-4. In certain embodiments, the compound is of Formula IIb-5. In certain embodiments, the compound is of Formula II -6.
• the compound is of Formula lie:
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula lie wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl;
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.
• a compound of Formula lie or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R ) 2 -;
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-C 6 alkyl or -S(0) 2 -Ci-C 6 alkyl.
• the compound is of Formula lie- 1 :
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-Ce alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IIc-2. In certain embodiments, the compound is of Formula IIc-3. In certain embodiments, the compound is of Formula lie -4. In certain embodiments, the compound is of Formula IIc-5. In certain embodiments, the compound is of Formula IIc-6.
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R 8 )2-;
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-C 6 alkyl or -S(0) 2 -Ci-C 6 alkyl.
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl;
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• the compound is not 5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3- b] [ 1 ,4]oxazepin-3 -yl]-3 -isoxazolecarboxamide ; or
• the compound is of Formula lid wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.
• the compound is of Formula lid- 1 :
• q 0, 1 or 2;
• R is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-C 6 alkyl;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IId-2. In certain embodiments, the compound is of Formula IId-3. In certain embodiments, the compound is of Formula IId-4. In certain embodiments, the compound is of Formula IId-5. In certain embodiments, the compound is of Formula
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0) 2 -Ci-C6 alkyl.
• the compound is of Formula He or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;
• q 0, 1 or 2;
• R 1 is H or Ci-C 6 alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula He wherein
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl;
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs:
• R 3 and R 4 are halo or optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 )2-; and two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.
• a compound of Formula He or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R 8 )2-; each R is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-C 6 alkyl or -S(0) 2 -Ci-C 6 alkyl.
• the compound is of Formula He- 1 :
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-C 6 alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IIe-2. In certain embodiments, the compound is of Formula IIe-3. In certain embodiments, the compound is of Formula IIe-4. In certain embodiments, the compound is of Formula IIe-5. In certain embodiments, the compound is of Formula
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R 8 )2-;
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0) 2 -Ci-C 6 alkyl.
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0)2-Ci-C6 alkyl.
• the compound is of Formula Ilf or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof;
• q 0, 1 or 2;
• R 1 is H or Ci-C 6 alkyl optionally substituted with halo, hydroxy or cyano;
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula Ilf wherein
• R 1 is H or optionally substituted Ci-C 6 alkyl
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs:
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 )2-, and two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 ) 2 -; and two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -; each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R 8 )2-;
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0)2-Ci-C6 alkyl.
• the compound is of Formula Ilf- 1 :
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• R 4 is H, halo, or optionally substituted Ci-C 6 alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• R 7 is H or optionally substituted Ci-C 6 alkyl; each R is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula IIf-2. In certain embodiments, the compound is of Formula IIf-3. In certain embodiments, the compound is of Formula IIf-4. In certain embodiments, the compound is of Formula IIf-5. In certain embodiments, the compound is of Formula IIf-6
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -O- or -C(R 8 ) 2 -;
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl or -S(0)2-Ci-C6 alkyl.
• R 3 is H. In certain embodiments of compounds of Formula I (or subformula thereof), R 4 is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R 3 is H and R 4 is optionally substituted Ci-Ce alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R 3 is H and R 4 is methyl.
• R 3 is H and R 4 is H.
• R 3 is H. In certain embodiments of compounds of Formula II (or subformula thereof), R 4 is optionally substituted Ci-C 6 alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R 3 is H and R 4 is optionally substituted Ci-C 6 alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R 3 is H and R 4 is Ci-C 6 alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R 3 is H and R 4 is methyl.
• R 3 is H and R 4 is H.
• R 3 is H and R 4 is H.
• the A ring is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is an unsubstituted heteroaryl ring. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a oxadiazolyl. In certain embodiments of compounds of Formula I (or subformula thereof), the A ring is a triazolyl.
• the A ring is an optionally substituted heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an unsubstituted heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an optionally substituted 5-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an unsubstituted 5-membered heteroaryl ring. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is an optionally substituted 6-membered heteroaryl ring.
• the A ring is a heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a 5-membered heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is oxadiazolyl. In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is a triazolyl.
• the A ring is of the formula:
• X 10 , X 11 and X 12 are each S, O, N, CR 13 or NR 13 , and X 13 is C or N;
• each R 13 is independently H, halo, cyano or optionally substituted Ci-C 6 alkyl.
• At least one of X 10 , X 11 and X 12 is CR 13 or NR 13 and at least one R 13 is halo, cyano or optionally substituted Ci-C 6 alkyl.
• at least one of X 10 , X 11 and X 1 is CR" or NR" and at least one R is halo.
• each R is independently H, fluoro, chloro, cyano or methyl.
• the A ring is one of the following:
• each ring may optionally substituted with one or more halo, cyano or Ci-Ce alkyl.
• the A ring is one
• L is absent, -O- or -C(R 8 ) 2 -; and each R 8 is independently H or Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl.
• L is -C(R 8 )2- and each R 8 is taken together with the carbon atom to which they are attached to form cyclopropyl.
• L is absent, -O- or -C(R 8 )2-; and each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• L is absent, -O- or -C(R 8 )2-; and each R 8 is independently H or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl.
• L is absent. In certain embodiments of compounds of Formula II (or subformula thereof), L is -0-. In certain embodiments of compounds of Formula II (or subformula thereof), L is -C(R and each R is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring. In certain embodiments of compounds of Formula II (or subformula thereof), L is
• each R 8 is independently H, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl.
• L is -C(R 8 ) 2 - and each R 8 is taken together with the carbon atom to which they are attached to form cyclopropyl.
• R 9 is optionally substituted aryl. In certain embodiments of compounds of Formula I (or subformula thereof), R 9 is phenyl optionally substituted with one or more halo, cyano or Ci-Ce alkyl optionally substituted with halo. In certain embodiments of compounds of Formula I (or subformula thereof), R 9 is phenyl.
• R 9 is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
• R 9 is phenyl, dihydroindenyl, pyridyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4- difluorophenyl, 3-cyano-4-fluorophenyl, or 5-fluoropyridin-3-yl.
• q is 0. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl, or -S(0)2-Ci-C6 alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R 10 is independently cyano, halo, methyl, or -S(0)2-methyl.
• q 0, 1 or 2;
• R is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• X 1 and X 2 are each N or CH; X 3 , X 4 and X 5 are each S, O, N, NH, or CH
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-C 6 alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• R 3 and R 4 are halo or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is absent or -C(R 8 ) 2 -, and each R 8 is optionally substituted Ci-C 6 alkyl or halo or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or
• Y 2 is -C(R 6 ) 2 -; and one R 6 is hydrogen, halo, or optionally substituted Ci-Ce alkyl, and the other R 6 is halo or optionally substituted Ci-Ce alkyl; or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.
• the compound is of Formula III wherein
• X 1 and X 2 are each N or CH;
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-C 6 alkyl
• each R 6 is independently H, halo, optionally substituted Ci-C 6 alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-C 6 alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-C 6 alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• the compound is of Formula Ilia, Illb, or IIIc:
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 1 is H or Ci-Ce alkyl
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken- l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, or optionally substituted Ci-Ce alkyl, or R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula Ilia- 1 , IIIb-1, or IIIc- 1 :
• q 0, 1 or 2;
• R 1 is H or Ci-Ce alkyl optionally substituted with halo, hydroxy or cyano;
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH;
• R 1 is H or Ci-Ce alkyl
• R 4 is H, halo, or optionally substituted Ci-Ce alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-C 6 alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo or optionally substituted alkyl.
• the compound is of Formula Ilia, Illb, or IIIc:
• X 3 , X 4 and X 5 are each S, O, N, NH, or CH
• Y 2 is -0-, -S-, -S(O)-, -S(0) 2 -, -S(0)(NH)-, -NR 5 - or -C(R 6 ) 2 -;
• R 5 is H or optionally substituted Ci-Ce alkyl
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 6 together with the carbon atom to which they are attached, form a Ci-Ce alken-l-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 3 and R 4 are independently H, halo, optionally substituted Ci-Ce alkyl, R 3 and R 4 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• the compound is of Formula Ilia- 1 , IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9:
• the compound is of Formula IVa, IVb IVc IVd, IVe IVf or IVg:
• q 0, 1 or 2;
• R 4 is H, halo, or optionally substituted Ci-Ce alkyl
• A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring;
• L is absent, -0-, -S-, -S(O)-, -S(0) 2 -, -NR 7 - or -C(R 8 ) 2 -;
• R 7 is H or optionally substituted Ci-Ce alkyl
• each R 8 is independently H, halo, or optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
• each R 10 is independently cyano, halo, optionally substituted Ci-C 6 alkyl, or -S(0) 2 -Ci-C 6 alkyl.
• q is 0, 1, or 2; X 6 and X 9 are independently N or CR 14 ;
• R 1 is H or optionally substituted Ci-Ce alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, optionally substituted Ci-Ce alkyl
• R 3 is H, halo, optionally substituted Ci-C 6 alkyl, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is -C(R 8 ) 2 -;
• each R 8 is independently H, halo, optionally substituted Ci-C 6 alkyl, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted aryl or optionally substituted heteroaryl
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted Ci-Ce alkoxy, or -S(0)2-Ci-C6 alkyl; and
• each R 14 is independently hydrogen, cyano, halo, C 1 -C3 alkyl optionally substituted with halo, or C 1 -C3 alkoxy optionally substituted with halo;
• X 9 is N. In certain embodiments X 9 is N and X 6 is CR 14 . In certain embodiments X 9 and X 6 are N.
• Y 2 is O.
• R 3 is H.
• R 3 is methyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.
• X 6 and X 9 are CR 14 and R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl. In certain embodiments R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring. In certain embodiments X 9 is CH. In certain embodiments X 9 is CF.
• X 6 and X 9 are CR 14 and L is -C(R 8 )2- and each R 8 is taken together with the carbon atom to which they are attached to form cyclopropyl.
• X 6 and X 9 are CR 14 , L is -C(R 8 ) 2 - and each R 8 is taken together with the carbon atom to which they are attached to form cyclopropyl and R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.
• each R 10 is independently cyano, halo, or -S(0)2-Ci-C6 alkyl.
• q is 1 or 2 and each R 10 is independently cyano, halo, or -S(0)2-Ci-C6 alkyl.
• q is two and both R 10 are halo.
• q is two and both R 10 are fluoro.
• q is two and at least one R 10 is fluoro.
• R 1 is H or methyl. In certain embodiments of compounds of Formula V (or subformula thereof), R 1 is H.
• R 1 is methyl
• L is CH 2 or two R 8 together with the carbon atom to which they are attached form a cycloalkyl ring.
• L is CH 2 .
• R 9 is optionally substituted phenyl.
• R 9 is phenyl. In certain embodiments R 9 is phenyl substituted by one to two substituents independently selected from the group consisting of cyano and halo. In certain embodiments R 9 is phenyl substituted by cyano.
• R 14 is hydrogen, halo or methyl optionally substituted with 1-3 fluoro. In certain embodiments, R 14 is hydrogen or halo. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is halo. In certain embodiments, R 14 is fluoro.
• q 0, 1, or 2;
• X 6 is N or CR 14 ;
• R 1 is H or optionally substituted Ci-C 6 alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, optionally substituted Ci-C 6 alkyl
• R 3 is H, halo, optionally substituted Ci-C 6 alkyl, or R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is -C(R 8 ) 2 -;
• each R 8 is independently H, halo, optionally substituted Ci-Ce alkyl, or two R 8 together with the carbon atom to which they are attached form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted aryl or optionally substituted heteroaryl
• each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted Ci-Ce alkoxy, or -S(0)2-Ci-C6 alkyl; and
• R 14 is hydrogen, cyano, halo, C1-C3 alkyl optionally substituted with halo or oxo, or C1-C3 alkoxy optionally substituted with halo or oxo.
• X 6 is CR 14 . In certain embodiments X 6 is N.
• each R 10 is independently cyano, halo, or -S(0) 2 -Ci-C 6 alkyl.
• q is at least one and at least one R 10 is halo.
• q is at least one and at least one R 10 is fluoro.
• q is at least one and at least one R 10 is cyano.
• Y 2 is O.
• R 3 is H.
• R 3 is methyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.
• R 1 is H or methyl.
• R 1 is methyl
• L is CH 2 or two R 8 together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments L is CH 2 .
• R 9 is optionally substituted phenyl. In certain embodiments R 9 is phenyl. In certain embodiments R 9 is phenyl substituted by one to two substituents independently selected from the group consisting of cyano and halo. In certain embodiments R 9 is phenyl substituted by cyano.
• R 14 is hydrogen, cyano, halo or methyl optionally substituted with 1-3 fluoro or oxo. In certain embodiments, R 14 is hydrogen or halo. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is cyano.
• the compounds of Formula V and Va do not readily cross the blood brain barrier.
• the compounds of Formula V and Va have a MDCKII-MDR1 efflux ratio of greater than 2.5.
• the compounds of Formula II, Va and V wherein at least one of X 6 and X 9 are N have a hepatic clearance of less than 5, 4, 3, 2, or 1 mL/min/kg when tested according to the human hepatic stability assay described below.
• the compound is of Formula VI:
• q 0, 1, or 2;
• X 6 is N or CR 14 ;
• R 1 is H or optionally substituted Ci-C 6 alkyl
• Y 2 is -O- or -C(R 6 ) 2 -;
• each R 6 is independently H, halo, optionally substituted Ci-C 6 alkyl
• R 3 is H, halo, optionally substituted Ci-Ce alkyl, or R 3 and R 6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• L is -C(R 8 ) 2 -; each R is independently H, halo, optionally substituted Ci-Ce alkyl, or two R together with the carbon atom to which they are attached form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
• R 9 is optionally substituted aryl
• each R 10 is independently halo, optionally substituted Ci-C 6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted Ci-C 6 alkoxy; and
• R 14 is hydrogen, cyano, halo, C 1 -C3 alkyl optionally substituted with halo or oxo, or C 1 -C3 alkoxy optionally substituted with halo or oxo.
• X 6 is CR 14 . In certain embodiments X 6 is N.
• each R 10 is independently halo. In certain embodiments, q is one and R 10 is fluoro.
• Y 2 is O.
• R 3 is H.
• R 3 is methyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl.
• R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.
• R 1 is H or methyl.
• R 1 is methyl
• L is CH 2 or two R 8 together with the carbon atom to which they are attached form a cycloalkyl ring. In certain embodiments L is CH 2 .
• R 9 is phenyl. In certain embodiments R 9 is optionally substituted phenyl. In certain embodiments R 9 is phenyl substituted by one to two halo.
• R 14 is hydrogen, halo or methyl optionally substituted with 1-3 fluoro or oxo. In certain embodiments, R 14 is hydrogen or halo. In certain embodiments, R 14 is hydrogen.
• the compounds of Formula VI readily cross the blood brain barrier.
• the compounds of Formula VI have a MDCKII-MDRl efflux ratio of 2.5 or less.
• the compounds of Formula VI have a hepatic clearance of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 when tested according to the human hepatic stability assay described below.
• q is 0, 1 or 2; and each R 10 is independently cyano, halo or optionally substituted alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; and each R 10 is independently cyano, halo, or alkyl optionally substituted with 1-3 halo or oxo. [0218] In any of the embodiments described throughout, q is 0, 1 or 2; and each R is independently cyano, halo, optionally substituted Ci-Ce alkyl, or -S(0)2-Ci-C6 alkyl.
• q is 1 or 2; and each R 10 is independently cyano, halo, optionally substituted Ci-Ce alkyl, or -S(0)2-Ci-C6 alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; and each R 10 is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S(0) 2 -methyl. In any of the embodiments described throughout, q is 1 or 2; and each R 10 is independently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S(0) 2 -methyl.
• the A ring is an optionally substituted heteroaryl ring. In any of the embodiments described throughout, the A ring is an unsubstituted heteroaryl ring. In any of the embodiments described throughout, the A ring is an optionally substituted 5-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is an unsubstituted 5-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is an optionally substituted 6-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is a heteroaryl ring substituted with at least one halo. In any of the embodiments described throughout, the A ring is a 5-membered heteroaryl ring substituted with at least one halo.
• the A ring is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and L is -C(R 8 )2- and each R 8 is taken together with the carbon atom to which they are attached to form cyclopropyl.
• the A ring is optionally substituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.
• the A ring is of the formula:
• X 10 , X 11 and X 12 are each S, O, N, CR 13 or NR 13 , and X 13 is C or N;
• each R 13 is independently H, halo, cyano or optionally substituted Ci-Ce alkyl.
• At least one of X 10 , X 11 and X 12 is CR 13 or NR 13 and at least one R 13 is halo, cyano or optionally substituted Ci-C 6 alkyl. In certain embodiments, at least one of X 10 , X 11 and X 12 is CR 13 or NR 13 and at least one R 13 is halo.
• the A ring is one of the following:
• each ring may be optionally substituted.
• the A ring is one of the following:
• a compound may be selected from those compounds in Table 1, 2, 3 or 4. Also included within the disclosure are stereoisomers and mixtures of stereoisomers thereof. Also included within the disclosure is a compound selected from Table 1 , 2, 3 or 4, or pharmaceutically acceptable salt thereof.
• Treatment is an approach for obtaining beneficial or desired results including clinical results.
• beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g. , stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g. , ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease
• Prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
• Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
• Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
• the subject is a mammal. In one embodiment, the subject is a human.

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