N-azepinyl-carboxamide inhibitors of receptor-interacting protein kinase1

Abstract

The present disclosure relates generally to N-azepinyl-carboxamide derivatives Formula I: [Image disponible dans le document PDF, Image available in the PDF document] and pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers and mixture of stereoisomers thereof, and compositions thereof, and their use as inhibitors of receptor- interacting protein kinase 1 which is a key regulator of inflammation, apoptosis and necroptosis. In some embodiments, there is provided a compound of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] and pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers and mixture of stereoisomers thereof.

Description

DEMANDE OU BREVET VOLUMINEUX LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND PLUS D'UN TOME. CECI EST LE TOME 1 DE 3 CONTENANT LES PAGES 1 À 186 NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS / PATENTS THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE THAN ONE VOLUME THIS IS VOLUME 1 OF 3 CONTAINING PAGES 1 TO 186 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME : NOTE POUR LE TOME / VOLUME NOTE: N-AZEPINYL-CARBOXAMIDE INHIBITORS OF RECEPTOR-INTERACTING PROTEIN KINASE 1

[0001] This application claims priority to U.S. Patent Application Nos. 62 / 292,202, filed February 5, 2016, 62 / 341,019, filed May 24, 2016, 62 / 363,775, filed July 18, 2016, 62 / 385,217, filed September 8, 2016, and 62 / 417,219, filed November 3, 2016. FIELD

[0002] The present disclosure relates generally to inhibitors of kinase, therapeutic methods of use, and manufacture thereof. BACKGROUND

[0003] Although 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. Similarly, the activation of 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.

[0004] 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-kB). 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.

[0005] 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. DESCRIPTION

[0006] Provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. The disclosure also provides 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. Moreover, 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.

[0007] In certain embodiments, provided is a compound of Formula I. In certain embodiments, provided is a compound of Formula IIc. In certain embodiments, provided is a compound of Formula IIe. In certain embodiments, provided is a compound of Formula IIf. 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 pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 3, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. In certain embodiments, provided is a compound as in Table 4, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0008] Provided herein is a pharmaceutical composition comprising a compound, including those of any Formula described herein, and an excipient.

[0009] Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are for use in the treatment of a receptor-interacting protein kinase 1- mediated disease or disorder.

[0010] Provided herein is a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof.

[0011] In certain embodiments, 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, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, or peridontitis. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. 1. Definitions

[0012] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0013] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH<com:Sub>2< / com:Sub> 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.

[0015] The prefix "C<com:Sub>u-v< / com:Sub>" indicates that the following group has from u to v carbon atoms. For example, "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0016] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount <com:Math><semantics>±10%<annotation encoding="application / x-tex">\pm 10\%< / annotation>< / semantics>< / com:Math>. In certain embodiments, the term "about" includes the indicated amount <com:Math><semantics>±5%<annotation encoding="application / x-tex">\pm 5\%< / annotation>< / semantics>< / com:Math>. In certain embodiments, the term "about" includes the indicated amount <com:Math><semantics>±1%<annotation encoding="application / x-tex">\pm 1\%< / annotation>< / semantics>< / com:Math>. Also, to the term "about X" includes description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., 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.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., <com:Math><semantics>C1−20<annotation encoding="application / x-tex">C_{1-20}< / annotation>< / semantics>< / com:Math> alkyl), 1 to 8 carbon atoms (i.e., <com:Math><semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics>< / com:Math> alkyl), 1 to 6 carbon atoms (i.e., <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl), or 1 to 4 carbon atoms (i.e., <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl). In certain embodiments, alkyl has 1 to 12 carbon atoms (i.e., C<com:Sub>1-12< / com:Sub> alkyl). Examples of 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. When an 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<com:Sub>2< / com:Sub>)<com:Sub>3< / com:Sub>CH<com:Sub>3< / com:Sub>), sec-butyl (i.e. - CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>), isobutyl (i.e. -CH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>) and tert-butyl (i.e. -C(CH<com:Sub>3< / com:Sub>)<com:Sub>3< / com:Sub>); and "propyl" includes n- propyl (i.e. <com:Math><semantics>−(CH2)2CH3<annotation encoding="application / x-tex">-(CH_2)_2CH_3< / annotation>< / semantics>< / com:Math>) and isopropyl (i.e. <com:Math><semantics>−CH(CH3)2<annotation encoding="application / x-tex">-CH(CH_3)_2< / annotation>< / semantics>< / com:Math>).

[0018] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., <com:Math><semantics>C2−20<annotation encoding="application / x-tex">C_{2-20}< / annotation>< / semantics>< / com:Math> alkenyl), 2 to 8 carbon atoms (i.e., <com:Math><semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics>< / com:Math> alkenyl), 2 to 6 carbon atoms (i.e., <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl), or 2 to 4 carbon atoms (i.e., <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., <com:Math><semantics>C2−20<annotation encoding="application / x-tex">C_{2-20}< / annotation>< / semantics>< / com:Math> alkynyl), 2 to 8 carbon atoms (i.e., <com:Math><semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics>< / com:Math> alkynyl), 2 to 6 carbon atoms (i.e., <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl), or 2 to 4 carbon atoms (i.e., <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0020] "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.

[0021] "Alkylthio" refers to the group "alkyl-S-".

[0022] "Acyl" refers to a group -C(O)R, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0023] "Amido" refers to both a "C-amido" group which refers to the group -C(O)NR<com:Sup>y< / com:Sup>R<com:Sup>z< / com:Sup> and an "N- amido" group which refers to the group -NR<com:Sup>y< / com:Sup>C(O)R<com:Sup>z< / com:Sup>, wherein R<com:Sup>y< / com:Sup> and R<com:Sup>z< / com:Sup> are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0024] "Amino" refers to the group -NR<com:Sup>y< / com:Sup>R<com:Sup>z< / com:Sup> wherein R<com:Sup>y< / com:Sup> and R<com:Sup>z< / com:Sup> are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0025] "Amidino" refers to -C(NH)(NH<com:Sub>2< / com:Sub>). In certain embodiments, "Amidino" refers to -C(NR)(NR<com:Sub>2< / com:Sub>), 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.

[0026] "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. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C<com:Sub>6-20< / com:Sub> aryl), 6 to 12 carbon ring atoms (i.e., C<com:Sub>6-12< / com:Sub> aryl), or 6 to 10 carbon ring atoms (i.e., <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl). In certain embodiments, aryl has 6 to 18 carbon ring atoms (i.e., <com:Math><semantics>C6−18<annotation encoding="application / x-tex">C_{6-18}< / annotation>< / semantics>< / com:Math> aryl). Examples of 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.

[0027] "Azido" refers to -N<com:Sub>3< / com:Sub>.

[0028] "Arylalkyl" or "Aralkyl" refers to the group "aryl-alkyl-".

[0029] "Carbamoyl" refers to both an "O-carbamoyl" group which refers to the group -O-C(O)NR<com:Sup>y< / com:Sup>R<com:Sup>z< / com:Sup> and an "N-carbamoyl" group which refers to the group -NR<com:Sup>y< / com:Sup>C(O)OR<com:Sup>2< / com:Sup>, wherein R<com:Sup>y< / com:Sup> and R<com:Sup>z< / com:Sup> are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0030] "Carboxyl" refers to -C(O)OH.

[0031] "Carboxyl ester" or "ester" refer to both -OC(O)R and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] "Cyano" or "carbonitrile" refers to the group -CN.

[0033] "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. The term "cycloalkyl" includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., <com:Math><semantics>C3−20<annotation encoding="application / x-tex">C_{3-20}< / annotation>< / semantics>< / com:Math> cycloalkyl), 3 to 12 ring carbon atoms (i.e., <com:Math><semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics>< / com:Math> cycloalkyl), 3 to 10 ring carbon atoms (i.e., <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl), 3 to 8 ring carbon atoms (i.e., <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C<com:Sub>3-6< / com:Sub> cycloalkyl). In certain embodiments, cycloalkyl has from 3 to 15 ring carbon atoms (i.e., C<com:Sub>3-15< / com:Sub> cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, the term 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.

[0034] In certain embodiments, 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. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like.

[0035] "Guanidino" refers to -NHC(NH)(NH<com:Sub>2< / com:Sub>). In certain embodiments, "guanidino" refers to - NRC(NR)(NR<com:Sub>2< / com:Sub>), wherein each R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0036] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0037] "Hydrazino" refers to -NHNH<com:Sub>2< / com:Sub>.

[0038] "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.

[0039] "Imido" refers to a group -C(O)NRC(O)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.

[0040] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0041] "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<com:Sub>2< / com:Sub>) and trifluoromethyl (-CF<com:Sub>3< / com:Sub>). In certain embodiments, examples of haloalkyl include difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0042] "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0043] "Hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxy group.

[0044] "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-, -O-, -S-, - S(O)-, -S(O)<com:Sub>2< / com:Sub>-, and the like, where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include - OCH<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>OCH<com:Sub>3< / com:Sub>, -SCH<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>SCH<com:Sub>3< / com:Sub>, -NRCH<com:Sub>3< / com:Sub>, and -CH<com:Sub>2< / com:Sub>NRCH<com:Sub>3< / com:Sub>, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. In certain embodiments, examples of heteroalkyl groups include -CH<com:Sub>2< / com:Sub>OCH<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>SCH<com:Sub>3< / com:Sub>, and -CH<com:Sub>2< / com:Sub>NRCH<com:Sub>3< / com:Sub>, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. As used 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. In certain embodiments, the term "heteroalkyl" requires that the point of attachment to the remainder of the molecule is through a carbon atom.

[0045] "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. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C<com:Sub>1-20< / com:Sub> heteroaryl), 3 to 12 ring carbon atoms (i.e., <com:Math><semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics>< / com:Math> heteroaryl), or 3 to 8 carbon ring atoms (i.e., <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> 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. In certain embodiments, the term "heteroaryl" refers to a 5- 14 membered ring system. In certain embodiments, heteroaryl includes 1 to 13 ring carbon atoms (i.e., <com:Math><semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics>< / com:Math> heteroaryl). In certain embodiments, heteroaryl includes 1 to 6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. In certain embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0046] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0047] "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. In certain embodiments, heterocyclyl may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties. Any non- aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., <com:Math><semantics>C2−20<annotation encoding="application / x-tex">C_{2-20}< / annotation>< / semantics>< / com:Math> heterocyclyl), 2 to 12 ring carbon atoms (i.e., <com:Math><semantics>C2−12<annotation encoding="application / x-tex">C_{2-12}< / annotation>< / semantics>< / com:Math> heterocyclyl), 2 to 10 ring carbon atoms (i.e., <com:Math><semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics>< / com:Math> heterocyclyl), 2 to 8 ring carbon atoms (i.e., <com:Math><semantics>C2−8<annotation encoding="application / x-tex">C_{2-8}< / annotation>< / semantics>< / com:Math> heterocyclyl), 3 to 12 ring carbon atoms (i.e., <com:Math><semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics>< / com:Math> heterocyclyl), 3 to 8 ring carbon atoms (i.e., <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> heterocyclyl), or 3 to 6 ring carbon atoms (i.e., <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> 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. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. In certain embodiments, examples of heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Also used herein, the term "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. Examples of the 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-1- azaspiro[3.3]heptanyl. Examples of the 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.

[0048] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0049] "Oxo" refers to the group (=0) or (0).

[0050] "Nitro" refers to the group -NO<com:Sub>2< / com:Sub>.

[0051] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0052] "Oxime" refers to the group -CR(=NOH) wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0053] "Sulfonyl" refers to the group -S(O)<com:Sub>2< / com:Sub>R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0054] "Sulfinyl" refers to the group -S(O)R, where 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.

[0055] "Sulfonamido" refers to the groups -SO<com:Sub>2< / com:Sub>NRR and -NRSO<com:Sub>2< / com:Sub>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.

[0056] "Alkylsulfonyl" refers to the group -S(O)<com:Sub>2< / com:Sub>R, where R is alkyl.

[0057] "Alkylsulfinyl" refers to the group -S(O)R, where R is alkyl.

[0058] "Thiocyanate" refers to the group -SCN.

[0059] "Thiol" refers to the group -SH.

[0060] "Thioxo" or "thione" refer to the group (=S) or (S).

[0061] In certain embodiments of any of the terms defined above, R<com:Sup>y< / com:Sup> and R<com:Sup>z< / com:Sup> are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0062] In certain embodiments of any of the terms defined above, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Certain commonly used alternative chemical names may be used. For example, 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. Also, unless indicated explicitly otherwise, where 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.

[0063] The terms "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0064] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded. 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.

[0065] In certain embodiments, 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, heteroaryl, heteroarylalkyl, heterocyclyl, 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<com:Sup>100< / com:Sup>)<com:Sub>3< / com:Sub> wherein each R<com:Sup>100< / com:Sup> is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0066] In certain embodiments, 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, Cl, 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 in groups such as thiol groups, thioalkyl groups, thiohaloalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "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.

[0067] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -NR<com:Sup>g< / com:Sup>C(=O)R<com:Sup>h< / com:Sup>, -NR<com:Sup>g< / com:Sup>C(=O)NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -NR<com:Sup>g< / com:Sup>C(=O)OR<com:Sup>h< / com:Sup>, <com:Math><semantics>−NRgS(=O)1−2Rh<annotation encoding="application / x-tex">-NR^gS(=O)_{1-2}R^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rg<annotation encoding="application / x-tex">-C(=O)R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)ORg<annotation encoding="application / x-tex">-C(=O)OR^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)ORg<annotation encoding="application / x-tex">-OC(=O)OR^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)Rg<annotation encoding="application / x-tex">-OC(=O)R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NRgRh<annotation encoding="application / x-tex">-C(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NRgRh<annotation encoding="application / x-tex">-OC(=O)NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ORg<annotation encoding="application / x-tex">OR^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SRg<annotation encoding="application / x-tex">-SR^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)Rg<annotation encoding="application / x-tex">-S(=O)R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2Rg<annotation encoding="application / x-tex">-S(=O)_2R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)1−2Rg<annotation encoding="application / x-tex">-OS(=O)_{1-2}R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)1−2ORg<annotation encoding="application / x-tex">-S(=O)_{1-2}OR^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRgS(=O)1−2NRgRh<annotation encoding="application / x-tex">-NR^gS(=O)_{1-2}NR^gR^h< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>=NSO2Rg<annotation encoding="application / x-tex">=NSO_2R^g< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>=NORg<annotation encoding="application / x-tex">=NOR^g< / annotation>< / semantics>< / com:Math>, -S(=O)<com:Sub>1-2< / com:Sub>NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -SF<com:Sub>5< / com:Sub>, -SCF<com:Sub>3< / com:Sub> or -OCF<com:Sub>3< / com:Sub>. In certain embodiments, "substituted" also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)R<com:Sup>g< / com:Sup>, -C(=O)OR<com:Sup>g< / com:Sup>, -C(=O)NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -CH<com:Sub>2< / com:Sub>SO<com:Sub>2< / com:Sub>R<com:Sup>g< / com:Sup>, -CH<com:Sub>2< / com:Sub>SO<com:Sub>2< / com:Sub>NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>. In certain embodiments, "substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by -NR<com:Sup>g< / com:Sup>S(O)<com:Sub>1-2< / com:Sub>NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -CH<com:Sub>2< / com:Sub>S(O)R<com:Sup>g< / com:Sup>, -CH<com:Sub>2< / com:Sub>S(O)NR<com:Sup>g< / com:Sup>R<com:Sup>h< / com:Sup>, -OC(=O)OR<com:Sup>g< / com:Sup>, -SF<com:Sub>5< / com:Sub>, -SCF<com:Sub>3< / com:Sub> or -OCF<com:Sub>3< / com:Sub>. In certain embodiments, "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. In the foregoing, R<com:Sup>g< / com:Sup> and R<com:Sup>h< / com:Sup> and R<com:Sup>i< / com:Sup> 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<com:Sup>g< / com:Sup> and R<com:Sup>h< / com:Sup> and R<com:Sup>i< / com:Sup> 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. In an embodiment, each of said alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl are independently optionally substituted with one or more oxo, alkyl, halo, amino, hydroxy or alkoxy. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0068] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl- groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term "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. For example, in certain embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, 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. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0069] 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. Examples of 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 <com:Sup>2< / com:Sup>H (deuterium, D), <com:Sup>3< / com:Sup>H (tritium), <com:Sup>11< / com:Sup>C, <com:Sup>13< / com:Sup>C, <com:Sup>14< / com:Sup>C, <com:Sup>15< / com:Sup>N, <com:Sup>18< / com:Sup>F, <com:Sup>31< / com:Sup>P, <com:Sup>32< / com:Sup>P, <com:Sup>35< / com:Sup>S, <com:Sup>36< / com:Sup>Cl and <com:Sup>125< / com:Sup>I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as <com:Sup>3< / com:Sup>H, <com:Sup>13< / com:Sup>C and <com:Sup>14< / com:Sup>C are incorporated. Such 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.

[0070] 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. 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 Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0071] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). 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 <com:Sup>18< / com:Sup>F, <com:Sup>3< / com:Sup>H, <com:Sup>11< / com:Sup>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.

[0072] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0073] In many cases, 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.

[0074] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers, and prodrugs of the compounds described herein. "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.

[0075] 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. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, 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. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. 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. Likewise, 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<com:Sub>2< / com:Sub>(alkyl)), dialkyl amines (i.e., HN(alkyl)<com:Sub>2< / com:Sub>), trialkyl amines (i.e., N(alkyl)<com:Sub>3< / com:Sub>), substituted alkyl amines (i.e., NH<com:Sub>2< / com:Sub>(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)<com:Sub>2< / com:Sub>), tri(substituted alkyl) amines (i.e., N(substituted alkyl)<com:Sub>3< / com:Sub>), alkenyl amines (i.e., NH<com:Sub>2< / com:Sub>(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)<com:Sub>2< / com:Sub>), trialkenyl amines (i.e., N(alkenyl)<com:Sub>3< / com:Sub>), substituted alkenyl amines (i.e., NH<com:Sub>2< / com:Sub>(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)<com:Sub>2< / com:Sub>), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)<com:Sub>3< / com:Sub>, mono-, di- or tri- cycloalkyl amines (i.e., NH<com:Sub>2< / com:Sub>(cycloalkyl), HN(cycloalkyl)<com:Sub>2< / com:Sub>, N(cycloalkyl)<com:Sub>3< / com:Sub>), mono-, di- or tri- arylamines (i.e., NH<com:Sub>2< / com:Sub>(aryl), HN(aryl)<com:Sub>2< / com:Sub>, N(aryl)<com:Sub>3< / com:Sub>), or mixed amines, etc. Specific examples of 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.

[0076] The term "hydrate" refers to the complex formed by the combining of a compound of Formula I and water.

[0077] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.

[0078] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0079] 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, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0080] "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space and include enantiomers and diastereomers. In certain embodiments, 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 nonsuperimposeable mirror images of one another.

[0081] "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.

[0082] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0083] 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.

[0084] "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. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series; "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0085] As used herein, "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 [Image disponible dans le document PDF, Image available in the PDF document] 3. Compounds

[0086] Provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, provided is a compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is O or <com:Math><semantics>NR2<annotation encoding="application / x-tex">NR^2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^{1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^{2}< / annotation>< / semantics>< / com:Math> are each independently nitrogen or carbon and either <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R<com:Sup>1< / com:Sup> is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo, hydroxy or cyano or when Y<com:Sup>1< / com:Sup> is NR<com:Sup>2< / com:Sup>, then R<com:Sup>2< / com:Sup> and R<com:Sup>1< / com:Sup> together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^{1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; [Image disponible dans le document PDF, Image available in the PDF document] provided that when the moiety and the aromatic ring is optionally substituted then at least one of the following occurs: (1) L is absent or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^8)_{2^-}< / annotation>< / semantics>< / com:Math>, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>- and at least one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is other than hydrogen; (3) Y<com:Sup>2< / com:Sup> is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring; (4) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than isoxazole and phenyl or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−S(O)(NH)−;<annotation encoding="application / x-tex">-S(O)(NH)-;< / annotation>< / semantics>< / com:Math> (5) Y<com:Sup>2< / com:Sup> is -NR<com:Sup>5< / com:Sup>- 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 (7) R<com:Sup>9< / com:Sup> is substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, wherein at least one substituent is cyano; (8) R<com:Sup>1< / com:Sup> is C<com:Sub>2< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo, hydroxy or cyano; or (9) when <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> form an optionally substituted phenyl ring as in the moiety [Image disponible dans le document PDF, Image available in the PDF document] , 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 [Image disponible dans le document PDF, Image available in the PDF document] wherein the nitrogen containing aromatic ring is optionally substituted; and with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]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][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 4- (1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1- benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide; or 4-(2-aino-7-chloro-4-quinolinyl)- N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

[0087] In certain embodiments, provided is a compound of Formula I or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof wherein <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is O or <com:Math><semantics>NR2<annotation encoding="application / x-tex">NR^2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are each independently nitrogen or carbon and either <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R<com:Sup>1< / com:Sup> is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo, hydroxy or cyano or when Y<com:Sup>1< / com:Sup> is NR<com:Sup>2< / com:Sup>, then R<com:Sup>2< / com:Sup> and R<com:Sup>1< / com:Sup> together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; [Image disponible dans le document PDF, Image available in the PDF document] provided that when the moiety and the aromatic ring is optionally substituted then at least one of the following occurs: (1) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>- and at least one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is other than hydrogen; (3) Y<com:Sup>2< / com:Sup> is -O- and A is substituted with halo or cyano or A is thiazolyl or a 3- or 4-membered ring; (4) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than isoxazole and phenyl or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−S(0)(NH)−;<annotation encoding="application / x-tex">-S(0)(NH)-;< / annotation>< / semantics>< / com:Math> (5) Y<com:Sup>2< / com:Sup> is -NR<com:Sup>5< / com:Sup>- and A is other than isoxazole, pyrazole and triazole; or (6) the carbonyl moiety and L are substituted other than 1,3- on ring A; (7) <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ2<annotation encoding="application / x-tex">\mathbb{C}_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; or (8) when <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> form an optionally substituted phenyl ring as in the moiety [Image disponible dans le document PDF, Image available in the PDF document] , 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 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] is not , or wherein the nitrogen containing aromatic ring is optionally substituted; and with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]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][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 4- (1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1- benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4- quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

[0088] In certain embodiments, at least one of <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> are halo or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0089] In certain embodiments, L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1−C6<annotation encoding="application / x-tex">C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl or halo, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0090] In certain embodiments, <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^{1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>NR2<annotation encoding="application / x-tex">NR^{2}< / annotation>< / semantics>< / com:Math>.

[0091] In certain embodiments, <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> 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.

[0092] In certain embodiments, <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is - <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_{2}< / annotation>< / semantics>< / com:Math>-.

[0093] In certain embodiments, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>-; and one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is hydrogen, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, and the other <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0094] In certain embodiments, Y<com:Sup>2< / com:Sup> is -O- and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring.

[0095] In certain embodiments, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than isoxazole and phenyl or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−S(O)(NH)<annotation encoding="application / x-tex">-S(O)(NH)< / annotation>< / semantics>< / com:Math>-.

[0096] In certain embodiments, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -NR<com:Sup>5< / com:Sup>-; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted pyridyl, and A is other than triazole; or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are optionally substituted pyrimidyl, and A is other than pyrazole and triazole.

[0097] In certain embodiments, the carbonyl moiety and L are substituted other than 1,3- on ring A.

[0098] In certain embodiments, provided is a compound of Formula I or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is O or <com:Math><semantics>NR2<annotation encoding="application / x-tex">NR^2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are each independently nitrogen or carbon and either <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R<com:Sup>1< / com:Sup> is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo, hydroxy or cyano or when Y<com:Sup>1< / com:Sup> is NR<com:Sup>2< / com:Sup>, then R<com:Sup>2< / com:Sup> and R<com:Sup>1< / com:Sup> together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> are halo or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) X<com:Sup>1< / com:Sup> and X<com:Sup>2< / com:Sup> 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; (5) X<com:Sup>1< / com:Sup> and R<com:Sup>1< / com:Sup> together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; (6) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is hydrogen, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, and the other <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (7) Y<com:Sup>2< / com:Sup> is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring; (8) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than isoxazole and phenyl or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−S(O)(NH)−;<annotation encoding="application / x-tex">-S(O)(NH)-;< / annotation>< / semantics>< / com:Math> (9) Y<com:Sup>2< / com:Sup> is -NR<com:Sup>5< / com:Sup>-; X<com:Sup>1< / com:Sup> and X<com:Sup>2< / com:Sup> together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted pyridyl, and A is other than triazole; or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; (10) the carbonyl moiety and L are substituted other than 1,3- on ring A; (11) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -O-; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted pyridyl, and A is other than isoxazole; (12) <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ2<annotation encoding="application / x-tex">\mathbb{C}_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; or (13) when <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> form an optionally substituted phenyl ring as in the moiety [Image disponible dans le document PDF, Image available in the PDF document] , 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 with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]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][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 4- (1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1- benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4- quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

[0099] In certain embodiments, 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-[(3S)-2,3,4,5-tetrahydro-4-oxo-1,5-benzoxazepin-3-yl]-3- isoxazolecarboxamide.

[0100] Also provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, provided is a compound of Formula I wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; (a) <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are each independently nitrogen or carbon, and together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (b) <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; Y<com:Sup>1< / com:Sup> is O or NR<com:Sup>2< / com:Sup>, where R<com:Sup>2< / com:Sup> and R<com:Sup>1< / com:Sup> together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo provided that the compound is not 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> 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; (5) X<com:Sup>1< / com:Sup> and R<com:Sup>1< / com:Sup> together with the atoms to which they are attached, form a 5 or 6 membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring; and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is -CH<com:Sub>2< / com:Sub>-; (6) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is hydrogen, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, and the other <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (7) Y<com:Sup>2< / com:Sup> is -O-; 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][1,4]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; (8) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than 1,3-isoxazole or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S(O)N(H)-; (9) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−NR5<annotation encoding="application / x-tex">-NR^5< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted pyridyl, and A is other than triazole; or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or (10) the carbonyl moiety and L are substituted other than 1,3- on ring A; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0101] In certain embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl. In certain embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is methyl.

[0102] In certain embodiments, the moiety: [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math> are each S, O, N, NH, or CH; <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are each N or CH; q is 0, 1 or 2; each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or <com:Math><semantics>−S(O)2<annotation encoding="application / x-tex">-S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0103] In certain embodiments, the moiety: [Image disponible dans le document PDF, Image available in the PDF document] wherein X<com:Sup>3< / com:Sup>, X<com:Sup>4< / com:Sup> and X<com:Sup>5< / com:Sup> are each S, O, N, NH, or CH; <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are each N or CH; q is 0, 1 or 2; each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0104] In certain embodiments, the moiety: [Image disponible dans le document PDF, Image available in the PDF document] wherein X<com:Sup>3< / com:Sup>, X<com:Sup>4< / com:Sup> and X<com:Sup>5< / com:Sup> are each S, O, N, NH, or CH; <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are each N or CH; q is 0, 1 or 2; each R<com:Sup>10< / com:Sup> is independently halo or optionally substituted alkyl.

[0105] In certain embodiments, the moiety: [Image disponible dans le document PDF, Image available in the PDF document] - F [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ٨ , or [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0107] In certain embodiments, the moiety [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0108] In certain embodiments, the moiety

[0109] In certain embodiments, <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is O.

[0110] In certain embodiments, R<com:Sup>1< / com:Sup> is methyl. In certain embodiments, R<com:Sup>1< / com:Sup> is ethyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0111] In certain embodiments, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is where n is 1, 2, 3 or 4,

[0112] In certain embodiments, Y<com:Sup>2< / com:Sup> is -O-; 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.

[0113] In certain embodiments, both R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are fluoro, or either R<com:Sup>3< / com:Sup> or R<com:Sup>4< / com:Sup> are fluoro and the other is hydrogen, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> form a cyclopropyl or R<com:Sup>3< / com:Sup> joins with R<com:Sup>6< / com:Sup> to form a cyclopropyl. In certain embodiments, R<com:Sup>3< / com:Sup> or R<com:Sup>4< / com:Sup> is methyl.

[0114] In certain embodiments, A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

[0115] In certain embodiments, A is isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H- pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

[0116] In certain embodiments, A is phenyl.

[0117] In certain embodiments, L is absent, <com:Math><semantics>−S(O)2<annotation encoding="application / x-tex">-S(O)_2< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-.

[0118] In certain embodiments, two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0119] In certain embodiments, R<com:Sup>9< / com:Sup> is phenyl or 2,3-dihydro-1H-indenyl. In certain embodiments, R<com:Sup>9< / com:Sup> is phenyl. In certain embodiments, R<com:Sup>9< / com:Sup> is 2-F-phenyl. In certain embodiments, R<com:Sup>9< / com:Sup> is pyridyl. In certain embodiments, R<com:Sup>9< / com:Sup> is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl.

[0120] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, R<com:Sup>10< / com:Sup> is methyl.

[0121] In one aspect, provided is a compound of Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is O or <com:Math><semantics>NR2<annotation encoding="application / x-tex">NR^2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are each independently nitrogen or carbon and either <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl and R<com:Sup>1< / com:Sup> is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo, hydroxy or cyano or when Y<com:Sup>1< / com:Sup> is NR<com:Sup>2< / com:Sup>, then R<com:Sup>2< / com:Sup> and R<com:Sup>1< / com:Sup> together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> together with the atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, and X<com:Sup>2< / com:Sup> is -CH<com:Sub>2< / com:Sub>-; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0122] In certain embodiments, the moiety is . In certain [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, when the moiety 3 , q is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is halo or alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring. In certain embodiments, the moiety [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] is , and when the moiety S 2 q is 0 or R<com:Sup>10< / com:Sup> is halo or alkyl, and L is absent, then ring A is a 3-, 4- or 5-membered monocyclic ring.

[0123] In certain embodiments, in any Formula disclosed herein, R<com:Sup>9< / com:Sup> is substituted with at least one cyano.

[0124] In certain embodiments, the compound is of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1, or 2; <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are each N or CH; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) at least one of <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> are halo or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is hydrogen, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, and the other <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) Y<com:Sup>2< / com:Sup> is -O-; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4- membered ring; (5) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than isoxazole or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S(O)(NH)-; (6) Y<com:Sup>2< / com:Sup> is -NR<com:Sup>5< / com:Sup>-; X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup> and X<com:Sup>9< / com:Sup> together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup> and X<com:Sup>9< / com:Sup> together form an optionally substituted pyridyl, and A is other than triazole; or <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or (7) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -O-; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> together form an optionally substituted pyridyl, and A is other than isoxazole; (8) <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ2<annotation encoding="application / x-tex">\mathbb{C}_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; or (9) when <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> form an optionally substituted phenyl ring as in the moiety [Image disponible dans le document PDF, Image available in the PDF document] , 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 with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]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][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 4- (1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1- benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4- quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

[0125] In certain embodiments, the compound is of Formula II wherein q is 0, 1, or 2; <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are each N or CH; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or halo provided that the compound is not 5-(diffuoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and one <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is hydrogen, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, and the other <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) Y<com:Sup>2< / com:Sup> is -O-; 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][1,4]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; (5) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S-, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; and A is other than 1,3-isoxazole or <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is -S(O)N(H)-; (6) Y<com:Sup>2< / com:Sup> is -NR<com:Sup>5< / com:Sup>-; X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup> and X<com:Sup>9< / com:Sup> together form an optionally substituted phenyl, and A is other than isoxazole, pyrazole and triazole; X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup> and X<com:Sup>9< / com:Sup> together form an optionally substituted pyridyl, and A is other than triazole; or <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> are optionally substituted pyrimidyl, and A is other than pyrazole and triazole; or or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0126] In certain embodiments, the compound is of Formula II and L is absent or -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>-, and two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring.

[0127] In any of the embodiments of Formula II (or subformula thereof), R<com:Sup>1< / com:Sup> is H or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In any of the embodiments of Formula II (or subformula thereof), R<com:Sup>1< / com:Sup> is H or C<com:Sub>1< / com:Sub>- C<com:Sub>6< / com:Sub> alkyl.

[0128] In any of the embodiments of Formula II (or subformula thereof), q is 0, 1 or 2 and when present, each R<com:Sup>10< / com:Sup> is independently cyano, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl or -S(O)<com:Sub>2< / com:Sub>-C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In any of the embodiments of Formula II (or subformula thereof), q is 0, 1 or 2 and when present, each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl. In any of the embodiments of Formula II (or subformula thereof), each R<com:Sup>10< / com:Sup> is independently halo. In certain embodiments, each R<com:Sup>10< / com:Sup> is independently fluoro. In any of the embodiments of Formula II (or subformula thereof), 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.

[0129] In certain embodiments, the compound is of Formula IIa: [Image disponible dans le document PDF, Image available in the PDF document] l or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ℂ2<annotation encoding="application / x-tex">\mathbb{C}_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; or (5) when <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> form an optionally substituted phenyl ring as in the moiety [Image disponible dans le document PDF, Image available in the PDF document] , 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 with the further proviso that the compound is not: 5-(difluoro(phenyl)methyl)-N-(4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]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][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 4- (1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1- benzazepin-3-yl]-1-piperidinecarboxamide; 4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide; or 4-(2-amino-7-chloro-4- quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

[0130] In certain embodiments, the compound is of Formula IIa wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0131] In certain embodiments, the compound is of Formula IIa-1: [Image disponible dans le document PDF, Image available in the PDF document] IIa-1 wherein one of <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics>< / com:Math> is halo and the other is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> cycloalkyl and the remaining variables are as defined throughout.

[0132] In certain embodiments, the compound is of Formula IIa-2: [Image disponible dans le document PDF, Image available in the PDF document] IIa-2 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0133] In certain embodiments, 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 IIa-5. [Image disponible dans le document PDF, Image available in the PDF document]

[0134] In certain embodiments, the compound is of Formula IIb: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_{1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_{6}< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) at least one of <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> are halo or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2−<annotation encoding="application / x-tex">-C(R^6)_{2^-}< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (4) the compound is not 5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2- oxopyrido[2,3-b][1,4]oxazepin-3-yl]-3-isoxazolecarboxamide; N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1- methyl-2-oxo-1H-pyrido[2,3-b][1,4]diazepin-3-yl]-3-(phenylmethyl)-1H-1,2,4-triazole-5-carboxamide; 5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][1,4]oxazepin-3-yl]-3- isoxazolecarboxamide; or N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido[2,3- b][1,4]diazepin-3-yl]-3-(phenylmethyl)-1H-1,2,4-triazole-5-carboxamide.

[0135] In certain embodiments, the compound is of Formula IIb wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>-, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0136] In certain embodiments, the compound is of Formula IIb-1: [Image disponible dans le document PDF, Image available in the PDF document] IIb-1 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0137] In certain embodiments, 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 IIb-6. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIb-2 IIb-3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIb-4 IIb-5 [Image disponible dans le document PDF, Image available in the PDF document] IIb-6

[0138] In certain embodiments, the compound is of Formula IIc: [Image disponible dans le document PDF, Image available in the PDF document] IIc or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0139] In certain embodiments, the compound is of Formula IIc wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> are independently H, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0140] In certain embodiments, provided is a compound of Formula IIc or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_{1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_{6}< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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(<com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>-; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -<com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0141] In certain embodiments, the compound is of Formula IIc-1: [Image disponible dans le document PDF, Image available in the PDF document] IIc-1 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0142] In certain embodiments, 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 IIc-4. In certain embodiments, the compound is of Formula IIc-5. In certain embodiments, the compound is of Formula IIc-6. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIc-2 IIc-3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIc-4 IIc-5 [Image disponible dans le document PDF, Image available in the PDF document] IIc-6

[0143] In certain embodiments, provided is a compound of Formula IIc-4: [Image disponible dans le document PDF, Image available in the PDF document] Пс-4 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−𝑶<annotation encoding="application / x-tex">-\mathbf{O}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−𝑪(𝑹8)2<annotation encoding="application / x-tex">-\mathbf{C}(\mathbf{R}^8)_2< / annotation>< / semantics>< / com:Math>-: each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -<com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0144] In certain embodiments, the compound is of Formula IId: [Image disponible dans le document PDF, Image available in the PDF document] IId or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^8)_{2^-}< / annotation>< / semantics>< / com:Math>, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (4) 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 5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-b][1,4]oxazepin-3-yl]-3- isoxazolecarboxamide.

[0145] In certain embodiments, the compound is of Formula IId wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> are halo or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>-, and two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2−<annotation encoding="application / x-tex">-C(R^6)_{2-}< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0146] In certain embodiments, the compound is of Formula IId-1: [Image disponible dans le document PDF, Image available in the PDF document] IId-1 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S(O)-, -S(O)<com:Sub>2< / com:Sub>-, -NR<com:Sup>7< / com:Sup>- or -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>-; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0147] In certain embodiments, 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 IId-6. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IId-2 IId-3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IId-4 IId-5 [Image disponible dans le document PDF, Image available in the PDF document] IId-6

[0148] In certain embodiments, provided is a compound of Formula IIe: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -<com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0149] In certain embodiments, the compound is of Formula IIe or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0150] In certain embodiments, the compound is of Formula IIe wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> are independently H, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^8)_{2-}< / annotation>< / semantics>< / com:Math>, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0151] In certain embodiments, provided is a compound of Formula IIe or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl: [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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 -<com:Math><semantics>C(R8)2<annotation encoding="application / x-tex">C(R^8)_2< / annotation>< / semantics>< / com:Math>-; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -S(O)<com:Sub>2< / com:Sub>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0152] In certain embodiments, the compound is of Formula IIe-1: [Image disponible dans le document PDF, Image available in the PDF document] IIe-1 wherein or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0153] In certain embodiments, 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 IIe-6. [Image disponible dans le document PDF, Image available in the PDF document]

[0154] In certain embodiments, provided is a compound of Formula IIe-4 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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 -<com:Math><semantics>C(R8)2<annotation encoding="application / x-tex">C(R^8)_2< / annotation>< / semantics>< / com:Math>-; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl or -S(O)<com:Sub>2< / com:Sub>-C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl.

[0155] In certain embodiments, provided is a compound of Formula IIf: [Image disponible dans le document PDF, Image available in the PDF document] If or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -<com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0156] In certain embodiments, the compound is of Formula IIf or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0157] In certain embodiments, the compound is of Formula IIf wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>ℂ1<annotation encoding="application / x-tex">\mathbb{C}_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>ℂ6<annotation encoding="application / x-tex">\mathbb{C}_6< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>8< / com:Sup> is independently H, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; provided that at least one of the following occurs: (1) at least one of R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are halo or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> together with the carbon atoms to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is absent or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>, and two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−C(R6)2<annotation encoding="application / x-tex">-C(R^6)_2< / annotation>< / semantics>< / com:Math>; and two <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

[0158] In certain embodiments, provided is a compound of Formula IIf or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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(<com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>-; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl or -<com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0159] In certain embodiments, the compound is of Formula IIf-1: [Image disponible dans le document PDF, Image available in the PDF document] ___-1 wherein or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_{2-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR^{7}< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^{8})_{2-}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is H or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H, halo, or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo or optionally substituted alkyl.

[0160] In certain embodiments, 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. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIf-2 IIf-3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] IIf-4 IIf-5 [Image disponible dans le document PDF, Image available in the PDF document] Пf-6

[0161] In certain embodiments, provided is a compound of Formula IIf-4 or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R<com:Sup>6< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>6< / com:Sup> together with the carbon atom to which they are attached, form a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> are independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or R<com:Sup>3< / com:Sup> and R<com:Sup>4< / com:Sup> together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R<com:Sup>3< / com:Sup> and R<com:Sup>6< / com:Sup> 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(<com:Math><semantics>ℝ8<annotation encoding="application / x-tex">\mathbb{R}^8< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>-; each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and each R<com:Sup>10< / com:Sup> is independently cyano, halo, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl or -S(O)<com:Sub>2< / com:Sub>-C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl.

[0162] In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>3< / com:Sup> is H. In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>4< / com:Sup> is optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is methyl.

[0163] In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is H.

[0164] In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>3< / com:Sup> is H. In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>4< / com:Sup> is optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is methyl.

[0165] In certain embodiments of compounds of Formula IIa, IIb, IIc, IId, IIe and IIf (or subformula thereof), R<com:Sup>3< / com:Sup> is H and R<com:Sup>4< / com:Sup> is H. In certain embodiments of compounds of Formula IIe-4 and IIe-5, R<com:Sup>3< / com:Sup> is H and <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H.

[0166] In certain embodiments of compounds of Formula I (or subformula thereof), 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.

[0167] In certain embodiments of compounds of Formula II (or subformula thereof), 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. In certain embodiments of compounds of Formula II (or subformula thereof), 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.

[0168] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is of the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>X10<annotation encoding="application / x-tex">X^{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X11<annotation encoding="application / x-tex">X^{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X12<annotation encoding="application / x-tex">X^{12}< / annotation>< / semantics>< / com:Math> are each S, O, N, <com:Math><semantics>CR13<annotation encoding="application / x-tex">CR^{13}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>NR13<annotation encoding="application / x-tex">NR^{13}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>X13<annotation encoding="application / x-tex">X^{13}< / annotation>< / semantics>< / com:Math> is C or N; and each <com:Math><semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics>< / com:Math> is independently H, halo, cyano or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0169] In certain embodiments, at least one of <com:Math><semantics>X10<annotation encoding="application / x-tex">X^{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X11<annotation encoding="application / x-tex">X^{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X12<annotation encoding="application / x-tex">X^{12}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CR13<annotation encoding="application / x-tex">CR^{13}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>NR13<annotation encoding="application / x-tex">NR^{13}< / annotation>< / semantics>< / com:Math> and at least one <com:Math><semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics>< / com:Math> is halo, cyano or optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl. In certain embodiments, at least one of <com:Math><semantics>X10<annotation encoding="application / x-tex">X^{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X11<annotation encoding="application / x-tex">X^{11}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X12<annotation encoding="application / x-tex">X^{12}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CR13<annotation encoding="application / x-tex">CR^{13}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>NR13<annotation encoding="application / x-tex">NR^{13}< / annotation>< / semantics>< / com:Math> and at least one <com:Math><semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics>< / com:Math> is halo. In certain embodiments, each <com:Math><semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics>< / com:Math> is independently H, fluoro, chloro, cyano or methyl.

[0170] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] wherein each ring may optionally substituted with one or more halo, cyano or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl.

[0171] In certain embodiments of compounds of Formula II (or subformula thereof), the A ring is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] 7

[0172] In certain embodiments of compounds of Formula I (or subformula thereof), L is absent, -O- or <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>; and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl. In certain embodiments of compounds of Formula I (or subformula thereof), L is -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>- and each R<com:Sup>8< / com:Sup> is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0173] In certain embodiments of compounds of Formula II (or subformula thereof), L is absent, -O- or -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>-; and each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> 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 absent, -O- or -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>-; and each R<com:Sup>8< / com:Sup> is independently H or two R<com:Sup>8< / com:Sup> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl.

[0174] In certain embodiments of compounds of Formula II (or subformula thereof), L is absent. In certain embodiments of compounds of Formula II (or subformula thereof), L is -O-. In certain embodiments of compounds of Formula II (or subformula thereof), L is -C(R<com:Sup>8< / com:Sup>)<com:Sub>2< / com:Sub>- and each R<com:Sup>8< / com:Sup> is independently H, halo, or optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or two R<com:Sup>8< / com:Sup> 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 <com:Math><semantics>−C(R8)2−<annotation encoding="application / x-tex">-C(R^8)_{2^-}< / annotation>< / semantics>< / com:Math> and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is independently H, or two <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl. In certain embodiments of compounds of Formula II (or subformula thereof), L is <com:Math><semantics>−C(R8)2<annotation encoding="application / x-tex">-C(R^8)_2< / annotation>< / semantics>< / com:Math>- and each <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is taken together with the carbon atom to which they are attached to form cyclopropyl.

[0175] In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>9< / com:Sup> is optionally substituted aryl. In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>9< / com:Sup> is phenyl optionally substituted with one or more halo, cyano or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl optionally substituted with halo. In certain embodiments of compounds of Formula I (or subformula thereof), R<com:Sup>9< / com:Sup> is phenyl.

[0176] In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>9< / com:Sup> is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments of compounds of Formula II (or subformula thereof), R<com:Sup>9< / com:Sup> 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.

[0177] In certain embodiments of compounds of Formula II (or subformula thereof), q is 0. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R<com:Sup>10< / com:Sup> is independently cyano, halo, optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl, or -S(O)<com:Sub>2< / com:Sub>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl. In certain embodiments of compounds of Formula II (or subformula thereof), q is 1 or 2; and each R<com:Sup>10< / com:Sup> is independently cyano, halo, methyl, or -S(O)<com:Sub>2< / com:Sub>-methyl.

[0178] In certain embodiments, the compound is of Formula III: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; wherein q is 0, 1 or 2; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_{1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_{6}< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with halo, hydroxy or cyano; <com:Math><semantics>X1<annotation encoding="application / x-tex">...

Claims

1. A compound of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2; X 6 , X 7 , and X 8 are each N or CH; X 9 X^9 is N; R 1 R^1 is H or C 1 C_1 - C 6 C_6 alkyl optionally substituted with deuterium, halo, hydroxy, or cyano; Y 2 Y^2 is -O- or -C( R 6 R^6 ) 2 -; each R 6 is independently H, halo, or optionally substituted C 1 -C 6 alkyl, or two R 6 together with the carbon atom to which they are attached form a C 1 -C 6 alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; R 3 and R 4 are independently H, halo, or optionally substituted C 1 -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, 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; A is an optionally substituted heteroaryl ring, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl; L is − C ( R 8 ) 2 -C(R^8)_2 , or is absent, − O 7 -O_7 , − S 7 -S_7 , − S ( O ) 7 -S(O)_7 , − S ( O ) 2 -S(O)_2 , or − N R 7 -NR^7 -; R 7 R^7 is H or optionally substituted C 1 C_1 - C 6 C_6 alkyl; each R 8 is independently H, halo, or optionally substituted C 1 -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, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; and each R 10 is independently cyano, halo, or optionally substituted alkyl; further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and / or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro; and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein the compound is of Formula (IIe) or (IIf): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

3. The compound of claim 2, wherein the compound is of Formula IIf-1 or IIe-1: [Image disponible dans le document PDF, Image available in the PDF document] IIf-1 [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

4. The compound of claim 2, wherein the compound is of Formula (IIe): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

5. The compound of claim 4, wherein the compound is of Formula IIe-2, Formula IIe-3, Formula IIe-4, Formula IIe-5, or Formula IIe-6: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

6. The compound of claim 5, wherein the compound is of Formula IIe-2 or IIe-4, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

7. The compound of claim 2, wherein the compound is of Formula IIf, or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

8. The compound of claim 7, wherein the compound is of Formula IIf-2, Formula IIf-3, Formula IIf-4, Formula IIf-5, or Formula IIf-6: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

9. The compound of any one of claims 1-8, wherein the A ring is an optionally substituted heteroaryl ring.

10. The compound of claim 9, wherein the A ring is an optionally substituted 5-membered heteroaryl ring.

11. The compound any one of claims 1-8, wherein A is phenyl.

12. The compound of any one of claims 1-8, wherein the A ring is: [Image disponible dans le document PDF, Image available in the PDF document] wherein each ring is optionally substituted with one or more halo, cyano or C 1 -C 6 alkyl.

13. The compound of any one of claims 1-8, wherein A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

14. The compound of claim 13, wherein A is pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl.

15. The compound of claim 13, wherein A is oxadiazolyl.

16. The compound of claim 13, wherein A is triazolyl.

17. The compound of any one of claims 1-16, wherein L is − C ( R 8 ) 2 -C(R^8)_2 -.

18. A compound of Formula V: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2; X 6 X^6 is N or C R 14 CR^{14} ; X 9 X^9 is N; R 1 is H, optionally substituted or optionally deuterated C 1 -C 6 alkyl; [Image disponible dans le document PDF, Image available in the PDF document] each R 6 is independently H, halo, or optionally substituted C 1 -C 6 alkyl; R 3 R^3 is H, halo, or optionally substituted C 1 C_1 - C 6 C_6 alkyl, or R 3 R^3 and R 6 R^6 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; [Image disponible dans le document PDF, Image available in the PDF document] each R 8 is independently H, halo, or optionally substituted C 1 -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 R^{10} is independently cyano, halo, optionally substituted C 1 C_1 - C 6 C_6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C 1 -C 6 alkoxy, or -S(O) 2 -C 1 -C 6 alkyl; and each R 14 is independently hydrogen, cyano, halo, C 1 -C 3 alkyl optionally substituted with halo, or C 1 -C 3 alkoxy optionally substituted with halo; wherein each optionally substituted pyridyl, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom's normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, -SH, thioxo, N-oxide, − S i ( R 100 ) 3 -Si(R^{100})_3 wherein each R 100 R^{100} is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,-OC(O)R, and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; and further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and / or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro; and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

19. The compound of claim 18, wherein the compound of Formula V is represented by Formula Va: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

20. The compound of claim 18 or claim 19, wherein R 14 is hydrogen, cyano, halo or methyl optionally substituted with 1-3 fluoro or oxo.

21. A compound of Formula VI: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein q is 0, 1, or 2; X 6 X^6 is N or C R 14 CR^{14} ; R 1 R^1 is H, optionally substituted C 1 C_1 - C 6 C_6 alkyl, or optionally deuterated C 1 C_1 - C 6 C_6 alkyl; Y 2 Y^2 is -O- or -C( R 6 R^6 ) 2 -; each R 6 is independently H, halo, or optionally substituted C 1 -C 6 alkyl; R 3 R^3 is H, halo, or optionally substituted C 1 C_1 - C 6 C_6 alkyl, or R 3 R^3 and R 6 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 -C(R^8)_2 -; each R 8 is independently H, halo, or optionally substituted C 1 -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 aryl; each R 10 is independently halo, optionally substituted C 1 -C 6 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted C 1 -C 6 alkoxy; and R 14 is hydrogen, cyano, halo, C 1 -C 3 alkyl optionally substituted with halo or oxo, or C 1 -C 3 alkoxy optionally substituted with halo or oxo, wherein each optionally substituted pyridyl, optionally substituted C 1 C_1 - C 6 C_6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the designated atom's normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, -SH, thioxo, N-oxide, − S i ( R 100 ) 3 -Si(R^{100})_3 wherein each R 100 R^{100} is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,-OC(O)R, and -C(O)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; and further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties and / or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro; and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

22. The compound of any one of claims 19-21, wherein X 6 X^6 is C R 14 CR^{14} .

23. The compound of any one of claims 19-21, wherein X 6 X^6 is N N .

24. The compound of claim 21 or claim 22, wherein R 14 is hydrogen.

25. The compound of any one of claims 1-24, wherein R 1 R^1 is C 1 C_1 - C 6 C_6 alkyl.

26. The compound of claim 25, wherein R 1 is methyl.

27. The compound of any one of claims 1, 18, and 21, wherein Y 2 Y^2 is O.

28. The compound of any one of claims 1, 18, and 21, wherein R 3 is hydrogen or fluoro.

29. The compound of claim 28, wherein R 3 is H.

30. The compound of any one of claims 1, 18, and 21, wherein R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl.

31. The compound of claim 30, wherein R 3 and R 6 together with the carbon atoms to which they are attached form an optionally substituted cyclopropyl ring.

32. The compound of any one of claims 1-17, wherein R 4 R^4 is optionally substituted C 1 C_1 - C 6 C_6 alkyl.

33. The compound of claim 32, wherein R 4 is methyl.

34. The compound of any one of claims 1-17, wherein R 4 is H.

35. The compound of any one of claims 1-34, wherein L is − C ( R 8 ) 2 -C(R^8)_2 - and each R 8 R^8 is independently H, or two R 8 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl.

36. The compound of claim 35, wherein L is − C ( R 8 ) 2 -C(R^8)_2 - and two R 8 R^8 together with the carbon atom to which they are attached, form a cycloalkyl ring.

37. The compound of claim 36, wherein L is − C ( R 8 ) 2 -C(R^8)_2 - and two R 8 R^8 are taken together with the carbon atom to which they are attached to form cyclopropyl.

38. The compound of any one of claims 1-35, wherein L is CH 2 .

39. The compound of any one of claims 1-17, wherein R 9 is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl.

40. The compound of claim 39, wherein 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.

41. The compound of claim 39, wherein R 9 is optionally substituted aryl.

42. The compound of claim 39, wherein R 9 is phenyl optionally substituted with one or more halo, cyano, or C 1 C_1 - C 6 C_6 alkyl optionally substituted with halo.

43. The compound of claim 42, wherein R 9 is phenyl substituted by one to two halo.

44. The compound of any one of claims 1-39, wherein R 9 is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl.

45. The compound of any one of claims 1-44, wherein each R 10 is independently halo.

46. The compound of claim 45, wherein each R 10 is independently fluoro.

47. The compound of any one of claims 1-46, wherein q is 2.

48. A compound that is selected from: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof.

49. A compound having the following structure: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - - - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 447 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 448 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 452 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 453 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 454 [Image disponible dans le document PDF, Image available in the PDF document] • or a tautomer, stereoisomer, or mixture stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

50. The compound of claim 49, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] or a tautomer, stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

51. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] •52. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document]53. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] •54. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] •55. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document]56. The compound of claim 50, or pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document]57. A pharmaceutical composition comprising the compound, tautomer, stereoisomer or mixture of stereoisomers, or pharmaceutically acceptable salt thereof, as defined in any one of claims 1-56 and an excipient.

58. Use of the compound as defined in any one of claims 1 to 56, or the pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, or the pharmaceutical composition as defined in claim 57, in the manufacture of a medicament for the treatment of a receptor-interacting protein kinase 1-mediated disease or disorder.

59. The use of claim 58, wherein the disease or disorder is an inflammatory disease or disorder, a necrotic cell disease, a neurodegenerative disease, a central nervous system disease, an ocular disease, a malignancy, an immune-mediated disease, an allergic disease, an autoimmune disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, 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, myocardial or cardiac infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher's disease, Krabbe disease, Niemann- Pick disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's Disease), HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, brain injury, spinal cord injury, dementia, Huntington's disease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, Friedreich's ataxia, Lewy body disease, or a prion disorder.

60. The use of claim 59, wherein the disease or disorder is multiple sclerosis, amyotrophic lateral sclerosis (ALS / Lou Gehrig's Disease), Alzheimer's disease, rheumatoid arthritis, or psoriasis.