Didehydro-3 '-deoxy-4'-ethynylthymidine and related compounds and their use in treatment of medical conditions

Abstract

The present invention provides substituted 2 ', 3'-didehydro-3 '-deoxy-4'-ethynyl thymidine and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase activity, their use for inhibiting HERV-K reverse transcriptase activity, and their use in the treatment of medical conditions such as cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 333,914, filed April 22, 2022, the entire disclosure of which is incorporated herein by reference in its entirety.

[0003] Reference Electronic Sequence Listing

[0004] This application contains a sequence listing, which was submitted electronically via the Patent Center in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on April 21, 2023, is named 199646_seqlist.xml, and is 2,700 bytes in size. Technical Field

[0005] The present invention provides substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidines and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase activity, their use for inhibiting HERV-K reverse transcriptase activity, and their use in treating medical conditions such as cancer. Background Art

[0006] Despite the extensive research and scientific progress reported in the literature on cancer treatment, the disease remains a significant health problem. Solid tumors, including prostate, breast, and lung cancer, remain common in the world's population. Leukemias and lymphomas also account for a significant portion of new cancer diagnoses. Current treatment options for these cancers are not effective for all patients and / or may result in severe adverse side effects. New therapies are needed to address this unmet need in cancer treatment.

[0007] Therefore, there is a need for new therapeutic approaches that provide improved efficacy and / or reduced side effects for treating medical conditions such as cancer.The present invention satisfies the above needs and provides other related advantages. Summary of the Invention

[0008] The present invention provides substituted 2',3'-didehydro-3'-deoxy-4'-ethynyl thymidines and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase activity, their use for inhibiting HERV-K reverse transcriptase activity, and their use in treating medical conditions such as cancer. Specifically, one aspect of the present invention provides a collection of substituted 2',3'-didehydro-3'-deoxy-4'-ethynyl thymidines and related compounds, such as compounds represented by Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the Detailed Description. Further description of additional classes of substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidines and related compounds is described in the Detailed Description. The compound may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0011] Another aspect of the present invention provides a method for treating a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the condition, as further described in the detailed description.

[0012] Another aspect of the present invention provides a method for treating a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions other than viral infections. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II to treat the condition; wherein Formula II is represented by:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Additional features of the methods are described in the detailed description.

[0015] Another aspect of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity, comprising contacting the LINE1 reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula I, to inhibit the activity of the LINE1 reverse transcriptase, as further described in the detailed description.

[0016] Another aspect of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a condition selected from the group consisting of cancer, an inflammatory condition, a neurodegenerative condition, and an immune condition other than a viral infection. The method comprises contacting the LINE1 reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula II, to inhibit the activity of the LINE1 reverse transcriptase, as further described in the specific embodiments.

[0017] Another aspect of the present invention provides a method for inhibiting HERV-K reverse transcriptase activity. The method comprises contacting the HERV-K reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula I, to inhibit the activity of the HERV-K reverse transcriptase, as further described in the specific embodiments.

[0018] Another aspect of the present invention provides a method for inhibiting the activity of HERV-K reverse transcriptase in a subject having a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions other than viral infections. The method comprises contacting the HERV-K reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula II, to inhibit the activity of the HERV-K reverse transcriptase, as further described in the specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is a graph depicting inhibition of LINE1 reverse transcriptase by test compounds in an artificial intron cis-LINE1 reporter gene assay, as described in Example 5. DETAILED DESCRIPTION

[0020] The present invention provides substituted 2', 3'-didehydro-3'-deoxy-4'-ethynyl thymidine and related compounds, pharmaceutical compositions, their uses for inhibiting LINE1 reverse transcriptase activity, their uses for inhibiting HERV-K reverse transcriptase activity, and their uses in treating medical conditions such as cancer. Unless otherwise indicated, the practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant technology), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, ed., 1991-1992); "Handbook of experimental immunology" (DM Weir & C.C. Blackwell, ed.); "Current protocols in molecular biology" (FM Ausubel et al., ed., 1987, and periodic updates); and "Current protocols in immunology" (JE Coligan et al., ed., 1991), each of which is incorporated herein by reference in its entirety.

[0021] The following subsections set forth various aspects of the present invention; however, the aspects of the present invention described in a particular section are not limited to any particular section. In addition, when a variable is not accompanied by a definition, the previous definition of the variable shall prevail.

[0022] definition

[0023] The compounds of the present invention include those compounds generally described herein and further described by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. Unless otherwise indicated, these definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" as well as "-O-alkyl" and the like. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0024] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "cycloaliphatic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0025] As used herein, the term "bicyclic" or "bicyclic ring system" refers to any bicyclic ring system having one or more common atoms between the two rings of the ring system, saturated or having one or more unsaturated units, i.e., carbocyclic or heterocyclic. Therefore, the term includes any allowed ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a "bicyclic" subgroup that requires one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present in the ring junction and are optionally substituted and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge bond, saturated or partially unsaturated, i.e., carbocyclic or heterocyclic. As defined by IUPAC, a "bridge" is a non-branched chain or an atom or a valence bond connecting multiple atoms of two bridgeheads, wherein a "bridgehead" is any backbone atom bonded to a ring system of three or more backbone atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups listed below, wherein each group is connected to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic groups include:

[0026]

[0027] Exemplary bridged double rings include:

[0028]

[0029] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0030] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0031] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0032] The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

[0033] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to divalent alkylene, alkenylene and alkynylene chains as defined herein that are straight or branched.

[0034] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. Substituted alkylene chains are polymethylene chains in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0035] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C0 alkylene)-" 0-3 Alkylene)-" encompasses bonds (i.e., C0) and -(C 1-3 alkylene)-group.

[0036] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0037] The term "halogen" means F, Cl, Br or I.

[0038] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkyloxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may bear one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, and the like. Groups in which an aromatic ring is fused to one or more non-aromatic rings (such as dihydroindanyl, phthalimide, naphthimide, phenanthridinyl, or tetrahydronaphthyl, etc.) are also included within the scope of the term "aryl" as used herein. The term "phenylene" refers to a polyvalent phenyl group with an appropriate number of open valences to account for the groups to which it is attached. For example, "phenylene" is a divalent phenyl group (e.g., ); "Phenylene" when it has three groups attached to it, is a trivalent phenyl group (e.g., ). The term "arylene" refers to a divalent aromatic group.

[0039] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the ring arrangement; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaromatic-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein, unless otherwise specified, an attachment group or point is located on the heteroaromatic ring or on one of the rings fused to the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl and tetrahydroisoquinolyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0040] The term "heteroarylene" refers to a polyvalent heteroaryl group with an appropriate number of open valences to account for the groups attached to it. For example, "heteroarylene" is a divalent heteroaryl group when it has two groups attached to it, and "heteroarylene" is a trivalent heteroaryl group when it has three groups attached to it. The term "pyridinylene" refers to a polyvalent pyridine group with an appropriate number of open valences to account for the groups attached to it. For example, "pyridinylene" is a divalent pyridine group (e.g., ); "Pyridyl" is a trivalent pyridine radical when it has three groups attached to it (e.g., ).

[0041] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety which may be saturated or partially unsaturated and which has one or more (preferably one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used with respect to a ring atom of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0042] Heterocycle can be connected to its side group at any heteroatom or carbon atom that produces stable structure, and any one of ring atoms can be optionally substituted.The example of such saturated or partially unsaturated heterocyclic radical includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic group" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinium, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl portion and the heterocyclyl portion are independently optionally substituted. The term "oxoheterocyclyl" refers to a heterocyclyl substituted with an oxo group. The term "heterocyclylene" refers to a polyvalent heterocyclyl group having an appropriate number of open valences to account for the groups attached thereto. For example, "heterocyclylene" is a divalent heterocyclyl group when two groups are attached thereto; "heterocyclylene" is a trivalent heterocyclyl group when three groups are attached thereto.

[0043] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0044] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Typically, whether or not the term "optionally" is present, the term "substituted" means that one or more hydrogens of the designated moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure can be substituted by more than one substituent selected from a specified group, the substituents may be the same or different at each position. The substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow compound preparation, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0045] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2); 0–4 R°;–(CH2) 0–4 OR°; -O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR°;–(CH2) 0–4 CH(OR°)2;–(CH2) 0– 4SR°;–(CH2) 0–4 Ph, which may be substituted by R°; –(CH2) 0–4 O(CH2) 0–1 Ph, which may be substituted by R°; –CH=CHPh, which may be substituted by R°; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be substituted by R°; –NO2; –CN; –N3; -(CH2) 0–4 N(R°)2;–(CH2) 0–4 N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2) 0–4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2) 0–4 N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; –N(R°)N(R°)C(O)OR°; –(CH2) 0–4 C(O)R°; –C(S)R°; –(CH2) 0–4 C(O)OR°;–(CH2) 0–4 C(O)SR°;-(CH2) 0–4 C(O)OSiR°3;–(CH2) 0–4OC(O)R°;–OC(O)(CH2) 0–4 SR–, SC(S)SR°;–(CH2) 0–4 SC(O)R°;–(CH2) 0–4 C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2) 0–4 OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2) 0–4 SSR°; -(CH2) 0–4 S(O)2R°;–(CH2) 0–4 S(O)2OR°;–(CH2) 0–4 OS(O)2R°; –S(O)2NR°2; –S(O)(NR°)R°; –S(O)2N=C(NR°2)2; –(CH2) 0–4 S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; –P(O)R°2; –OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C 1–4 linear or branched alkylene)O–N(R°)2; or –(C 1–4 linear or branched alkylene) C(O)O–N(R°)2.

[0046] Each R° is independently hydrogen, C 1–6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaromatic ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted on the saturated carbon atom of R° with a divalent substituent selected from ═O and ═S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2) 0–2 R ● 、–(halogen R ● ),–(CH2) 0–2 OH, –(CH2) 0–2 OR ● 、–(CH2) 0–2 CH(OR ● )2;-O(halogen R ●), –CN, –N3, –(CH2) 0–2 C(O)R ● 、–(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ● 、–(CH2) 0–2 SR ● 、–(CH2) 0–2 SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR ● 、–(CH2) 0–2 NR ● 2. –NO2, –SiR ● 3. –OSiR ● 3. -C(O)SR ● 、–(C 1–4 linear or branched alkylene)C(O)OR ● or –SSR ● .

[0047] Each R ● Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ● unsubstituted or, when preceded by a halo, substituted only with one or more halogens; or wherein the optional substituents on a saturated carbon are divalent substituents independently selected from: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、–O(C(R * 2)) 2–3 O–or–S(C(R * 2)) 2–3 S—, or a divalent substituent attached to an ortho-substitutable carbon of an “optionally substituted” group is —O(CR * 2) 2–3 O–, where each independent occurrence of R * Selected from hydrogen, C 1–6 An aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0048] When R * C1–6 When aliphatic, R * Optionally halogen, –R ● 、-(halogen R ● ),-OH, –OR ● 、–O(halogen R ● ), –CN, –C(O)OH, –C(O)OR ● , –NH2, –NHR ● ,–NR ● 2 or –NO2, where each R ● Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ● It is unsubstituted or, when preceded by a halo group, is substituted only by one or more halo groups.

[0049] The optional substituents on the substitutable nitrogen are independently

[0050] or Each of these are independently hydrogen, C 1–6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with their intervening atoms, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when C 1–6 When aliphatic, Optionally halogen, –R ● 、-(halogen R ● ),-OH, –OR ● 、–O(halogen R ● ), –CN, –C(O)OH, –C(O)OR ● , –NH2, –NHR ● ,–NR ● 2 or –NO2, where each R ● Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ●It is unsubstituted or, when preceded by a halo group, is substituted only by one or more halo groups.

[0051] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with human and lower animal tissues without producing excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment and with a commensurate and reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0052] In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic pharmaceutical compounds have been discussed, for example, by P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, DC Con their website). The disclosures of these are incorporated herein by reference.

[0053] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Further pharmaceutically acceptable salts include (when appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0054] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as mixtures of enantiomers, diastereoisomers, and geometric (or conformational) isomers of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of a hydrogen by deuterium or tritium, or replacement of a carbon by 13 C- or 14 Compounds having the structures of the present invention that are C-enriched and substituted with carbon atoms are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0055] A mixture of diastereoisomers can be separated into their individual diastereomers by known methods (such as, for example, by chromatography and / or fractional crystallization) based on their physicochemical differences. Enantiomer mixtures can be converted into diastereoisomer mixtures by reacting with appropriate optically active compounds (e.g., chiral auxiliary agents, such as chiral alcohols or methoxy-trifluoromethylphenylacetyl chloride (Mosher'sacid chloride)), separating diastereomers and converting (e.g., hydrolyzing) individual diastereomers into corresponding pure enantiomers to separate enantiomers. Alternatively, specific enantiomers of the compounds of the present invention can be prepared by asymmetric synthesis. Further, when a molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxylic acid), diastereomeric salts are formed with appropriate optically active acids or bases, and the formed diastereomers are then separated by fractional crystallization or chromatographic means known in the art, and the pure enantiomers are subsequently recovered.

[0056] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.

[0057] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound, and there is an ambiguity between the structure and the name, the structure controls. It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein are assumed to have the sufficient number of hydrogen atoms to satisfy the valences.

[0058] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0059] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C 12 Alkyl, C1-C 10Alkyl and C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0060] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbon atoms derived from a cycloalkane, referred to herein as, for example, "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0061] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0062] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0063] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length that may replace the alkyl groups described above, but that contain at least one double or triple bond, respectively.

[0064] The term "carbocyclylene" refers to a multivalent carbocyclyl group with an appropriate number of open valences to account for the groups to which it is attached. For example, "carbocyclylene" is a divalent carbocyclyl group when two groups are attached to it, and "carbocyclylene" is a trivalent carbocyclyl group when three groups are attached to it.

[0065] The term "alkoxy" or "alkoxy" is art-recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc.

[0066] The term "oxo" is art-recognized and refers to a "=0" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0067] symbol Indicates an attachment point.

[0068] When a chemical structure containing a ring is depicted with a substituent having a bond that spans a ring bond, the substituent may be attached at any available position on the ring. For example, the chemical structure Covered In the context of polycyclic fused rings, when a chemical structure containing a polycyclic fused ring is described as having one or more substituents that span multiple rings, the one or more substituents can be independently attached to any ring spanned by the bond. For example, the chemical structure Covering e.g.

[0069] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0070] One or more compounds of the present invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to include both solvated and unsolvated forms. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. This physical connection involves varying degrees of ionization and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. "Hydrate" refers to a solvate in which the solvent molecule is H2O.

[0071] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), and most preferably include humans.

[0072] The term "IC 50 ” is art-recognized and refers to the concentration of compound required to achieve 50% inhibition of the target.

[0073] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventive result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treat" includes any effect, such as alleviating, reducing, regulating, improving, or eliminating, thereby improving a condition, disease, disorder, or the like, or improving its symptoms.

[0074] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0075] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier such as phosphate buffered saline solution, water, emulsions (e.g., such as oil / water emulsions or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0076] For therapeutic use, salts of the compounds of the invention are considered pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0077] In addition, when the compounds of the present invention contain both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the present invention can be formed, for example, by reacting the compounds of the present invention with an amount of acid or base (such as an equal amount) in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0078] Throughout this specification, where compositions are described as having, including, or comprising particular components, or where processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additionally compositions of the invention consisting essentially of, or consisting of, those components, and that there are processes and methods of the invention consisting essentially of, or consisting of, those process steps.

[0079] Generally, percentages of compositions specified are by weight unless otherwise specified.

[0080] I. Substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine and Related Compounds

[0081] The present invention provides substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine and related compounds. The compounds can be used in the pharmaceutical compositions and treatment methods described herein. The following sections describe exemplary compounds and exemplary procedures for preparing the compounds.

[0082] One aspect of the present invention provides a compound represented by Formula I:

[0083]

[0084] or a pharmaceutically acceptable salt thereof; wherein:

[0085] R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 ;

[0086] R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen; or

[0087] R 2 and R 4 , or R 2 Two examples of, together with their intervening atoms, form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 Replace p instances of ;

[0088] R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0089] R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0090] R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring;

[0091] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0092] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2;

[0093] R 8is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 m instances of substituted; and wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0094] m and p are independently 0, 1, 2, or 3 at each occurrence; and

[0095] n is 1, 2 or 3.

[0096] The definitions of the variables in Formula I above encompass a variety of chemical groups. This application contemplates embodiments in which, for example, i) a variable is defined as a single chemical group selected from those described above, ii) a variable is defined as a set of two or more chemical groups selected from those described above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0097] In certain embodiments, the compound is a compound of Formula I.

[0098] As generally defined above, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 .

[0099] In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2 or -P(O)(N(R 3 )(R 4 ))2. In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -P(O)(N(R 3 )(R 4 ))2. In certain embodiments, R 1 -P(O)(OR 2 )2 or -P(O)(N(R 3 )(R 4 ))2.

[0100] In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))or-P(O)(OR 2 )2. In certain embodiments, R 1 -C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 .

[0101] In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4)). In certain embodiments, R 1 -P(O)(OR 2 )2. In certain embodiments, R 1 -P(O)(N(R 3 )(R 4 ))2. In certain embodiments, R 1 -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 -C(O)R 8 .

[0102] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0103] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0104] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0105] In certain embodiments, R 1 for

[0106]

[0107] In certain embodiments, R 1 for

[0108] In certain embodiments, R 1 for

[0109] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0110] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0111] In certain embodiments, R 1 for In certain embodiments, R 1 A group selected from the group depicted for the compounds in Tables 1, 2, 3, 4 and 5 below.

[0112] As generally defined above, R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen; or R 2 and R 4 , or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 .

[0113] In certain embodiments, R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R 7m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 , or R 2 The two examples of are taken together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring.

[0114] In certain embodiments, R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents phenyl or naphthyl; each of which is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0115] In certain embodiments, R 2 Each occurrence independently represents phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R 2 Each occurrence independently represents phenyl or naphthyl. In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0116] In certain embodiments, R 2 To be R 7 In certain embodiments, R 2 for In certain embodiments, R 2 To be R 7 In certain embodiments, R 2Each occurrence independently represents a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl is replaced by R 7 Replace m instances of .

[0117] In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 Each occurrence independently represents an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0118] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; wherein the C 1-20 Alkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is additionally selected from hydrogen; or R 2Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 .

[0119] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10Each of the alkyl groups is optionally substituted with one hydroxy group.

[0120] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0121] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is additionally selected from hydrogen.

[0122] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 alkylene)-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-10 alkyl) or -CH2-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-6 alkyl) or -CH2-OC(O)-N(H)-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 3-5 Cycloalkyl) or -CH2-OC(O)-N(H)-(C 3-5 cycloalkyl).

[0123] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 3-5 cycloalkyl).

[0124] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 alkylene)-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(R 9 )-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(R 9 )-(C 3-5 cycloalkyl).

[0125] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted.

[0126] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with a hydroxy group.

[0127] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one methylene unit in each of the alkyl groups is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one methylene unit in each of the alkyl groups is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10In certain embodiments, one methylene unit in each of the alkyl groups is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with a hydroxy group.

[0128] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one of the methylene units in the alkyl group is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with a hydroxy group.

[0129] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one of the methylene units in the alkyl group is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with a hydroxy group.

[0130] In certain embodiments, R 2 Each occurrence represents a separate

[0131] In certain embodiments, R 2 Each occurrence represents a separate In certain embodiments, R 2 Each occurrence represents a separate

[0132] In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0133] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-20 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C1-20 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is replaced by an -O-(C 1-20 alkyl) substituted; and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen.

[0134] In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl), -(CH2)3-O-(C1-20 alkyl), -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl) or -(CH2)3-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl) or -(CH2)3-O-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is (CH2)3-O-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl) or -(CH2)3-S-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is (CH2)3-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen.

[0135] In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-20 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-7 In certain embodiments, R 2Each occurrence independently represents C optionally substituted with one hydroxyl group 1-4 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-20 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-10 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-4 Halogenated alkyl.

[0136] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0137] In certain embodiments, R 2 Each occurrence represents C independently 1-20 In certain embodiments, R 2 Each occurrence represents C independently 1-7 In certain embodiments, R 2 Each occurrence represents C independently 1-4 In certain embodiments, R 2 Each occurrence represents C independently 1-20 In certain embodiments, R 2 Each occurrence represents C independently 1-10 In certain embodiments, R 2 Each occurrence represents C independently1-4 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0138] In certain embodiments, R 2 Each occurrence represents a separate In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0139] In certain embodiments, R 2 and R 4 , or R 2 Two examples of, together with their intervening atoms, form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms they form a 4-7 membered saturated heterocyclic ring.

[0140] In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form 7In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle fused ortho to a benzene ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle fused ortho to the benzene ring; and wherein the benzene ring is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 10-membered bicyclic heterocycle; wherein said ring is a 6-membered monocyclic partially unsaturated heterocycle fused ortho to a benzene ring.

[0141] In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 5-6 membered heteroaromatic ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 6 membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 and R 4 Together with their intervening atoms they form a 10-membered bicyclic heterocycle; wherein said ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms.

[0142] In certain embodiments, R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 In certain embodiments, R 2The two instances of R together with their intervening atoms form 7 In certain embodiments, R 2 The two examples of are taken together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring.

[0143] In certain embodiments, R 2 The two instances of R together with their intervening atoms form 7 In certain embodiments, R 2 Two examples of together with their intervening atoms form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle fused ortho to a benzene ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of together with their intervening atoms form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a benzene ring; and wherein the benzene ring is R 7 In certain embodiments, R 2 The two examples of are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a benzene ring.

[0144] In certain embodiments, R 2 Two examples of the present invention are taken together with their intervening atoms to form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 5-6 membered heteroaromatic ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of the present invention are taken together with their intervening atoms to form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 6 membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of the present invention are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of EMI15.1 are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms.

[0145] In certain embodiments, R 2 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0146] As generally defined above, R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 3 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 3 Each occurrence represents C independently 1-4 alkyl.

[0147] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl; or R 3 and R 5 , or R 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0148] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0149] In certain embodiments, R 3 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0150] In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R 3 )(R 4 )for

[0151] As generally defined above, R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 Together with their intervening atoms, they form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 .

[0152] In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 Together with their intervening atoms they form a 4-7 membered saturated heterocyclic ring.

[0153] In certain embodiments, R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0154] In certain embodiments, R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkylene), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 For-(C1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0155] In certain embodiments, R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 In certain embodiments, R 4 Each occurrence represents a separate In certain embodiments, R 4 Each occurrence represents a separate In certain embodiments, R 4 Each occurrence represents a separate

[0156] In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 In certain embodiments, R 4 for

[0157] In certain embodiments, R 4 for

[0158] In certain embodiments, R 4 for

[0159] In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for

[0160] In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-20 In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-7 In certain embodiments, R 4 is C optionally substituted by one hydroxyl group 1-4 In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-20 In certain embodiments, R 4 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl), wherein the C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0161] In certain embodiments, R 4 C 1-20 In certain embodiments, R 4 C 1-7 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-20In certain embodiments, R 4 For-(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0162] In certain embodiments, R 4 For-(C 1-10 alkylene)-phenyl, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 In certain embodiments, R 4 For-(C 1-10 Alkylene)-phenyl, phenyl or naphthyl; wherein each of the phenyl and naphthyl groups is replaced by R 7 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0163] In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0164] In certain embodiments, R 4 For-(C 1-10 Alkylene)-phenyl, wherein the phenyl group is R 7 In certain embodiments, R 4 To be R 7 In certain embodiments, R 4 To be R 7 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 4 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 Replace m instances of .

[0165] In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 4 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0166] In certain embodiments, R 4 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0167] As generally defined above, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 Two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring; or R3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0168] In certain embodiments, R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0169] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 3-5 Cycloalkyl.

[0170] In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 Alkyl) or -SH substituted C 1-6 In certain embodiments, R 5 Each occurrence independently indicates that C 1-4 Alkoxy or hydroxy substituted C 1-6 alkyl.

[0171] In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 Alkyl) or -SH substituted C 1-6 In certain embodiments, R 5 For optionally C 1-4 Alkoxy or hydroxy substituted C 1-6 alkyl.

[0172] In certain embodiments, R 5 Each occurrence independently represents optionally phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 Each occurrence independently represents optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 Each occurrence independently represents C optionally substituted by phenyl or a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5Each occurrence independently represents C optionally substituted with 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0173] In certain embodiments, R 5 is optionally phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is optionally phenyl, C 3-7 Cycloalkyl or 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 5 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 is C optionally substituted by phenyl or a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is C optionally substituted by 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0174] In certain embodiments, R 5 For -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) or -SH substituted C 1-6 In certain embodiments, R 5 To be C 1-4 Alkoxy or hydroxy substituted C 1-6 alkyl.

[0175] In certain embodiments, R 5 For phenyl, C 3-7C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 For phenyl, C 3-7 Cycloalkyl or 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 5 Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 is C substituted by phenyl or a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is a C substituted 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0176] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 Each occurrence represents C independently 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 Alkyl; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring.

[0177] In certain embodiments, R 5Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 Each occurrence represents C independently 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0178] In certain embodiments, R 5 Each occurrence represents C independently 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0179] In certain embodiments, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 alkyl), phenyl or C3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) substituted C 1-6 In certain embodiments, R 5 C substituted by phenyl 1-6 In certain embodiments, R 5 To be C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0180] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-4 alkyl.

[0181] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-4 In certain embodiments, R 5 In certain embodiments, R 5 For hydrogen.

[0182] In certain embodiments, R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 The two instances of , together with the carbon atoms to which they are attached, form a 3-membered saturated carbocyclic ring.

[0183] In certain embodiments, R 5 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0184] As generally defined above, R 6 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group is substituted with a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0185] In certain embodiments, R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group is substituted with a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0186] In certain embodiments, R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 In certain embodiments, R 6 C 1-6 In certain embodiments, R 6 is a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0187] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0188] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C1-6 In certain embodiments, R 6 is C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0189] In certain embodiments, R 6 Each occurrence represents C independently 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 In certain embodiments, R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom is substituted.

[0190] In certain embodiments, R 6 Each occurrence represents C independently 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 In certain embodiments, R 6 C 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 cycloalkyl).

[0191] In certain embodiments, R 6 C 1-4 Alkyl, each occurrence independently represents C 3-5 In certain embodiments, R 6 Each occurrence represents C independently 1-4 In certain embodiments, R 6 Each occurrence independently represents a methyl group or an ethyl group. In certain embodiments, R 6 Each occurrence represents C independently 3-5 Cycloalkyl.

[0192] In certain embodiments, R 6 C 1-4 Alkyl or C 3-5 In certain embodiments, R 6 C 1-4 In certain embodiments, R 6 In certain embodiments, R 6 C 3-5 In certain embodiments, R 6 It is cyclobutyl.

[0193] In certain embodiments, R 6 Each occurrence represents C independently 3-5 Cycloalkyl, In certain embodiments, R 6 C 3-5 Cycloalkyl,

[0194] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 For optionally C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 is optionally phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by phenyl 1-6 In certain embodiments, R 6 For optionally C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0195] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 To be C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 For phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 C substituted by phenyl 1-6 In certain embodiments, R 6 To be C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is a C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0196] In certain embodiments, R 6 C 2-6 In certain embodiments, R 6 C 3-7 In certain embodiments, R 6 It is a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom.

[0197] In certain embodiments, R 6 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0198] As generally defined above, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2. In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0199] In certain embodiments, R7 Each occurrence independently represents a halo. In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents independently -N(R 9 )2. In certain embodiments, R 7 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0200] As generally defined above, R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 m instances of substituted; and wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0201] In certain embodiments, R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 In certain embodiments, R8 is phenyl or naphthyl; wherein the phenyl group is replaced by R 7 n instances of substituted and the naphthyl group is R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0202] In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0203] In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 8 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 Replace m instances of .

[0204] In certain embodiments, R 8 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0205] In certain embodiments, R 8C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 C substituted by hydroxyl 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0206] In certain embodiments, R 8 C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 8 C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0207] In certain embodiments, R 8 C substituted by a hydroxyl group 1-20 In certain embodiments, R 8 C substituted by a hydroxyl group 1-7 In certain embodiments, R 8 C substituted by a hydroxyl group 1-4 In certain embodiments, R 8 is C optionally substituted by a hydroxyl group 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-10 Alkylene)-OC(O)-(C1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl), wherein the C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0208] In certain embodiments, R 8 C 1-7 In certain embodiments, R 8 C 1-4 In certain embodiments, R 8 C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0209] In certain embodiments, R 8 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0210] As generally defined above, R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl, or R 9 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 9 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 9 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 9 Each occurrence represents C independently1-4 In certain embodiments, R 9 In certain embodiments, R 9 For hydrogen.

[0211] In certain embodiments, R 9 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 9 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0212] As generally defined above, m is independently 0, 1, 2, or 3 at each occurrence. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is independently 0 or 1 at each occurrence. In certain embodiments, m is independently 1 or 2 at each occurrence. In certain embodiments, m is independently 2 or 3 at each occurrence. In certain embodiments, m is independently 0, 1, or 2 at each occurrence. In certain embodiments, m is independently 1, 2, or 3 at each occurrence. In certain embodiments, m is selected from the values ​​represented by the compounds in Tables 1, 2, 3, 4, and 5 below.

[0213] As generally defined above, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is selected from the values ​​represented by the compounds in Tables 1, 2, 3, 4, and 5 below.

[0214] As generally defined above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values ​​represented by the compounds in Tables 1, 2, 3, 4, and 5 below.

[0215] The above description describes various embodiments in relation to compounds of formula I. All combinations of the embodiments are specifically contemplated by this patent application.

[0216] One aspect of the present invention provides a compound represented by formula I-1:

[0217]

[0218] or a pharmaceutically acceptable salt thereof; wherein:

[0219] R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 ;

[0220] R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 , or R 2 The two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring;

[0221] R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0222] R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0223] R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0224] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0225] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4alkoxy;

[0226] R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 m instances of substituted; and wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0227] m is independently 0, 1, 2, or 3 at each occurrence; and

[0228] n is 1, 2 or 3.

[0229] The definitions of the variables in Formula I-1 above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups described above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups described above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0230] In certain embodiments, the compound is a compound of formula 1-1.

[0231] As generally defined above, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 In certain embodiments, R1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))or-P(O)(OR 2 )2. In certain embodiments, R 1 -C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 .

[0232] In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )). In certain embodiments, R 1 -P(O)(OR 2 )2. In certain embodiments, R 1 -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 -C(O)R 8 .

[0233] In certain embodiments, R 1 for

[0234] In certain embodiments, R 1 for

[0235] In certain embodiments, R 1 for

[0236] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0237] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0238] In certain embodiments, R 1 for In certain embodiments, R 1 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 5 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0239] As generally defined above, R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 , or R 2 The two examples of are taken together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring.

[0240] In certain embodiments, R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents phenyl or naphthyl; each of which is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0241] In certain embodiments, R 2 Each occurrence independently represents phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R 2 Each occurrence independently represents phenyl or naphthyl. In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0242] In certain embodiments, R 2 To be R 7 In certain embodiments, R 2 for In certain embodiments, R 2 To be R 7 In certain embodiments, R 2Each occurrence independently represents a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 2 Each occurrence independently represents an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl is replaced by R 7 Replace m instances of .

[0243] In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 Each occurrence independently represents a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 Each occurrence independently represents an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0244] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0245] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0246] In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-20 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-7 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-4 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-20 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-10 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-4 Halogenated alkyl.

[0247] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0248] In certain embodiments, R 2 Each occurrence represents C independently 1-20In certain embodiments, R 2 Each occurrence represents C independently 1-7 In certain embodiments, R 2 Each occurrence represents C independently 1-4 In certain embodiments, R 2 Each occurrence represents C independently 1-20 In certain embodiments, R 2 Each occurrence represents C independently 1-10 In certain embodiments, R 2 Each occurrence represents C independently 1-4 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0249] In certain embodiments, R 2 Each occurrence represents a separate In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0250] In certain embodiments, R 2 and R 4 Together with their intervening atoms, they form a 4-7 membered saturated heterocyclic ring. 2 The two examples of are taken together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring.

[0251] In certain embodiments, R 2 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 2The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0252] As generally defined above, R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 3 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 3 Each occurrence represents C independently 1-4 alkyl.

[0253] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl; or R 3 and R 5 , or R 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0254] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0255] In certain embodiments, R 3 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 3 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0256] In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R 3 )(R 4 )for

[0257] As generally defined above, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 Together with their intervening atoms they form a 4-7 membered saturated heterocyclic ring.

[0258] In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 -C(H)(R 5 )-CO2R 6 、C1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0259] In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0260] In certain embodiments, R 4 -C(H)(R 5 )-CO2R 6 In certain embodiments, R 4 for

[0261] In certain embodiments, R 4 for

[0262] In certain embodiments, R 4 for

[0263] In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for

[0264] In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-20 In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-7 In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-4 In certain embodiments, R 4 is C optionally substituted by a hydroxyl group 1-20 In certain embodiments, R 4 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl), wherein the C 1-10Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 4 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl), wherein the C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0265] In certain embodiments, R 4 C 1-20 In certain embodiments, R 4 C 1-7 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-20 In certain embodiments, R 4 For-(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-S-(C 1-10 In certain embodiments, R 4 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0266] In certain embodiments, R 4 For-(C 1-10 alkylene)-phenyl, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 In certain embodiments, R 4 For-(C 1-10 Alkylene)-phenyl, phenyl or naphthyl; wherein each of the phenyl and naphthyl groups is replaced by R 7 In certain embodiments, R 4is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0267] In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0268] In certain embodiments, R 4 For-(C 1-10 Alkylene)-phenyl, wherein the phenyl group is R 7 In certain embodiments, R 4 To be R 7 In certain embodiments, R 4 To be R 7 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 4 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 Replace m instances of .

[0269] In certain embodiments, R 4 For-(C 1-10 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 4is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0270] In certain embodiments, R 2 and R 4 Together with their intervening atoms they form a 4-7 membered saturated heterocyclic ring.

[0271] In certain embodiments, R 4 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 4 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0272] As generally defined above, R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0273] In certain embodiments, R 5 C 1-6 Alkyl, C 1-6 In certain embodiments, R 5 C 1-6 Halogenated alkyl.

[0274] In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 Alkyl) or -SH substituted C 1-6 In certain embodiments, R 5 For optionally C 1-4Alkoxy or hydroxy substituted C 1-6 alkyl.

[0275] In certain embodiments, R 5 is optionally phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is optionally phenyl, C 3-7 Cycloalkyl or 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 5 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 is C optionally substituted by phenyl or a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is C optionally substituted by 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0276] In certain embodiments, R 5 For the -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) or -SH substituted C 1-6 In certain embodiments, R 5 To be C 1-4 Alkoxy or hydroxy substituted C 1-6 alkyl.

[0277] In certain embodiments, R 5 For phenyl, C 3-7C substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 For phenyl, C 3-7 Cycloalkyl or 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 5 Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 is C substituted by phenyl or a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 In certain embodiments, R 5 is a C substituted 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0278] In certain embodiments, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0279] In certain embodiments, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) substituted C 1-6 In certain embodiments, R 5 C substituted by phenyl 1-6 In certain embodiments, R 5 To be C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0280] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-4 In certain embodiments, R 5 In certain embodiments, R 5 For hydrogen.

[0281] In certain embodiments, R 5 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 5 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0282] As generally defined above, R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group is substituted with a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0283] In certain embodiments, R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 In certain embodiments, R 6 C 1-6 In certain embodiments, R 6is a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0284] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0285] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur substituted C 1-6 In certain embodiments, R 6 is C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur 1-6 alkyl.

[0286] In certain embodiments, R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom is substituted.

[0287] In certain embodiments, R 6 C 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 cycloalkyl).

[0288] In certain embodiments, R 6 C 1-4 Alkyl or C 3-5 In certain embodiments, R 6 C 1-4 In certain embodiments, R 6 In certain embodiments, R6 C 3-5 In certain embodiments, R 6 It is cyclobutyl.

[0289] In certain embodiments, R 6 C 3-5 Cycloalkyl,

[0290] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 For optionally C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 is optionally phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by phenyl 1-6 In certain embodiments, R 6 For optionally C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0291] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 To be C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 For phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 C substituted by phenyl 1-6 In certain embodiments, R 6 To be C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is a C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0292] In certain embodiments, R 6 C 2-6 In certain embodiments, R 6 C 3-7 In certain embodiments, R 6 It is a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom.

[0293] In certain embodiments, R 6 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 6 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0294] As generally defined above, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halo. In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 7 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0295] As generally defined above, R 8is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 m instances of substituted; and wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0296] In certain embodiments, R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the phenyl group is replaced by R 7 wherein each of the naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is substituted by R 7 In certain embodiments, R 8 is phenyl or naphthyl; wherein the phenyl group is replaced by R 7 n instances of substituted and the naphthyl group is R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace m instances of .

[0297] In certain embodiments, R 8 To be R 7In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0298] In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 To be R 7 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 In certain embodiments, R 8 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl group is replaced by R 7 Replace m instances of .

[0299] In certain embodiments, R 8 In certain embodiments, R 8 is a 5-6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8 is an 8-10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0300] In certain embodiments, R 8 C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 C substituted by hydroxyl 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0301] In certain embodiments, R 8 C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 8 C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0302] In certain embodiments, R 8 C substituted by a hydroxyl group 1-20 In certain embodiments, R 8 C substituted by a hydroxyl group 1-7 In certain embodiments, R 8 C substituted by a hydroxyl group 1-4 In certain embodiments, R 8 is C optionally substituted by a hydroxyl group 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 alkyl), wherein the C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 8 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl), wherein the C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0303] In certain embodiments, R 8 C 1-7 In certain embodiments, R 8 C 1-4 In certain embodiments, R 8 C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 8 For-(C 1-8 Alkylene)-S-(C 1-10 In certain embodiments, R 8 For-(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0304] In certain embodiments, R 8 is selected from the group depicted by the compounds in Tables 1 and 2 below. In certain embodiments, R 8 The values ​​indicated are for compounds selected from Tables 1, 2 and 3 below.

[0305] As generally defined above, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values ​​represented by the compounds in Tables 1 and 2 below. In certain embodiments, m is selected from the values ​​represented by the compounds in Tables 1, 2, and 3 below.

[0306] As generally defined above, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is selected from the values ​​represented by the compounds in Tables 1 and 2 below. In certain embodiments, n is selected from the values ​​represented by the compounds in Tables 1, 2, and 3 below.

[0307] The above description describes various embodiments related to compounds of formula 1- 1. All combinations of the embodiments are specifically contemplated by this patent application.

[0308] Another aspect of the present invention provides a compound represented by Formula IA:

[0309]

[0310] or a pharmaceutically acceptable salt thereof; wherein:

[0311] R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2;

[0312] R 2 is phenyl or naphthyl, each of which is replaced by R 7 Replace m instances of ;

[0313] R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0314] R 4 -C(H)(R 5 )-CO2R 6 ;

[0315] R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substitution,

[0316] R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by a cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom;

[0317] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4Haloalkyl or C 1-4 alkoxy; and

[0318] m is 0, 1, 2 or 3.

[0319] The definitions of the variables in Formula IA above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) a variable is defined as a single chemical group selected from those described above, ii) a variable is defined as a set of two or more chemical groups selected from those described above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0320] In certain embodiments, the compound is of Formula IA.

[0321] As generally defined above, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )).

[0322] In certain embodiments, R 1 -C(O)-C(H)(R 5 )-N(R 3 )2. In certain embodiments, R 1 for

[0323] In certain embodiments, R 1 for

[0324] In certain embodiments, R 1 for

[0325] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0326] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0327] In certain embodiments, R 1 for In certain embodiments, R 1 A group selected from the group depicted by the compounds in Tables 1 and 2 below.

[0328] In certain embodiments, R 1 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 1 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0329] As generally defined above, R 2 is phenyl or naphthyl; each of which is replaced by R 7 In certain embodiments, R 2 To be R 7 In certain embodiments, R 2 for In certain embodiments, R 2 To be R 7 m examples of substituted naphthyl.

[0330] In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2In certain embodiments, R 2 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 2 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0331] As generally defined above, R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 3 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 3 Each occurrence represents C independently 1-4 alkyl.

[0332] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl; or R 3 and R 5 , or R 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0333] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0334] In certain embodiments, R 3 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 3 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0335] In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R 3 )(R 4 )for In certain embodiments, -N(R3 )(R 4 )for

[0336] As generally defined above, R 4 -C(H)(R 5 )-CO2R 6 In certain embodiments, R 4 for

[0337] In certain embodiments, R 4 for

[0338] In certain embodiments, R 4 for

[0339] In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for

[0340] In certain embodiments, R 4 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 4 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0341] As generally defined above, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0342] In certain embodiments, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) substituted C 1-6 In certain embodiments, R 5 C substituted by phenyl 1-6 In certain embodiments, R 5 To be C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0343] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-4 In certain embodiments, R 5 In certain embodiments, R 5 For hydrogen.

[0344] In certain embodiments, R 5 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 5 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0345] As generally defined above, R6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom is substituted.

[0346] In certain embodiments, R 6 C 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 cycloalkyl).

[0347] In certain embodiments, R 6 C 1-4 Alkyl or C 3-5 In certain embodiments, R 6 C 1-4 In certain embodiments, R 6 In certain embodiments, R 6 C 3-5 In certain embodiments, R 6 It is cyclobutyl.

[0348] In certain embodiments, R 6 C 3-5 Cycloalkyl,

[0349] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 For optionally C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 is optionally phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R6 is C optionally substituted by phenyl 1-6 In certain embodiments, R 6 For optionally C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0350] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 To be C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 For phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 C substituted by phenyl 1-6 In certain embodiments, R 6 To be C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is a C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0351] In certain embodiments, R 6 C 2-6 In certain embodiments, R 6 C 3-7 In certain embodiments, R 6 It is a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom.

[0352] In certain embodiments, R 6 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 6 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0353] As generally defined above, R 7Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halo. In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 is selected from the group depicted by the compounds in Table 1 below. In certain embodiments, R 7 A group selected from the group depicted by the compounds in Tables 1 and 3 below.

[0354] As generally defined above, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is selected from the values ​​represented by the compounds in Table 1 below. In certain embodiments, m is selected from the groups depicted by the compounds in Tables 1 and 3 below.

[0355] The above description describes various embodiments associated with compounds of formula IA. All combinations of the embodiments are specifically contemplated by this patent application.

[0356] Another aspect of the present invention provides a compound represented by Formula IB:

[0357]

[0358] or a pharmaceutically acceptable salt thereof; wherein:

[0359] R 1 -P(O)(OR 2 )2 or -P(O)(N(R 3 )(R 4 ))2;

[0360] R 2 Each occurrence represents C independently1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is additionally selected from hydrogen; or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 Replace p instances of ;

[0361] R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0362] R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 ;

[0363] R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring;

[0364] R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by a cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom;

[0365] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2; and

[0366] P is 0, 1, 2 or 3.

[0367] The definitions of the variables in Formula IB above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) a variable is defined as a single chemical group selected from those described above, ii) a variable is defined as a set of two or more chemical groups selected from those described above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0368] In certain embodiments, the compound is of Formula IB.

[0369] As generally defined above, R 1 -P(O)(OR 2 )2 or -P(O)(N(R 3 )(R 4 ))2. In certain embodiments, R 1 -P(O)(OR 2 )2. In certain embodiments, R 1 -P(O)(N(R 3 )(R 4 ))2.

[0370] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0371] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for

[0372] In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 for In certain embodiments, R 1 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0373] As generally defined above, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; wherein the C 1-20 Alkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2An example of is additionally selected from hydrogen; or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 .

[0374] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group. 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C1-10 Each of the alkyl groups is optionally substituted with one hydroxy group.

[0375] In certain embodiments, R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents C independently 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0376] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is additionally selected from hydrogen.

[0377] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 alkylene)-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-10 alkyl) or -CH2-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-6 alkyl) or -CH2-OC(O)-N(H)-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 3-5 Cycloalkyl) or -CH2-OC(O)-N(H)-(C 3-5 cycloalkyl).

[0378] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)O-(C1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)O-(C 3-5 cycloalkyl).

[0379] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 alkylene)-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(H)-(C 1-10 Alkyl); wherein said C 1-10 One methylene unit in the alkyl group is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(R 9 )-(C 1-6 In certain embodiments, R 2 Each occurrence independently represents -CH2-OC(O)-N(R 9 )-(C 3-5 cycloalkyl).

[0380] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted.

[0381] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in each of the alkyl groups is replaced by C 3-5 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with a hydroxy group.

[0382] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one methylene unit in each of the alkyl groups is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one methylene unit in each of the alkyl groups is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with one hydroxy group; and wherein the C 1-10In certain embodiments, one methylene unit in each of the alkyl groups is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 alkyl) or -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 Each of the alkyl groups is substituted with a hydroxy group.

[0383] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one of the methylene units in the alkyl group is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -OC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with a hydroxy group.

[0384] In certain embodiments, R 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 One methylene unit in the alkyl group is optionally replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with one hydroxy group; and wherein the C 1-10 In certain embodiments, one of the methylene units in the alkyl group is replaced by a cyclopropylene group. 2 Each occurrence represents independently -(CH2) 1-2 -SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is substituted with a hydroxy group.

[0385] In certain embodiments, R 2 Each occurrence represents a separate

[0386] In certain embodiments, R 2 Each occurrence represents a separate In certain embodiments, R 2 Each occurrence represents a separate

[0387] In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0388] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-20 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C1-20 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein said C 1-10 Each of the alkylene groups is replaced by an -O-(C 1-20 alkyl) substituted; and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example of -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen.

[0389] In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl), -(CH2)3-O-(C1-20 alkyl), -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl) or -(CH2)3-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl) or -(CH2)3-O-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-O-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is (CH2)3-O-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl) or -(CH2)3-S-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is -CH2-C(H)(-O-(C 1-20 Alkyl))-CH2-S-(C 1-20 alkyl), and R 2 Any second instance of is hydrogen. In certain embodiments, R 2 An example is (CH2)3-S-(C 1-20 alkyl); and R 2 Any second instance of is hydrogen.

[0390] In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-20 In certain embodiments, R 2 Each occurrence independently represents C optionally substituted with one hydroxyl group 1-7 In certain embodiments, R 2Each occurrence independently represents C optionally substituted with one hydroxyl group 1-4 alkyl.

[0391] In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 Alkyl); wherein said C 1-10 Alkyl is optionally substituted with one hydroxyl group. In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein said C 1-10 The alkyl group is optionally substituted with one hydroxy group.

[0392] In certain embodiments, R 2 Each occurrence represents C independently 1-20 In certain embodiments, R 2 Each occurrence represents C independently 1-7 In certain embodiments, R 2 Each occurrence represents C independently 1-4 In certain embodiments, R 2 Each occurrence represents C independently 1-20 In certain embodiments, R 2 Each occurrence represents C independently 1-10 In certain embodiments, R 2 Each occurrence represents C independently 1-4 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 In certain embodiments, R2 Each occurrence represents independently -(C 1-10 Alkylene)-S-(C 1-10 In certain embodiments, R 2 Each occurrence represents independently -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl).

[0393] In certain embodiments, R 2 Each occurrence represents a separate In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for

[0394] In certain embodiments, R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 In certain embodiments, R 2 The two instances of R together with their intervening atoms form 7 In certain embodiments, R 2 The two examples of are taken together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring.

[0395] In certain embodiments, R 2 The two instances of R together with their intervening atoms form 7 In certain embodiments, R 2 Two examples of together with their intervening atoms form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle fused ortho to a benzene ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of together with their intervening atoms form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a benzene ring; and wherein the benzene ring is R 7 In certain embodiments, R 2 The two examples of are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a benzene ring.

[0396] In certain embodiments, R2 Two examples of the present invention are taken together with their intervening atoms to form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 5-6 membered heteroaromatic ring; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of the present invention are taken together with their intervening atoms to form a 7-12 membered bicyclic heterocycle; wherein the ring is a 5-7 membered monocyclic partially unsaturated heterocycle ortho-fused to a 6 membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of the present invention are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms; and wherein the bicyclic heterocycle is replaced by R 7 In certain embodiments, R 2 Two examples of EMI15.1 are taken together with their intervening atoms to form a 10-membered bicyclic heterocycle; wherein the ring is a 6-membered monocyclic partially unsaturated heterocycle ortho-fused to a 6-membered heteroaromatic ring containing one or two nitrogen atoms.

[0397] In certain embodiments, R 2 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0398] As generally defined above, R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 3 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 3 Each occurrence represents C independently 1-4 alkyl.

[0399] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl; or R 3 and R 5 , or R 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0400] In certain embodiments, R 3 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 3In certain embodiments, R 3 In certain embodiments, R 3 and R 5 Together with the atoms to which they are attached, they form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. 3 The two examples of are taken together with the atoms to which they are attached to form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom.

[0401] In certain embodiments, R 3 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0402] As generally defined above, R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 In certain embodiments, R 4 Each occurrence represents a separate In certain embodiments, R 4 Each occurrence represents a separate In certain embodiments, R 4 Each occurrence represents a separate

[0403] In certain embodiments, R 4 Each occurrence represents independently -C(H)(R 5 )-CO2R 6 In certain embodiments, R 4 Each occurrence represents a separate

[0404] In certain embodiments, R 4 Each occurrence represents a separate In certain embodiments, R 4 Each occurrence represents a separate

[0405] In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for In certain embodiments, R 4 for

[0406] In certain embodiments, R 4 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0407] As generally defined above, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring.

[0408] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 3-5 Cycloalkyl.

[0409] In certain embodiments, R 5Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 Each occurrence represents C independently 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 Alkyl; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring.

[0410] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 Each occurrence represents C independently 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 In certain embodiments, R 5 Each occurrence independently represents optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0411] In certain embodiments, R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4alkyl), phenyl or C 3-7 In certain embodiments, R 5 is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 5 For the -S-(C 1-4 Alkyl) substituted C 1-6 In certain embodiments, R 5 C substituted by phenyl 1-6 In certain embodiments, R 5 To be C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0412] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-4 alkyl.

[0413] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-4 In certain embodiments, R 5 In certain embodiments, R 5 For hydrogen.

[0414] In certain embodiments, R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring. In certain embodiments, R 5 The two instances of , together with the carbon atoms to which they are attached, form a 3-membered saturated carbocyclic ring.

[0415] In certain embodiments, R 5 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0416] As generally defined above, R 6Each occurrence represents C independently 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom is substituted.

[0417] In certain embodiments, R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 The cycloalkyl group or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom is substituted.

[0418] In certain embodiments, R 6 Each occurrence represents C independently 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 In certain embodiments, R 6 C 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 cycloalkyl).

[0419] In certain embodiments, R 6 C 1-4 Alkyl, each occurrence independently represents C 3-5 In certain embodiments, R 6 Each occurrence represents C independently 1-4 In certain embodiments, R 6 Each occurrence independently represents a methyl group or an ethyl group. In certain embodiments, R 6 Each occurrence represents C independently 3-5 Cycloalkyl.

[0420] In certain embodiments, R 6 C 1-4 Alkyl or C 3-5 In certain embodiments, R 6 C 1-4In certain embodiments, R 6 In certain embodiments, R 6 C 3-5 In certain embodiments, R 6 It is cyclobutyl.

[0421] In certain embodiments, R 6 Each occurrence represents C independently 3-5 Cycloalkyl, In certain embodiments, R 6 C 3-5 Cycloalkyl,

[0422] In certain embodiments, R 6 For optionally C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 For optionally C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R 6 is optionally phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 is optionally phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by phenyl 1-6 In certain embodiments, R 6 For optionally C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is C optionally substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0423] In certain embodiments, R 6 To be C 1-4 Alkoxy, phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 To be C 1-4 Alkoxy-substituted C 1-6 In certain embodiments, R6 For phenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom, substituted C 1-6 In certain embodiments, R 6 Phenyl or C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 C substituted by phenyl 1-6 In certain embodiments, R 6 To be C 3-7 Cycloalkyl substituted C 1-6 In certain embodiments, R 6 is a C substituted by a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom 1-6 alkyl.

[0424] In certain embodiments, R 6 C 2-6 In certain embodiments, R 6 C 3-7 In certain embodiments, R 6 is a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom. 6 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0425] As generally defined above, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2. In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In certain embodiments, R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0426] In certain embodiments, R 7 Each occurrence independently represents a halo. In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents C independently 1-4 In certain embodiments, R 7Each occurrence represents C independently 1-4 In certain embodiments, R 7 Each occurrence represents independently -N(R 9 )2. In certain embodiments, R 7 A group selected from the group depicted by the compounds in Tables 4 and 5 below.

[0427] As generally defined above, R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl, or R 9 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 9 Each occurrence independently represents hydrogen or C 1-4 In certain embodiments, R 9 Each occurrence independently represents hydrogen or methyl. In certain embodiments, R 9 Each occurrence represents C independently 1-4 In certain embodiments, R 9 In certain embodiments, R 9 For hydrogen.

[0428] In certain embodiments, R 9 The two instances of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom. In certain embodiments, R 9 A group selected from the group depicted by the compounds in Tables 1, 2, 3, 4 and 5 below.

[0429] As generally defined above, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 1, 2, or 3. In certain embodiments, p is selected from the values ​​represented by the compounds in Tables 4 and 5 below.

[0430] The above description describes various embodiments associated with compounds of formula IB. All combinations of the embodiments are specifically contemplated by this patent application.

[0431] In certain other embodiments, the compound is a compound in Table 1, 2, 3, 4, or 5 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, or 5 below. In certain other embodiments, the compound is a compound in Table 1, 2, or 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, or 3 below. In certain other embodiments, the compound is a compound in Table 1 or 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 below. In certain other embodiments, the compound is a compound in Table 4 or 5 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4 or 5 below.

[0432] Table 1.

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] Table 2.

[0440]

[0441]

[0442]

[0443]

[0444] Table 3.

[0445]

[0446]

[0447]

[0448]

[0449] Table 4.

[0450]

[0451]

[0452]

[0453] Table 5.

[0454]

[0456]

[0457] For example, methods for preparing 2',3'-didehydro-3'-deoxy-4'-ethynyl thymidine are provided in US 7,589,078; US 9,051,288; US 2016 / 0060252; and references therein. For example, methods for preparing phosphoramidate and phosphonate compounds described herein (e.g., from 2',3'-didehydro-3'-deoxy-4'-ethynyl thymidine) are provided in US 8,022,083; WO 2006 / 110157; WO 2006 / 015261; and related patents and applications (such as US 7,871,991; US ​​8,318,701 and US 8,329,926). For example, other strategies for preparing the phosphoramidate compounds described herein are described in Slusarczyk, M. et al. "Phosphoramidates and phosphonamidates (ProTides) with antiviral activity," Antiviral Chemistry and Chemotherapy (2018), Vol. 26, pp. 1-31, and references therein. Each of the foregoing references is hereby incorporated by reference in its entirety.

[0458] The following synthetic schemes and the following examples also illustrate methods for preparing the compounds described herein. These schemes are provided for the purpose of illustrating the present invention and are not intended to limit the scope or spirit of the invention. The starting materials shown in the schemes can be obtained from commercial sources or can be prepared according to procedures described in the literature.

[0459] In these schemes, it will be appreciated by those skilled in the art of organic synthesis that the functionality present on each part of the molecule should be compatible with the reagent and reaction proposed. Substituents incompatible with reaction conditions are apparent to those skilled in the art, and therefore alternative methods (e.g., using blocking groups or substitution reactions) have been described. Blocking group chemistry and strategy are well known in the art, for example, as described in detail in " Protecting Groups in Organic Synthesis ", TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference.

[0460] The synthetic route shown in Scheme 1 is a general method for preparing phosphoramidate compound C. An aromatic alcohol reacts with phosphorus oxychloride to produce intermediate A. Intermediate A reacts with an amino acid ester to produce phosphorus oxychloride intermediate B, which is coupled with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine to produce phosphoramidate compound C.

[0461] Solution 1.

[0462]

[0463] As shown in Scheme 2, the phosphorus oxychloride intermediate of Scheme 1 can be coupled with pentafluorophenol to provide intermediate A, which is further condensed with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine to provide phosphoramidate compound B. Intermediate A is initially a mixture of diastereomers that can be separated into each pure diastereomer by chromatography or recrystallization. Each pure diastereomer of intermediate A can then be condensed separately with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine to provide phosphoramidate compound B, which is stereochemically pure at the phosphorus stereocenter.

[0464] Option 2.

[0465]

[0466] The synthetic route shown in Scheme 3 is another general method for preparing phosphoramidate compounds E. Chiral auxiliary A is condensed with phosphorus oxychloride to provide dichloride intermediate B, which is further condensed with an aryl alcohol to provide intermediate C. Intermediate C is condensed with an amino acid ester to provide intermediate D, which can be used as a stereochemical mixture at the phosphorus position or can be separated into individual phosphorus diastereomers by chromatography. Intermediate D is reacted with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine to provide phosphoramidate compound E, which is either stereochemically pure or a mixture of diastereomers at the phosphorus position.

[0467] Option 3.

[0468]

[0469] Schemes 4 and 5 illustrate another general method for preparing phosphoramidate compound B. 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine undergoes a phosphite transesterification reaction to afford intermediate A, which is further reacted with an amino acid ester to afford the desired product B via oxidative amination.

[0470] Solution 4.

[0471]

[0472] Option 5.

[0473]

[0474] As shown in Scheme 6, the ester compounds described herein can be prepared by coupling 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine with an appropriate carboxylic acid, for example, using an amide coupling reagent such as DCC or HATU. To prepare amino acid esters, an N-protected amino acid (e.g., NBoc or NFmoc) can be used in the coupling reaction and then deprotected under appropriate conditions (e.g., acid deprotection for NBoc or base deprotection for NFmoc). Protecting group chemistry and strategies are well known in the art, for example, as described in detail in "Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference.

[0475] Option 6.

[0476]

[0477] The synthetic route shown in Scheme 7 is a general method for preparing the phosphate compounds described herein by condensing 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine with a dialkyl chlorophosphate.

[0478] Plan 7.

[0479]

[0480] The synthetic scheme shown in Scheme 8 is a general method for preparing dialkylphosphonates and related compounds E. Trimethylphosphonate A is alkylated with an electrophile B (wherein X is a leaving group such as chloride or sulfonate) under nucleophilic substitution conditions (using, for example, a polar aprotic solvent such as acetone, and optionally in the presence of NaI) to produce dialkylphosphonate C. Phosphate C is coupled with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine D (using, for example, amide coupling conditions such as BOPCl and NMI in a polar aprotic solvent such as acetonitrile) to produce dialkylphosphonate E.

[0481] Plan 8.

[0482]

[0483] The synthetic scheme shown in Scheme 9 is a general method for preparing phosphonate esters D. For example, PCl3, diisopropylamine and alcohol R are reacted in a polar aprotic solvent such as THF and in the presence of a base such as triethylamine. 2 OH (or diol, when R 2 ) to give aminophosphine A. Coupling of aminophosphine A with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine B (using, for example, tetrazole or pyridinium chloride in a polar aprotic solvent such as acetonitrile) provides phosphite C. Oxidation of phosphite C (using, for example, mCPBA or tert-butyl hydroperoxide in dichloromethane) provides phosphonate D.

[0484] Plan 9.

[0485]

[0486] The synthetic scheme shown in Scheme 10 is a general method for preparing dialkyl hydrogen phosphates F. Coupling of a chlorophosphonium reagent A with an alcohol B (using, for example, a base such as pyridine in a polar aprotic solvent such as 1,4-dioxane) followed by hydrolysis (using, for example, a base such as sodium bicarbonate with water and an organic solvent such as chloroform) provides an alkyl hydrogen phosphonate C. Coupling of hydrogen phosphonate C with 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine D (using, for example, an activating agent such as pivaloyl chloride and a base such as pyridine) provides dialkyl hydrogen phosphite E. Oxidation of E (using, for example, iodine in THF and water) provides dialkyl hydrogen phosphate F.

[0487] Plan 10.

[0488]

[0489] The synthetic scheme shown in Scheme 11 is a general method for preparing diaminophosphonates D. PCl3, aminoester B, and 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine A are coupled to give diaminophosphite C. Oxidation of C (using, for example, mCPBA in dichloromethane) gives diaminophosphonate D.

[0490] Plan 11.

[0491]

[0492] Those skilled in the art of organic synthesis can also readily modify the modular synthetic routes described herein and in the aforementioned references to provide additional substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine and related compounds using strategies and reactions well known in the art, for example, as described in "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992).

[0493] II. Methods of Treating Medical Conditions

[0494] Another aspect of the present invention provides a method for treating a medical condition, which is described in more detail below.

[0495] A. First treatment method

[0496] It is expected that the substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidines and related compounds described herein, such as compounds of Formula I, I-1, IA or IB or other compounds in Section I above, provide therapeutic benefits to subjects suffering from cancer and other conditions. Thus, one aspect of the present invention provides a method for treating a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described in Section I above, such as a compound of Formula I, I-1, IA or IB, to treat the condition. In certain embodiments, a specific compound of Formula I, I-1, IA or IB is a compound defined by one of the embodiments described in Section I above.

[0497] Viral infection

[0498] In certain embodiments, the disorder is an immune disorder caused by a viral infection. In certain embodiments, the viral infection is an infection with human immunodeficiency virus 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia virus 1 or 2 (HTLV-1 or HTLV-2), respiratory syncytial virus (RSV), human papillomavirus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus 1 or 2 (HSV-1 or HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus), or a flavivirus selected from yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus.

[0499] In certain embodiments, the viral infection is an infection with human immunodeficiency virus 1 or 2 (HIV-1 or HIV-2). In certain embodiments, the viral infection is an infection with human immunodeficiency virus 1 (HIV-1). In certain embodiments, the viral infection is an infection with human immunodeficiency virus 2 (HIV-2). In certain embodiments, the viral infection is an infection with human T-cell leukemia virus 1 or 2 (HTLV-1 or HTLV-2). In certain embodiments, the viral infection is an infection with respiratory syncytial virus (RSV). In certain embodiments, the viral infection is an infection with human papillomavirus (HPV). In certain embodiments, the viral infection is an infection with adenovirus. In certain embodiments, the viral infection is an infection with hepatitis B virus (HBV). In certain embodiments, the viral infection is an infection with hepatitis C virus (HCV). In certain embodiments, the viral infection is an infection with Epstein-Barr virus (EBV). In certain embodiments, the viral infection is an infection with varicella-zoster virus (VZV). In certain embodiments, the viral infection is an infection with cytomegalovirus (CMV). In certain embodiments, the viral infection is an infection with herpes simplex virus 1 or 2 (HSV-1 or HSV-2). In certain embodiments, the viral infection is an infection with human herpesvirus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus). In certain embodiments, the viral infection is an infection with a flavivirus selected from yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus.

[0500] Additional exemplary features that may characterize the first treatment methods described herein are provided below, and include, for example, the disorder and patient to be treated.

[0501] B. Second treatment method

[0502] Another aspect of the present invention provides a method for treating a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions other than viral infections. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II to treat the condition; wherein Formula II is represented by:

[0503]

[0504] or a stereoisomer thereof; or a pharmaceutically acceptable salt of any of the foregoing; wherein:

[0505] R 1 is hydrogen, -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 2 ;

[0506] R 2 Each occurrence independently represents hydrogen, -P(O)(OH)2, -P(O)(OH)-OP(O)(OH)2, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; or R 2 and R 4 , or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 Replace p instances of ;

[0507] R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 Instances of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0508] R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0509] R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring;

[0510] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0511] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2; and

[0512] m and p are independently 0, 1, 2 or 3 at each occurrence.

[0513] The definitions of the variables in Formula II above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0514] In certain embodiments, the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula II.

[0515] In certain embodiments, a particular compound of Formula II is a compound defined by one of the embodiments described in Section I above, such as a compound of Formula I, I-1, IA, or IB. Additionally, the variable R described in Section I above is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 The embodiments of m and p also apply to compounds of formula II. For example, in certain embodiments, the compound is a compound of formula II, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

[0516] In certain embodiments, the compound of formula II is In certain embodiments, the compound of formula II is

[0517] In certain embodiments, the compound of formula II is

[0518] Another aspect of the present invention provides a method for treating a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions other than viral infections. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula II-1 to treat the condition; wherein formula II-1 is represented by:

[0519]

[0520] or a pharmaceutically acceptable salt thereof; wherein:

[0521] R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2、-C(O)R 2 or hydrogen;

[0522] R 2Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, hydrogen, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 , or R 2 The two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring;

[0523] R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0524] R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0525] R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0526] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0527] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy; and

[0528] m is independently 0, 1, 2 or 3 at each occurrence.

[0529] The definitions of the variables in Formula II-1 above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups described above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups described above, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0530] In certain embodiments, the compound is of Formula II-1.

[0531] In certain embodiments, a particular compound of Formula II-1 is a compound defined by one of the embodiments described in Section I above, such as a compound of Formula I-1 or IA. Additionally, the variable R of Formula I-1 described in Section I above is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 The embodiments of and m also apply to compounds of formula II-1. For example, in certain embodiments, the compound is a compound of formula II-1, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

[0532] In certain embodiments, the compound of formula II-1 is In certain embodiments, the compound of formula II-1 is

[0533] Additional exemplary features that may characterize the second treatment methods described herein are provided below, and include, for example, the disorder and patient to be treated.

[0534] C. Other Exemplary Features of the First and Second Treatment Methods

[0535] Other exemplary features that can characterize the first and second treatment methods described herein are provided below, and include, for example, conditions and patients to be treated. A more detailed description of these features is provided below. The present invention encompasses all permutations and combinations of these features.

[0536] Pharmaceutical compositions and additional therapeutic agents

[0537] In certain embodiments, a compound of Formula II, or a compound defined by one of the embodiments described in Section I above (such as a compound of Formula I, I-1, IA, or IB), is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, as further described in Section V below.

[0538] In certain embodiments, the method further comprises administering an effective amount of an additional therapeutic agent, as further described in Section IV below.

[0539] cancer

[0540] In certain embodiments, the condition is cancer. In certain embodiments, the cancer is a solid tumor or leukemia. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is carcinoma or melanoma. In certain embodiments, the cancer is carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia.

[0541] In certain embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct and gallbladder cancer, bladder cancer, urinary tract cancer, colon cancer, rectal cancer, thyroid cancer, pancreatic cancer, kidney cancer, liver cancer, brain cancer, skin cancer, or eye cancer.

[0542] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; (ii) LINE1 reverse transcriptase activity; (iii) expression of HERV-K RNA and / or (iv) HERV-K reverse transcriptase activity.

[0543] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; and / or (II) LINE1 reverse transcriptase activity. In certain embodiments, the cancer has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has expression of LINE1 RNA. In certain embodiments, the cancer has expression of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has expression of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has LINE1 reverse transcriptase activity.

[0544] In certain embodiments, the cancer has (i) expression of HERV-K RNA, and / or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the cancer has expression of HERV-K RNA. In certain embodiments, the cancer has HERV-K reverse transcriptase activity.

[0545] In certain embodiments, the cancer has elevated (i) LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide levels; (ii) LINE1 reverse transcriptase activity; (iii) HERV-K RNA levels and / or (iv) HERV-K reverse transcriptase activity.

[0546] In certain embodiments, the cancer has elevated levels of (i) LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; and / or (II) LINE1 reverse transcriptase activity. In certain embodiments, the cancer has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 RNA. In certain embodiments, the cancer has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated LINE1 reverse transcriptase activity.

[0547] In certain embodiments, the cancer has elevated (i) HERV-K RNA levels, and / or (ii) HERV-K reverse transcriptase activity. In certain embodiments, the cancer has elevated HERV-K RNA levels. In certain embodiments, the cancer has elevated HERV-K reverse transcriptase activity.

[0548] In certain embodiments, the cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer comprises microsatellite instability (MSI) colorectal cancer or microsatellite stable (MSS) colorectal cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is kidney cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer or small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is small cell lung cancer.

[0549] In certain embodiments, the cancer is an epithelial cancer. In certain embodiments, the epithelial cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer, ovarian cancer or lung cancer. In certain embodiments, the epithelial cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, ovarian cancer or lung cancer. In certain embodiments, colorectal cancer includes microsatellite instability (MSI) colorectal cancer or microsatellite stable (MSS) colorectal cancer.

[0550] In certain embodiments, the cancer is a precancerous or early-stage cancer. In certain embodiments, the cancer is intraductal papillary mucinous neoplasia (IPMN), pancreatic intraepithelial neoplasia (PanIN), ductal carcinoma in situ (DCIS), or Barrett's esophagus. In certain embodiments, the cancer is intraductal papillary mucinous neoplasia (IPMN). In certain embodiments, the cancer is pancreatic intraepithelial neoplasia (PanIN). In certain embodiments, the cancer is ductal carcinoma in situ (DCIS). In certain embodiments, the cancer is Barrett's esophagus.

[0551] In certain embodiments, the cancer has elevated pericentrometric human satellite II (HSATII) RNA levels. In some embodiments, the cancer is a microsatellite unstable (MSI) cancer. In some embodiments, the cancer is a microsatellite stable (MSS) cancer.

[0552] In certain embodiments, the cancer is selected from B cell lymphoma (e.g., B cell chronic lymphocytic leukemia, B cell non-Hodgkin lymphoma, cutaneous B cell lymphoma, diffuse large B cell lymphoma), basal cell carcinoma, bladder cancer, blastoma, brain metastasis, breast cancer, Burkitt lymphoma, carcinoma (e.g., adenocarcinoma (e.g., gastroesophageal junction adenocarcinoma)), cervical cancer, colon cancer, colorectal cancer (colon and rectum cancer), endometrial cancer, esophageal cancer, Ewing's sarcoma (Ewing's sarcoma), ovarian cancer, endometrial cancer, esophageal cancer, ovarian cancer, ovarian cancer, ovarian cancer, ovarian sarcoma ... sarcoma), follicular lymphoma, gastric cancer, gastroesophageal junction cancer, gastrointestinal cancer, glioblastoma (e.g., glioblastoma multiforme, e.g., newly diagnosed or recurrent), glioma, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver metastasis, Hodgkin lymphoma and non-Hodgkin lymphoma, kidney cancer (e.g., renal cell carcinoma and Wilms' tumors), laryngeal cancer, leukemia (e.g., chronic myeloid leukemia, hairy cell leukemia), liver cancer (e.g., liver cancer and hepatoma), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), lymphoblastic lymphoma, lymphoma, mantle cell lymphoma, metastatic brain tumor, metastatic cancer, myeloma (e.g., multiple myeloma), ), neuroblastoma, ocular melanoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), prostate cancer (e.g., hormone-refractory (e.g., castration-resistant), metastatic, metastatic hormone-refractory (e.g., castration-resistant, androgen-independent)), renal cell carcinoma (e.g., metastatic), salivary gland cancer, sarcoma (e.g., rhabdomyosarcoma), skin cancer (e.g., melanoma (e.g., metastatic melanoma)), soft tissue sarcoma, solid tumors, squamous cell carcinoma, synovial sarcoma, testicular cancer, thyroid cancer, transitional cell carcinoma (urothelial cell carcinoma), uveal melanoma (e.g., metastatic), verrucous carcinoma, vulvar cancer, and Waldenstrom macroglobulinemia.

[0553] In some embodiments, cancer is a virus-related cancer. As used herein, the term "virus-related cancer" means any cancer in which a known virus plays a role. For example, it is reported that Epstein-Barr virus (EBV) is associated with Burkitt's lymphoma and some other lymphomas. It is believed that infection with human papillomavirus (HPV) is the culprit causing certain types of cervical cancer and / or genital cancer. It is reported that human T-cell leukemia virus 1 (HTLV-1) is associated with adult T-cell leukemia / lymphoma (ATLL). It is reported that human T-cell leukemia virus 2 (HTLV-2) is associated with cutaneous T-cell lymphoma. It is believed that human herpes virus 8 (HHV-8) can cause AIDS patients to suffer from Kaposi's sarcoma. In certain embodiments, cancer is a cancer associated with EBV, HPV, HTLV-1, HTLV-2 or HHV-8. In certain embodiments, the cancer is Burkitt's lymphoma, cervical cancer, genital cancer, adult T-cell leukemia / lymphoma, cutaneous T-cell lymphoma, or Kaposi's sarcoma.

[0554] In some embodiments, the cancer is a cancer other than a virus-related cancer. In certain embodiments, the cancer is a cancer other than a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8. In certain embodiments, the cancer is a cancer other than Burkitt's lymphoma, cervical cancer, genital cancer, adult T-cell leukemia / lymphoma, cutaneous T-cell lymphoma, or Kaposi's sarcoma.

[0555] In some embodiments, the cancer is mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal area, stomach cancer, gastrointestinal tract (stomach, colorectal and duodenum) cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0556] In some embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic duct cancer, pancreatic adenocarcinoma, gastrointestinal / gastric (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma or brain cancer, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0557] In some embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), bile duct hepatocellular carcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic duct cancer, pancreatic adenocarcinoma, glioma, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0558] In some embodiments, the cancer is selected from the group consisting of: renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal cancer;

[0015] Cancers of the pancreas include: colorectal cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), ovarian cancer, epithelial ovarian cancer, ovarian cancer, or fallopian tube cancer, papillary serous cystadenoma or uterine papillary serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, bile duct hepatocellular carcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, anaplastic thyroid cancer, adrenocortical cancer, pancreatic cancer, pancreatic duct cancer or pancreatic adenocarcinoma, gastrointestinal tract / gastric (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, and medulloblastoma.

[0559] In some embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), bile duct hepatocellular carcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct cancer, pancreatic adenocarcinoma, glioma, brain cancer, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0560] In some embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenoma, uterine papillary serous carcinoma (UPSC), cholangiohepatoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic duct carcinoma, pancreatic adenocarcinoma, glioma, neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0561] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer (ovarian carcinoma). In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is serous papillary cystadenoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is bile duct hepatocellular carcinoma. In some embodiments, the cancer is synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic duct cancer. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1-associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0562] In certain embodiments, the cancer is a leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, or solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphoendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor). tumors, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct cancer, choriocarcinoma, seminoma, embryonal tumor, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also called glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0563] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0564] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - multiforme astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pinealoma, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor.

[0565] Inflammatory diseases

[0566] In certain embodiments, the disorder is an inflammatory disorder. In certain embodiments, the inflammatory disorder is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease or sclerosing cholangitis, psoriasis, dermatitis, vasculitis, scleroderma, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, gout, myositis, Sjogren's syndrome, or systemic lupus erythematosus.

[0567] In certain embodiments, the inflammatory condition is rheumatoid arthritis, osteoarthritis or ankylosing spondylitis. In certain embodiments, the inflammatory condition is inflammatory bowel disease, Crohn's disease or ulcerative colitis. In certain embodiments, the inflammatory condition is non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease or sclerosing cholangitis. In certain embodiments, the inflammatory condition is psoriasis, dermatitis, vasculitis or scleroderma. In certain embodiments, the inflammatory condition is asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis or pericarditis. In certain embodiments, the inflammatory condition is gout, myositis, Sjögren's syndrome or systemic lupus erythematosus.

[0568] immune disorders

[0569] In certain embodiments, the disorder is an immune disorder other than a viral infection. In certain embodiments, the immune disorder is arthritis, psoriasis, systemic lupus erythematosus (SLE), graft-versus-host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, Reiter's syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjögren's syndrome, autoimmune uveitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, psoriasis, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or Sjögren's syndrome.

[0570] In certain embodiments, the immune disorder is type 1 interferon disease, type 1 diabetes, Aicardi-Goutieres syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial lupus pernio, systemic sclerosis, STING-associated vasculopathy of infancy (SAVI), graft-versus-host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, Reiter's syndrome, exfoliative psoriatic dermatitis, Pemphigus vulgaris, Sjögren's syndrome, autoimmune uveitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or Sjögren's syndrome.

[0571] In certain embodiments, the immune disorder is type 1 interferon disease, type 1 diabetes, Aicardi-Goutier syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial lupus pernio, systemic sclerosis, STING-associated vasculopathy of infancy (SAVI), graft-versus-host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriatic arthritis, Lyme disease, Tell syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjögren's syndrome, autoimmune uveitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or Sjögren's syndrome.

[0572] In certain embodiments, the immune disorder is type 1 interferonopathy, type 1 diabetes, Aicardi-Goutier syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial lupus pernio, systemic sclerosis, STING-associated vasculopathy of infancy (SAVI), Sjögren's syndrome, dermatomyositis, inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

[0573] In certain embodiments, the immune disorder is type 1 interferon disease. In certain embodiments, the immune disorder is type 1 diabetes, Aicardi-Gutierre syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial lupus pernio, systemic sclerosis, STING-associated vasculopathy (SAVI) of infancy, Sjogren's syndrome, or dermatomyositis. In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), or familial lupus pernio. In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE), lupus nephritis, or cutaneous lupus erythematosus (CLE). In certain embodiments, the immune disorder is type 1 diabetes, Aicardi-Gutierre syndrome (AGS), systemic sclerosis, STING-associated vasculopathy (SAVI) of infancy, Sjogren's syndrome, or dermatomyositis. In certain embodiments, the immune disorder is Aicardi-Goodier syndrome (AGS), familial lupus pernio, or STING-associated vasculopathy of infancy (SAVI).

[0574] In certain embodiments, the immune disorder is type 1 diabetes. In certain embodiments, the immune disorder is Aicardi-Goodier syndrome (AGS). In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE). In certain embodiments, the immune disorder is lupus nephritis. In certain embodiments, the immune disorder is cutaneous lupus erythematosus (CLE). In certain embodiments, the immune disorder is familial lupus pernio. In certain embodiments, the immune disorder is systemic sclerosis. In certain embodiments, the immune disorder is STING-associated vasculopathy of infancy (SAVI). In certain embodiments, the immune disorder is Sjögren's syndrome. In certain embodiments, the immune disorder is dermatomyositis.

[0575] In certain embodiments, the immune disorder is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In certain embodiments, the immune disorder is inflammatory bowel disease. In certain embodiments, the immune disorder is Crohn's disease. In certain embodiments, the immune disorder is ulcerative colitis.

[0576] neurodegenerative diseases

[0577] In certain embodiments, the disorder is a neurodegenerative disorder. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, peripheral neuropathy, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depressive disorder. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, or dementia.

[0578] In certain embodiments, the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depressive disorder.

[0579] In certain embodiments, the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, dementia, or age-related macular degeneration. In certain embodiments, the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, or age-related macular degeneration. In certain embodiments, the neurodegenerative disorder is age-related macular degeneration.

[0580] In certain embodiments, the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, or dementia. In certain embodiments, the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease. In certain embodiments, the neurodegenerative disorder is Alzheimer's disease. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). In certain embodiments, the neurodegenerative disorder is multiple sclerosis. In certain embodiments, the neurodegenerative disorder is Parkinson's disease. In certain embodiments, the neurodegenerative disorder is Huntington's disease. In certain embodiments, the neurodegenerative disorder is dementia.

[0581] Subjects

[0582] In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; (ii) LINE1 reverse transcriptase activity; (iii) expression of HERV-K RNA and / or (iv) HERV-K reverse transcriptase activity.

[0583] In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; and / or (II) LINE1 reverse transcriptase activity. In certain embodiments, the subject has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the subject has expression of LINE1 RNA. In certain embodiments, the subject has expression of LINE1 ORF1 polypeptide. In certain embodiments, the subject has expression of LINE1 ORF2 polypeptide. In certain embodiments, the subject has LINE1 reverse transcriptase activity.

[0584] In certain embodiments, the subject has (i) expression of HERV-K RNA, and / or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the subject has expression of HERV-K RNA. In certain embodiments, the subject has HERV-K reverse transcriptase activity.

[0585] In certain embodiments, the subject has elevated (i) LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide levels; (ii) LINE1 reverse transcriptase activity; (iii) HERV-K RNA levels and / or (iv) HERV-K reverse transcriptase activity.

[0586] In certain embodiments, the subject has elevated levels of (i) LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; and / or (II) LINE1 reverse transcriptase activity. In certain embodiments, the subject has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 RNA. In certain embodiments, the subject has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated LINE1 reverse transcriptase activity.

[0587] In certain embodiments, the subject has elevated (i) HERV-K RNA levels, and / or (ii) HERV-K reverse transcriptase activity. In certain embodiments, the subject has elevated HERV-K RNA levels. In certain embodiments, the subject has elevated HERV-K reverse transcriptase activity.

[0588] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine animal.

[0589] Uses of compounds

[0590] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, I-1, IA or IB, or other compounds in Section I, or a compound of Formula II) for treating a medical condition, such as a medical condition described herein (e.g., cancer).

[0591] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, I-1, IA or IB, or other compounds in Section I, or a compound of Formula II) in the manufacture of a medicament. In certain embodiments, the medicament is used to treat a condition described herein, such as cancer.

[0592] III. Methods for Inhibiting LINE1 and / or HERV-K Reverse Transcriptase Activity

[0593] The substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidines and related compounds described herein (such as compounds of Formula I, I-1, IA, or IB, or other compounds described in Section I above) are expected to inhibit LINE1 reverse transcriptase activity. Thus, one aspect of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described in Section I above (such as a compound of Formula I, I-1, IA, or IB) to inhibit the activity of the LINE1 reverse transcriptase. In certain embodiments, the specific compound of Formula I, I-1, IA, or IB is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in a subject.

[0594] Another aspect of the present invention provides a method for inhibiting HERV-K reverse transcriptase activity. The method comprises contacting the HERV-K reverse transcriptase with an effective amount of a compound described in Section I above (such as a compound of Formula I, I-1, IA, or IB) to inhibit the activity of the HERV-K reverse transcriptase. In certain embodiments, the specific compound of Formula I, I-1, IA, or IB is a compound defined by one of the embodiments described in Section I above. In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in a subject.

[0595] Another aspect of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a condition selected from the group consisting of cancer, an inflammatory condition, a neurodegenerative condition, and an immune condition other than a viral infection. The method comprises contacting the LINE1 reverse transcriptase with an effective amount of a compound of Formula II to inhibit the activity of the LINE1 reverse transcriptase; wherein Formula II is represented by:

[0596]

[0597] or a stereoisomer thereof; or a pharmaceutically acceptable salt of any of the foregoing; wherein:

[0598] R 1 is hydrogen, -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 2 ;

[0599] R 2 Each occurrence independently represents hydrogen, -P(O)(OH)2, -P(O)(OH)-OP(O)(OH)2, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; or R 2 and R 4 , or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 Replace p instances of ;

[0600] R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 Instances of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0601] R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0602] R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring;

[0603] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0604] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2; and

[0605] m and p are independently 0, 1, 2 or 3 at each occurrence.

[0606] The definitions of the variables in Formula II above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0607] In certain embodiments, the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula II.

[0608] In certain embodiments, a particular compound of Formula II is a compound defined by one of the embodiments described in Section I above, such as a compound of Formula I, I-1, IA, or IB. Additionally, the variable R described in Section I above is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 The embodiments of m and p also apply to compounds of formula II. For example, in certain embodiments, the compound is a compound of formula II, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

[0609] In certain embodiments, the compound of formula II is In certain embodiments, the compound of formula II is

[0610] In certain embodiments, the compound of formula II is

[0611] In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject.In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section II above, such as cancer.

[0612] Another aspect of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a condition selected from the group consisting of cancer, an inflammatory condition, a neurodegenerative condition, and an immune condition other than a viral infection. The method comprises contacting the LINE1 reverse transcriptase with an effective amount of a compound of formula II-1 to inhibit the activity of the LINE1 reverse transcriptase; wherein formula II-1 is represented by:

[0613]

[0614] or a pharmaceutically acceptable salt thereof; wherein:

[0615] R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2、-C(O)R 2 or hydrogen;

[0616] R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, hydrogen, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; or R 2 and R 4 , or R 2 The two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring;

[0617] R 3 Each occurrence independently represents hydrogen or C1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0618] R 4 -C(H)(R 5 )-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0619] R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 substituted by cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0620] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0621] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy; and

[0622] m is independently 0, 1, 2 or 3 at each occurrence.

[0623] The definitions of the variables in Formula II-1 above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups described above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups described above, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0624] In certain embodiments, the compound is of Formula II-1.

[0625] In certain embodiments, a particular compound of Formula II-1 is a compound defined by one of the embodiments described in Section I above, such as a compound of Formula I-1 or IA. Additionally, the variable R of Formula I-1 described in Section I above is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 The embodiments of and m also apply to compounds of formula II-1. For example, in certain embodiments, the compound is a compound of formula II-1, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

[0626] In certain embodiments, the compound of formula II-1 is In certain embodiments, the compound of formula II-1 is

[0627] In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section II above, such as cancer. In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject.

[0628] Another aspect of the present invention provides a method for inhibiting the activity of HERV-K reverse transcriptase in a subject suffering from a condition selected from the group consisting of cancer, inflammatory conditions, neurodegenerative conditions, and immune conditions other than viral infections. The method comprises contacting the HERV-K reverse transcriptase with an effective amount of a compound of formula II to inhibit the activity of the HERV-K reverse transcriptase; wherein formula II is represented by:

[0629]

[0630] or a stereoisomer thereof; or a pharmaceutically acceptable salt of any of the foregoing; wherein:

[0631] R 1 is hydrogen, -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 2 ;

[0632] R 2 Each occurrence independently represents hydrogen, -P(O)(OH)2, -P(O)(OH)-OP(O)(OH)2, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group; and wherein the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally replaced by an -O-(C 1-20 alkyl) substituted; or R 2 and R 4 , or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is replaced by R 7 Replace p instances of ;

[0633] R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 Instances of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom;

[0634] R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 、C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein said C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxy group;

[0635] R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two instances of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring;

[0636] R 6 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by a C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or a 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0637] R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -N(R 9 )2; and

[0638] m and p are independently 0, 1, 2 or 3 at each occurrence.

[0639] The definitions of the variables in Formula II above encompass a variety of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from those chemical groups above, ii) the definition of a variable is a set of two or more chemical groups selected from those chemical groups above, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0640] In certain embodiments, the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula II.

[0641] In certain embodiments, a particular compound of Formula II is a compound defined by one of the embodiments described in Section I above, such as a compound of Formula I, I-1, IA, or IB. Additionally, the variable R described in Section I above is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 The embodiments of m and p also apply to compounds of formula II. For example, in certain embodiments, the compound is a compound of formula II, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

[0642] In certain embodiments, the compound of formula II is In certain embodiments, the compound of formula II is

[0643] In certain embodiments, the compound of formula II is

[0644] In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in the subject.In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section II above, such as cancer.

[0645] Compounds can be tested for their ability to inhibit LINE1 reverse transcriptase activity, for example, as described in the Examples. Compounds can be tested for their ability to inhibit HERV-K reverse transcriptase activity, for example, as described in the Examples.

[0646] IV. Combination Therapy

[0647] Another aspect of the present invention provides combination therapy. Substituted 2', 3'-didehydro-3'-deoxy-4'-ethynyl thymidine or related compounds described herein (e.g., compounds of Formula I, I-1, IA or IB, or other compounds in Section I, or compounds of Formula II, or other compounds in Section II) or pharmaceutically acceptable salts thereof can be used in combination with another therapeutic agent to treat a medical condition (e.g., according to the methods described in Section II, such as a condition of cancer). Therefore, in some embodiments, the methods of the present invention further comprise administering an effective amount of another therapeutic agent.

[0648] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and simultaneously or sequentially administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compounds and one or more additional therapeutic agents acts synergistically.

[0649] One or more other therapeutic agents can be used separately from the compound or composition of the present invention as a part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents can be a part of a single dosage form mixed with the compound of the present invention in a single composition. If used as a multiple dosing regimen, one or more other therapeutic agents and the compound or composition of the present invention can be used simultaneously, sequentially or at intervals of a certain time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23 or 24 hours). In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention are used as a multiple dosing regimen at intervals of more than 24 hours.

[0650] The dosage and dosing regimen of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, the substituted 2', 3'-didehydro-3'-deoxy-4'-ethynyl thymidine or related compounds described herein (e.g., compounds of Formula I, or other compounds in Part I, or compounds of Formula II, or other compounds in Part II) and additional therapeutic agents (e.g., the second, third, fourth, or fifth anticancer agents described below) are administered at doses typically employed when these agents are used as monotherapy for the treatment of the condition. In other embodiments, the substituted 2', 3'-didehydro-3'-deoxy-4'-ethynyl thymidine or related compounds described herein (e.g., compounds of Formula I, or other compounds in Part I, or compounds of Formula II, or other compounds in Part II) and additional therapeutic agents (e.g., the second, third, fourth, or fifth anticancer agents described below) are administered at doses lower than those typically employed when these agents are used as monotherapy for the treatment of the condition. In certain embodiments, a substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine or related compound described herein (e.g., a compound of Formula I, or other compounds in Section I, or a compound of Formula II, or other compounds in Section II) and an additional therapeutic agent (e.g., a second, third, fourth, or fifth anticancer agent described below) are present in the same composition suitable for oral administration.

[0651] In certain embodiments, the substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine or related compounds described herein (e.g., compounds of Formula I, or other compounds in Section I, or compounds of Formula II, or other compounds in Section II) and the additional therapeutic agent (e.g., the second, third, fourth, or fifth anticancer agent described below) may act additively or synergistically. Synergistic combinations allow the use of lower doses of one or more agents and / or less frequent administration of one or more agents of the combination therapy. Lower doses or less frequent administration of one or more agents can reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0652] Another aspect of the invention is a kit comprising a therapeutically effective amount of a substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine or related compound described herein (e.g., a compound of Formula I or other compounds in Part I, or a compound of Formula II or other compounds in Part II), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.

[0653] cancer

[0654] Therefore, another aspect of the present invention provides a method for treating cancer in a patient, comprising administering to a subject in need thereof (i) a therapeutically effective amount of a substituted 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine or a related compound described herein and (ii) a second anticancer agent to treat the cancer.

[0655] In certain embodiments, the second anticancer agent is radiation therapy.

[0656] In certain embodiments, the second anticancer agent is a therapeutic antibody. In certain embodiments, the therapeutic antibody targets one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, mucin, TAG-72, CAIX, PSMA, folate binding protein, ganglioside, Le, VEGF, VEGFR, VEGFR2, integrin αVβ3, integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin-1β, B4GALNT1, interleukin-6, and interleukin-6 receptor.

[0657] In certain embodiments, the second anticancer agent is a therapeutic antibody selected from the group consisting of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecamizumab, labetuzumab, huA33, pertumumab, ogovuzumab, minitumomab, cG250, J591, Mov18, fatumomab, farletuzumab), 3F8, ch14.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramucirumab, eptazolizumab, volociximab, cetuximab, panitumumab, nimotuzumab, 806, afatinib, erlotinib, gefitinib, osimertinib, vandetanib, trastuzumab, pertuzumab, MM-121, AMG 102, METMAB, SCH 900105, AVE1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA-4, mapatumumab, HGS-ETR2, CS-1008, denosumab, sibuluzumab, F19, 81C6, MEDI551, lirilumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab.

[0658] In certain embodiments, the second anticancer agent is a cytokine. In certain embodiments, the cytokine is IL-12, IL-15, GM-CSF, or G-CSF.

[0659] In certain embodiments, the second anticancer agent is sipuleucel-T, aldesleukin (a human recombinant interleukin-2 product, chemically named des-alanyl-1, serine-125 human interleukin-2), dabrafenib (a kinase inhibitor, chemically named N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor, chemically named propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), or 2-chloro-deoxyadenosine.

[0660] In certain embodiments, the second anticancer agent is placental growth factor, an antibody-drug conjugate, an oncolytic virus, or an anticancer vaccine. In certain embodiments, the second anticancer agent is placental growth factor. In certain embodiments, the second anticancer agent is placental growth factor comprising ziv-aflibercept. In certain embodiments, the second anticancer agent is an antibody-drug conjugate. In certain embodiments, the second anticancer agent is an antibody-drug conjugate selected from the group consisting of brentoxumab vedotin and trastuzumab emtransine.

[0661] In certain embodiments, the second anticancer agent is an oncolytic virus. In certain embodiments, the second anticancer agent is the oncolytic virus talimogene laherparepvec. In certain embodiments, the second anticancer agent is an anticancer vaccine. In certain embodiments, the second anticancer agent is an anticancer vaccine selected from the group consisting of GM-CSF tumor vaccine, STING / GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anticancer agent is a cytokine selected from IL-12, IL-15, GM-CSF, and G-CSF.

[0662] In certain embodiments, the second anticancer agent is an immune checkpoint inhibitor (also referred to as an immune checkpoint blocker). Immune checkpoint inhibitors are a class of therapeutic agents with blocking immune checkpoint effects. See, for example, Pardoll's Nature Reviews Cancer (2012) Vol. 12, pp. 252-264. In certain embodiments, immune checkpoint inhibitors are agents that suppress one or more of the following: (i) cytotoxic T lymphocyte-associated antigen 4 (CTLA4), (ii) programmed cell death protein 1 (Pd1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4 and (vii) TIM3. In certain embodiments, immune checkpoint inhibitors are ipilimumab (ipilumumab). In certain embodiments, immune checkpoint inhibitors are pembrolizumab.

[0663] In certain embodiments, the second anticancer agent is a monoclonal antibody that targets a non-checkpoint target (e.g., herceptin). In certain embodiments, the second anticancer agent is a non-cytotoxic agent (e.g., a tyrosine kinase inhibitor).

[0664] In certain embodiments, the second anticancer agent is selected from mitomycin, ribonucleoside, vincristine, tretinoin, etoposide, cladribine, gemcitabine, mitobromol, methotrexate, doxorubicin, carboquinone, valerate, nitrilene, zinothiazine, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasine, sobuzosine, nedaplatin, aminoglutethimide, amsacrine, proglumide, elitidium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozotocin, nimustine, vindesine, cytarabine, bicalutamide, cytosine ... Amine, vinorelbine, vinorelbine, vilsatamide, flutamide, dronidone, butocin, carmofur, razoxane, cizofilam, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, pilsibanib, levamisole, teniposide, improsulfan, enoxitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepistatin, epithiotanol, formestane, colony-stimulating factor-1, colony-stimulating factor-2, denileukin, interleukin-2, luteinizing hormone-releasing factor, interferon-α, interferon-2α, interferon-β, interferon-γ.

[0665] In certain embodiments, the second anticancer agent is an ALK inhibitor, an ATR inhibitor, an A2A antagonist, a base excision repair inhibitor, a Bcr-Abl tyrosine kinase inhibitor, a Bruton tyrosine kinase inhibitor, a CDC7 inhibitor, a CHK1 inhibitor, a cyclin-dependent kinase inhibitor, a DNA-PK inhibitor, an inhibitor of DNA-PK and mTOR, a DNMT1 inhibitor, a DNMT1 inhibitor plus 2-chlorodeoxyadenosine, an HDAC inhibitor, a Hedgehog signaling pathway inhibitor, an IDO inhibitor, a JAK inhibitor, an mTOR inhibitor, a MEK inhibitor, a MELK inhibitor, an MTH1 inhibitor, a PARP inhibitor, a phosphoinositide 3-kinase inhibitor, an inhibitor of PARP1 and DHODH, a proteasome inhibitor, a topoisomerase II inhibitor, a tyrosine kinase inhibitor, a VEGFR inhibitor, or a WEE1 inhibitor.

[0666] In certain embodiments, the second anticancer agent is an ALK inhibitor. In certain embodiments, the second anticancer agent is an ALK inhibitor including ceritinib or crizotinib. In certain embodiments, the second anticancer agent is an ATR inhibitor. In certain embodiments, the second anticancer agent is an ATR inhibitor including AZD6738 or VX-970. In certain embodiments, the second anticancer agent is an A2A antagonist. In certain embodiments, the second anticancer agent is a base excision repair inhibitor including methoxyamine. In certain embodiments, the second anticancer agent is a base excision repair inhibitor such as methoxyamine. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor including dasatinib or nilotinib. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor including ibrutinib. In certain embodiments, the second anticancer agent is a CDC7 inhibitor. In certain embodiments, the second anticancer agent is a CDC7 inhibitor, including RXDX-103 or AS-141.

[0667] In certain embodiments, the second anticancer agent is a CHK1 inhibitor. In certain embodiments, the second anticancer agent is a CHK1 inhibitor, including MK-8776, ARRY-575, or SAR-020106. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor, including palbociclib. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor, including MSC2490484A. In certain embodiments, the second anticancer agent is an inhibitor of DNA-PK and mTOR. In certain embodiments, the second anticancer agent includes CC-115.

[0668] In certain embodiments, the second anticancer agent is a DNMT1 inhibitor. In certain embodiments, the second anticancer agent is a DNMT1 inhibitor, including decitabine, RX-3117, guadecitabine, NUC-8000, or azacytidine. In certain embodiments, the second anticancer agent includes a DNMT1 inhibitor and 2-chloro-deoxyadenosine. In certain embodiments, the second anticancer agent inc...

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt thereof; wherein: R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2或-C(O)R 8 ; R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally substituted with an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen; or R 2 and R 4 , or R 2 together with their intervening atoms to form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 Replace p instances of ; R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 An instance of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom; R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 , C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring; R 6 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or -N(R 9 )2; R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is R 7 wherein each of the naphthyl, 5-6-membered monocyclic heteroaryl and 8-10-membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; m and p are independently 0, 1, 2 or 3 at each occurrence; and n is 1, 2 or 3.

2. The compound of claim 1, wherein the compound is a compound of formula I.

3. A compound represented by formula I-1: or a pharmaceutically acceptable salt thereof; wherein: R 1 -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 8 ; R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl are R 7 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; or R 2 and R 4 , or R 2 The two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring; R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom; R 4 -C(H)(R 5 )-CO2R 6 , C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; R 5 C 1-6 Alkyl, C 1-6 haloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 substituted with cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy; R 8 is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-7 Alkyl, C substituted by hydroxy 1-20 Alkyl, C 1-10 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-8 Alkylene)-S-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 alkyl); wherein the phenyl group is R 7 wherein each of the naphthyl, 5-6-membered monocyclic heteroaryl and 8-10-membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-10 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; m is independently 0, 1, 2 or 3 at each occurrence; and n is 1, 2 or 3.

4. The compound of claim 3, wherein the compound is a compound of formula I-1.

5. The compound of any one of claims 1 to 4, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2.

6. A compound as described in any one of claims 1 to 5, wherein R 2 Each occurrence independently represents phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R 7 Replace with m instances of .

7. A compound as described in any one of claims 1 to 6, wherein R 4 -C(H)(R 5 )-CO2R 6 .

8. A compound as described in any one of claims 1 to 7, wherein R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), phenyl or C 3-7 Cycloalkyl substitution.

9. The compound of claim 1, which is represented by Formula IA: or a pharmaceutically acceptable salt thereof; wherein: R 1 is -P(O)(OR 2 )(N(R 3 )(R 4 )) or -C(O)-C(H)(R 5 )-N(R 3 )2; R 2 is phenyl or naphthyl, each of which is replaced by R 7 Replace m instances of ; R 3 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or R 3 The two examples of together with the atoms to which they are attached form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom; R 4 -C(H)(R 5 )-CO2R 6 ; R 5 C 1-6 alkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 alkyl), phenyl or C 3-7 Cycloalkyl substitution, R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy; and m is 0, 1, 2 or 3.

10. The compound of claim 9, wherein the compound is a compound of formula IA.

11. The compound of any one of claims 1 to 10, wherein R 1 -P(O)(OR 2 )(N(R 3 )(R 4 )).

12. A compound as described in any one of claims 1 to 11, wherein R 2 For R 7 An example of m is substituted phenyl.

13. A compound as described in any one of claims 1 to 11, wherein R 2 for 14. The compound of any one of claims 1-12, wherein m is 1.

15. The compound of any one of claims 1-12, wherein m is 0.

16. A compound as described in any one of claims 1 to 14, wherein R 7 Each occurrence independently represents a halo.

17. A compound as described in any one of claims 1-5 and 8-10, wherein R 1 -C(O)-C(H)(R 5 )-N(R 3 )2.

18. The compound of claim 1, which is represented by Formula IB: or a pharmaceutically acceptable salt thereof; wherein: R 1 is -P(O)(OR 2 )2 or -P(O)(N(R 3 )(R 4 ))2; R 2 Each occurrence represents C independently 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein the C 1-20 Alkyl and C 1-10 Each of the C 1-20 Alkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally substituted with an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is further selected from hydrogen; or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 Replace p instances of ; R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 An instance of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom; R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 ; R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), phenyl or C 3-7 Cycloalkyl substituted; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring; R 6 Each occurrence represents C independently 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; wherein the C 1-6 The alkyl group is optionally replaced by C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or 4-7 membered saturated monocyclic heterocyclic group having one nitrogen or oxygen atom; R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or -N(R 9 )2; and p is 0, 1, 2 or 3.

19. The compound of claim 18, wherein the compound is a compound of formula IB.

20. The compound of any one of claims 1-2 or 18-19, wherein R 1 -P(O)(OR 2 )2.

21. A compound as described in any one of claims 1-2 or 18-20, wherein R 2 Each occurrence represents independently - (C 1-10 Alkylene)-OC(O)O-(C 1-10 alkyl) or -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl); wherein the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene substitution.

22. A compound as described in any one of claims 1-2 or 18-20, wherein R 2 Each occurrence represents independently -(C 1-10 Alkylene)-OC(O)-(C 1-10 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl); wherein the C 1-10 Each of the C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene substitution.

23. A compound as described in any one of claims 1-2 or 18-20, wherein R 2 Each occurrence represents independently -(C 1-10 Alkylene)-O-(C 1-20 alkyl) or -(C 1-10 Alkylene)-S-(C 1-20 Alkyl); wherein the C 1-10 Each of the alkylene groups is optionally substituted with an -O-(C 1-20 alkyl) substituted; and wherein R 2 An example of is additionally selected from hydrogen.

24. A compound as described in any one of claims 1-2 or 18-20, wherein R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 substituted by p instances of .

25. A compound as described in any one of claims 1-2 or 18-20, wherein R 1 for 26. A compound as described in any one of claims 1-2 or 18-19, wherein R 1 -P(O)(N(R 3 )(R 4 ))2.

27. A compound as described in any one of claims 1-16, 18-19 or 26, wherein R 6 C 1-6 Alkyl, allyl, C 3-5 Cycloalkyl, -CH2-phenyl or -CH2-(C 3-5 cycloalkyl).

28. A compound as described in any one of claims 1-16, 18-19 or 26, wherein R 6 C 1-4 Alkyl or C 3-5 Cycloalkyl.

29. A compound as described in any one of claims 1-19 or 26-28, wherein R 3 For hydrogen.

30. A compound as described in any one of claims 1-19 or 26-29, wherein R 5 C 1-6 Alkyl or hydrogen.

31. A compound as set forth in Table 1 or 2 herein, or a pharmaceutically acceptable salt thereof.

32. A compound of Table 1, 2, 3, 4 or 5 herein, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 32 and a pharmaceutically acceptable carrier.

34. A method of treating a condition selected from the group consisting of cancer, an inflammatory condition, a neurodegenerative condition, and an immune condition other than a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula II to treat the condition; wherein formula II is represented by: or a stereoisomer thereof; or a pharmaceutically acceptable salt of any of the foregoing; wherein: R 1 is hydrogen, -P(O)(OR 2 )(N(R 3 )(R 4 ))、-P(O)(OR 2 )2、-P(O)(N(R 3 )(R 4 ))2、-C(O)-C(H)(R 5 )-N(R 3 )2 or -C(O)R 2 ; R 2 Each occurrence independently represents hydrogen, -P(O)(OH)2, -P(O)(OH)-OP(O)(OH)2, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-20 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-N(R 9 )-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-20 alkyl) or -(C 1-10 Alkylene)-SC(O)-(C 1-10 wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 7 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 One methylene unit in each of the alkyl groups is optionally replaced by C 3-5 Cycloalkylene is replaced; and wherein said C 1-10 Each of the alkylene groups is optionally substituted with an -O-(C 1-20 alkyl) substituted; or R 2 and R 4 , or R 2 Two examples of together with their intervening atoms form a 4-7 membered saturated heterocyclic ring or a 7-12 membered bicyclic heterocyclic ring, each of which is R 7 Replace p instances of ; R 3 and R 9 Each occurrence independently represents hydrogen or C 1-4 Alkyl; or R 3 and R 5 , or two R 3 An instance of, or two R 9 Examples of , together with the atoms to which they are attached, form a 4-7 membered saturated heterocyclic ring containing 1 nitrogen atom; R 4 Each occurrence represents independently -C(R 5 )2-CO2R 6 , C 1-20 Alkyl, C 1-20 Haloalkyl, -(C 1-10 Alkylene)-O-(C 1-10 Alkyl), -(C 1-10 Alkylene)-OC(O)-(C 1-10 Alkyl), -(C 1-10 Alkylene)-S-(C 1-10 Alkyl), -(C 1-10 Alkylene)-SC(O)-(C 1-10 Alkyl), -(C 1-10 alkylene)-phenyl, phenyl; naphthyl; 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the phenyl, naphthyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl is replaced by R 6 m instances of substituted; and wherein C 1-20 Alkyl, C 1-20 Haloalkyl and C 1-10 Each of the alkyl groups is optionally substituted with one hydroxyl group; R 5 Each occurrence represents C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-5 Cycloalkyl or hydrogen, wherein the C 1-6 The alkyl group is optionally replaced by -S-(C 1-4 Alkyl), -SH, C 1-4 Alkoxy, hydroxy, phenyl, C 3-7 cycloalkyl, 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-10 membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 5 The two examples of together with the carbon atoms to which they are attached form a 3-5 membered saturated carbocyclic ring; R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl or a 4-7 membered saturated monocyclic heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 1-6 The alkyl group is optionally replaced by C 1-4 Alkoxy, phenyl, C 3-7 substituted by cycloalkyl or 4-7 membered saturated monocyclic heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur; R 7 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or -N(R 9 )2; and m and p are independently 0, 1, 2 or 3 at each occurrence.

35. A method of treating a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1-32 to treat the disorder.

36. The method of claim 35, wherein the disorder is a viral infection immune disorder.

37. The method of claim 36, wherein the viral infection is an infection with human immunodeficiency virus 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia virus 1 or 2 (HTLV-1 or HTLV-2), respiratory syncytial virus (RSV), human papillomavirus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus 1 or 2 (HSV-1 or HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus), or a flavivirus selected from yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus.

38. The method of claim 34 or 35, wherein the disorder is cancer.

39. The method of claim 38, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct and gallbladder cancer, bladder cancer, urinary tract cancer, colon cancer, rectal cancer, thyroid cancer, pancreatic cancer, kidney cancer, liver cancer, brain cancer, skin cancer, or eye cancer.

40. The method of claim 34 or 35, wherein the disorder is an inflammatory disorder.

41. The method of claim 40, wherein the inflammatory disorder is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, psoriasis, dermatitis, vasculitis, scleroderma, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, gout, myositis, Sjögren's syndrome, or systemic lupus erythematosus.

42. The method of claim 34 or 35, wherein the disorder is an immune disorder other than a viral infection.

43. The method of claim 42, wherein the immune disorder is type 1 interferon disease, type 1 diabetes, Aicardi-Gutierrez syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial lupus pernio, systemic sclerosis, STING-associated vasculopathy of infancy (SAVI), graft-versus-host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn's disease, vasculitis, psoriasis Arthritis, Reiter's syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjögren's syndrome, autoimmune uveitis, glomerulonephritis, post-myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), oophoritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or Sjögren's syndrome.

44. The method of claim 34 or 35, wherein the disorder is a neurodegenerative disorder.

45. The method of claim 44, wherein the neurodegenerative disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depressive disorder.

46. ​​The method of any one of claims 34-45, wherein the method further comprises administering an effective amount of an additional therapeutic agent.

47. The method of any one of claims 34-46, wherein the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide; and / or (II) LINE1 reverse transcriptase activity.

48. The method of any one of claims 34-47, wherein the subject has (i) expression of HERV-K RNA and / or (ii) activity of HERV-K reverse transcriptase.

49. The method of any one of claims 34-48, wherein the subject is a human.

50. A method for inhibiting LINE1 reverse transcriptase activity, comprising contacting LINE1 reverse transcriptase with an effective amount of the compound of any one of claims 1 to 32 to inhibit the activity of the LINE1 reverse transcriptase.

51. A method for inhibiting the activity of HERV-K reverse transcriptase, comprising contacting HERV-K reverse transcriptase with an effective amount of the compound according to any one of claims 1 to 32 to inhibit the activity of the HERV-K reverse transcriptase.

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