ERK inhibitors and uses thereof

[0001] The present application is a divisional application of U.S. patent application Ser. No. 14/175,273, filed Feb. 7, 2014, which claims priority to U.S. provisional application No. 61/785,126, filed Mar. 14, 2013, and U.S. provisional application No. 61/762,408, filed Feb. 8, 2013, the entirety of each of which is hereby incorporated by reference.

[0002] present invention relates to compounds useful as inhibitors of ERK kinases, for example one or both of ERK1 and ERK2 kinases. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

[0003] In accordance with 37 CFR 1.52(e)(5), the present specification makes reference to a Sequence Listing submitted electronically in the form of a text file (entitled “Sequence_Listing.txt,” created on Mar. 17, 2014, 7.37 KB in size). The entire contents of the Sequence Listing are herein incorporated by reference, with the intention that, upon publication (including issuance), this incorporated sequence listing will be inserted in the published document immediately before the claims.

[0004] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

[0005] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

[0006] The processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1 and/or ERK2. When activated, ERK1 and/or ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of ERK1 and/or ERK2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.

[0007] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

[0008] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of one or both of ERK1 and ERK2. Such compounds have general formula I:

[0009]
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R¹, R², R³, R^y, W, m, and p, with respect to the formula above, is as defined and described in embodiments herein. In certain embodiments, R¹ is a warhead group.

[0010] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by protein kinase-mediated events. Such diseases, disorders, or conditions include those described herein.

[0011] Compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

[0014] In certain embodiments, the present invention provides irreversible inhibitors of one or both of ERK1 and ERK2 and conjugates thereof. In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0015] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has 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.

[0017] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a 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 set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0018]

[0019] The term “lower alkyl” refers to a C_1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term “lower haloalkyl” refers to a C_1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0021] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

[0022] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0023] As used herein, the term “bivalent C_1-8 (or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0024] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH₂)_n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0026] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0027]

[0028] The term “halogen” means F, Cl, Br, or I.

[0029] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems 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” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0030] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. 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. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0031] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

[0032] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0033] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0034] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,

[0035]
refers to at least

[0036]
and

[0037]
refers to at least

[0038]
or

[0039]
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 any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0040] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH₂)_0-4R^∘; —(CH₂)_0-4OR^∘; —O(CH₂)_0-4R^∘, —O—(CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4CH(OR^∘₂; —(CH₂)_0-4SR^∘; —(CH₂)_0-4Ph, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1Ph which may be substituted with R^∘; —CH═CHPh, which may be substituted with R^∘; —(CH₂)_0-4O(CH₂)_0-1-pyridyl which may be substituted with R^∘; —NO₂; —CN; —N₃; —(CH₂)_0-4N(R^∘)₂; —(CH₂)_0-4N(R^∘)C(O)R^∘; —N(R^∘)C(S)R^∘; —(CH₂)_0-4N(R^∘)C(O)NR^∘₂; —N(R^∘)C(S)NR^∘₂; —(CH₂)_0-4N(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)_0-4C(O)R^∘; —C(S)R^∘; —(CH₂)_0-4C(O)OR^∘; —(CH₂)_0-4C(O)SR^∘; —(CH₂)_0-4C(O)OSiR^∘₃; —(CH₂)_0-4OC(O)R^∘; —OC(O)(CH₂)_0-4SR—, SC(S)SR^∘; —(CH₂)_0-4SC(O)R^∘; —(CH₂)_0-4C(O)NR^∘₂; —C(S)NR^∘₂; —C(S)SR^∘; —SC(S)SR^∘, —(CH₂)_0-4OC(O)NR^∘₂; —C(O)N(OR^∘)R^∘; —C(O)C(O)R^∘; —C(O)CH₂C(O)R^∘; —C(NOR^∘)R^∘; —(CH₂)_0-4SSR^∘; —(CH₂)_0-4S(O)₂R^∘; —(CH₂)_0-4S(O)₂OR^∘; —(CH₂)_0-4OS(O)₂R^∘; —S(O)₂NR^∘₂; —(CH₂)_0-4S(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 straight or branched)alkylene)O—N(R^∘)₂; or —(C_1-4 straight or branched)alkylene)C(O)O—N(R^∘)₂, wherein each R^∘ may be substituted as defined below and is independently hydrogen, C_1-6 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0041] Suitable monovalent substituents on R^∘ (or the ring formed by taking two independent occurrences of R^∘ together with their intervening atoms), are independently halogen, —(CH₂)_0-2R^•, -(haloR^•), —(CH₂)_0-2OH, —(CH₂)_0-2OR^•, —(CH₂)_0-2CH(OR^•)₂; —O(haloR^•), —CN, —N₃, —(CH₂)_0-2C(O)R^•, —(CH₂)_0-2C(O)OH, —(CH₂)_0-2C(O)OR^•, —(CH₂)_0-2SR^•, —(CH₂)_0-2SH, (CH₂)_0-2NH₂, —(CH₂)_0-2NHR^•, —(CH₂)_0-2NR^•₂, —NO₂, —SiR^•₃, —OSiR^•₃, —C(O)SR^•, —(C_1-4 straight or branched alkylene)C(O)OR^•, or —SSR^• wherein each R^• is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1-4 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^∘ include ═O and ═S.

[0042] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O (“oxo”), ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))_2-3O—, or —S(C(R*₂))_2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C_1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*₂)_2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C_1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] Suitable substituents on the aliphatic group of R* include halogen, —R*, -(haloR^•), —OH, —OR^•, —O(haloR^•), —CN, —C(O)OH, —C(O)OR^•, —NH₂, —NHR^•, —NR^•₂, or —NO₂, wherein each R^• is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R^†, —NR^†₂, —C(O)R^†, —C(O)OR^†, —C(O)C(O)R^†, C(O)CH₂C(O)R^†, —S(O)₂R^†, —S(O)₂NR^†₂, —C(S)NR^†₂, —C(NH)NR^†₂, or —N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1-6 aliphatic which may be substituted as defined below, 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, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Suitable substituents on the aliphatic group of R^† are independently halogen, —R^•, -(haloR^•), —OH, —OR^•, —O(haloR^•), —CN, —C(O)OH, —C(O)OR^•, —NH₂, —NHR^•, —NR^•₂, or —NO₂, wherein each R^• is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed 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, lauryl sulfate, 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 salts, and the like.

[0047] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1-4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0048] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the 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 enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds 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. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a warhead moiety, R¹, of a provided compound comprises one or more deuterium atoms.

[0049] As used herein, the term “irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a kinase in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond with) a kinase, and therefore can become dissociated from the a kinase, an irreversible inhibitor will remain substantially bound to a kinase once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme. In certain embodiments, an irreversible inhibitor will remain substantially bound to a kinase once covalent bond formation has occurred and will remain bound for a time period that is longer than the life of the protein.

[0050] Methods for identifying if a compound is acting as an irreversible inhibitor are known to one of ordinary skill in the art. Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with a kinase, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as “washout,” experiments, and the use of labeling, such as radiolabelled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.

[0051] One of ordinary skill in the art will recognize that certain reactive functional groups can act as “warheads.” As used herein, the term “warhead” or “warhead group” refers to a functional group present on a compound of the present invention wherein that functional group is capable of covalently binding to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified) present in the binding pocket of the target protein, thereby irreversibly inhibiting the protein. It will be appreciated that the -L-Y group, as defined and described herein, provides such warhead groups for covalently, and irreversibly, inhibiting the protein. In certain instances, a “pro-warhead group” is used in place of a warhead group. Such a pro-warhead group converts to a warhead group in vivo or in vitro.

[0052] As used herein, the term “inhibitor” is defined as a compound that binds to and/or inhibits a kinase with measurable affinity. In certain embodiments, an inhibitor has an IC₅₀ and/or binding constant of less about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0053] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a kinase, and an equivalent sample comprising a kinase, in the absence of said compound, or composition thereof.

[0054] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0055] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0056] As described herein, the present invention provides irreversible inhibitors of one or both of ERK1 and ERK2 kinase. The compounds of the invention comprise a warhead group, designated as R¹, as described herein. Without wishing to be bound by any particular theory, it is believed that such R¹ groups, i.e. warhead groups, are particularly suitable for covalently binding to a key cysteine residue in the binding domain of one or both of ERK1 and ERK2 kinase. One of ordinary skill in the art will appreciate that one or both of ERK1 and ERK2 kinase, and mutants thereof, have a cysteine residue in the binding domain. Without wishing to be bound by any particular theory, it is believed that proximity of a warhead group to the cysteine of interest facilitates covalent modification of that cysteine by the warhead group.

[0057] The cysteine residues of interest can also be described by an identifying portion of the Target's amino acid sequence which includes the cysteine of interest. Thus, in certain embodiments, Cys183 of ERK1 is characterized in that Cys183 is the cysteine embedded in the amino acid sequence of ERK1. FIG. 1 provides SEQ ID NO. 1, which is the amino acid sequence of ERK1. Cys183 is more clearly provided in the abbreviated amino acid sequence below where Cysteine 183 is highlighted in bold with underlining:

SEQ ID NO. 2: NLLINTTCDL KIC(183)DFGLARI.

[0058] Cys166 of ERK2 is characterized in that Cys166 is the cysteine embedded in the amino acid sequence of ERK2. FIG. 2 provides SEQ ID NO. 3, which is the amino acid sequence of ERK2. Cys166 is more clearly provided in the abbreviated amino acid sequence below where Cysteine 166 is highlighted in bold with underlining:

SEQ ID NO. 4: KPSNLLLNTT CDLKIC(166)DFGL.

[0059] In some embodiments, compounds of the present invention include a warhead group characterized in that provided compounds covalently modify one or more of Cys183 of ERK1 or Cys166 of ERK2.

[0060] In certain embodiments, compounds of the present invention include a warhead group characterized in that provided compounds bind to a target of Cys183 of ERK1 or Cys166 of ERK2, thereby irreversibly inhibiting the kinase.

[0061] Thus, in some embodiments, the R¹ warhead group is characterized in that the -L-Y moiety, as defined and described below, is capable of covalently binding to a cysteine residue thereby irreversibly inhibiting the enzyme. In some embodiments, the cysteine residue is Cys183 of ERK1. In some embodiments, the cysteine residue is Cys166 of ERK2. In some embodiments, it is both Cys183 of ERK1 and Cys166 of ERK2. One of ordinary skill in the art will recognize that a variety of warhead groups, as defined herein, are suitable for such covalent bonding. Such R¹ groups include, but are not limited to, those described herein and depicted infra.

[0062] According to one aspect, the present invention provides a compound of formula I,

[0063]
or a pharmaceutically acceptable salt thereof, wherein:

• [0064] Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
• [0065] Ring A is selected from

[0066]
and

[0067]

• [0068] R¹ is a warhead group, wherein when Ring A is a monocyclic ring, then R¹ is attached to an atom adjacent to where W is attached;
• [0069] each R² is independently hydrogen, an optionally substituted C_1-6 aliphatic, halogen, or —OR;
• [0070] Ring B (a) is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered bicyclic saturated, partially unsaturated or aryl ring, a 7-12 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  (b) is absent and (R³)_m is attached to —NH—;
• [0071] each R³ is independently selected from —R, -Cy, halogen, —OR, —SR, —CN, —NO₂, —SO₂NR, —SO₂R, —SOR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)N(R)₂, —C(O)N(R)₂, —C(O)N(R)—OR —C(O)C(O)R, —P(O)(R)₂, —NRC(O)OR, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; or two R³ groups on the same carbon atom together form —C(O)—, —C(S)—, or —C(N—R)—;
• [0072] each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • [0073] two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocylic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• [0074] Cy is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• [0075] R^y is hydrogen, optionally substituted C_1-6 aliphatic, halogen, haloalkyl, —CN, —C(O)R′, —C(O)N(R′)₂, —C(═N—R″)R′ or —N(R′)₂;
• [0076] each R′ is independently hydrogen or an optionally substituted C_1-6 aliphatic;
• [0077] R″ is hydrogen or —OR;
• [0078] W is —O—, —NH—, —S—, —CH₂—, or —C(O)—; and
• [0079] m and p are each independently 0-4;
• [0080] wherein:
• [0081] (a) when R^y is Cl and Ring B is phenyl para-substituted with morpholine, then R¹ is not

[0082]

• [0083] (b) when R^y is Cl and Ring B is phenyl di-substituted with methoxy, then R¹ is not

[0084]

• [0085] (c) when R^y is Cl and Ring B is a 7-12 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, then R¹ is not or

[0086]

• [0087] (d) when R^y is F and Ring B is phenyl tri-substituted with methoxy, then R¹ is not

[0088]

[0089] In certain embodiments, Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

Ring A is selected from

[0090]
and

[0091]

[0092] In certain embodiments, Ring A is phenyl.

[0093] In certain embodiments, Ring A is an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0094] In various embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, or xanthenyl.

[0095] In certain embodiments, Ring A is

[0096]
or

[0097]

[0098] In certain embodiments, Ring A is

[0099]
or

[0100]

[0101] In certain embodiments, Ring A is

[0102]
or

[0103]

[0104] In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, or —P(O)R—. In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated heterocylic ring having a —P(O)R— ring moiety. An exemplary Ring A group having a —P(O)R— ring moiety is

[0105]

[0106] In some embodiments, Ring A is

[0107]
or

[0108]

[0109] In certain embodiments, each R² is independently hydrogen.

[0110] In certain embodiments, each R² is independently an optionally substituted C_1-6 aliphatic, halogen, or —OR.

[0111] In certain embodiments, each R² is independently an optionally substituted methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight or branched pentyl, or a straight or branched hexyl.

[0112] In certain embodiments, each R² is independently F, Cl, Br, or I.

[0113] In certain embodiments, each R² is independently —OMe, —OEt, —O-i-Pr, —O-t-Bu,

[0114]
or

[0115]

[0116] In certain embodiments, each R² is independently hydrogen, F, Cl, Me, CF₃, or OMe.

[0117] In certain embodiments, Ring B is phenyl.

[0118] In certain embodiments, Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered bicyclic saturated, partially unsaturated or aryl ring, a 7-12 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0119] In various embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, or xanthenyl.

[0120] In certain embodiments, Ring B is selected from:

[0121]
and

[0122]

[0123] In certain embodiments, Ring B is absent and (R³)_m is attached to —NH.

[0124] As defined above, each R³ is independently selected from —R, -Cy, halogen, —OR, —SR, —CN, —NO₂, —SO₂NR, —SO₂R, —SOR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)N(R)₂, —C(O)N(R)₂, —C(O)N(R)—OR—C(O)C(O)R, —P(O)(R)₂, —NRC(O)OR, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; or two R³ groups on the same carbon atom together form —C(O)—, —C(S)—, or —C(N—R)—.

[0125] In certain embodiments, each R³ is independently hydrogen.

[0126] In certain embodiments, each R³ is independently —R. In other embodiments, one R³ is -Cy.

[0127] In certain embodiments, each R³ is independently an optionally substituted C_1-6 aliphatic.

[0128] In certain embodiments, each R³ is independently an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0129] In certain embodiments, each R³ is independently halogen, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

[0130] In certain embodiments, each R³ is independently halogen, —OR, —CN, —SO₂R, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

[0131] In certain embodiments, each R³ is independently -Me, -Et, -t-Bu, —CH₂OH, —CF₃, —(CH₂)₃NHBoc, —(CH₂)₃NH₂, —CN, —F, —Cl, —Br, —OH, —OMe, —OEt, —OCH₂CH₂OMe, —NHCH₂CH₂OMe, —OCH₂F, —OCHF₂, —OCF₃, —OCH₂CCH, —NH(Me), or —P(O)(Me)₂.

[0132] In certain embodiments, each R³ is independently

[0133]

[0134] In certain embodiments, each R³ is independently

[0135]

[0136] In certain embodiments, each R³ is independently an optionally substituted ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, or xanthenyl.

[0137] In certain embodiments, each R³ is independently an optionally substituted ring selected from piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, or azetidinyl In some embodiments, R³ is optionally substituted morpholinyl or thiomorpholinyl. In certain embodiments, the ring is substituted with Me, Et, OH, C(O)NH₂, or C(O)Me. In certain embodiments, the ring is substituted with C(O)Me.

[0138] In certain embodiments, each R³ is independently

[0139]
or

[0140]
In certain embodiments, each R³ is independently -Me, —OMe, —NHCH₂CH₂OMe,

[0141]
or

[0142]

[0143] In some embodiments, each R³ is independently selected from those depicted in Table 3, below.

[0144] In certain embodiments, R^y is hydrogen, optionally substituted C_1-6 aliphatic, halogen, —Cl, —CF₃, —CN, —C(O)R′, —C(O)N(R′)₂, —C(═N—R″)R′ or —N(R′)₂; wherein each R′ is independently hydrogen or an optionally substituted C₁ aliphatic; and R″ is hydrogen or —OR. In certain embodiments, each R′ is independently hydrogen, Me, or Et.

[0145] In certain embodiments, R^y is hydrogen.

[0146] In certain embodiments, R^y is -Me, —Cl, —F, —CF₃, —CN, —C(O)Me, —C(O)NH₂, —C(O)NH(Me), —C(O)NH(Et), —C(═N—OH)Me, —C(═N—OMe)Me, or —NH₂.

[0147] In some embodiments, R^y is haloaliphatic. In certain embodiments, R^y is —CF₃.

[0148] In certain embodiments, R^y is halogen. In certain embodiments, R^y is —Cl.

[0149] In some embodiments, R^y is selected from those depicted in Table 3, below.

[0150] In certain embodiments, W is NH. In certain embodiments, W is O.

[0151] In certain embodiments, R′ is independently hydrogen, Me, or Et.

[0152] In various embodiments, the invention provides a compound of formula I, wherein each of Ring A, Ring B, R¹, R², R³, R^y, W, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0153] In various embodiments, the invention provides a compound of formula I-a:

[0154]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0155] In various embodiments, the invention provides a compound of formula I-b:

[0156]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0157] In various embodiments, the invention provides a compound of formula I-c:

[0158]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0159] In various embodiments, the invention provides a compound of formula I-d:

[0160]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0161] In various embodiments, the invention provides a compound of formula I-e:

[0162]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0163] In various embodiments, the invention provides a compound of formula I-f:

[0164]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0165] In various embodiments, the invention provides a compound of formula I-g:

[0166]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0167] In various embodiments, the invention provides a compound of formula I-h:

[0168]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0169] In various embodiments, the invention provides a compound of formula I-j:

[0170]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0171] In various embodiments, the invention provides a compound of formula I-k:

[0172]
or a pharmaceutically acceptable salt thereof, wherein each of R^y, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0173] In various embodiments, the invention provides a compound selected from formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, and I-k, wherein R^y is haloaliphatic. In various embodiments, the invention provides a compound selected from formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, and I-k, wherein R^y is —CF₃.

[0174] In various embodiments, the invention provides a compound selected from formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, and I-k, wherein R^y is halogen. In various embodiments, the invention provides a compound selected from formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, and I-k, wherein R^y is —Cl.

[0175] In various embodiments, the invention provides a compound of formula II:

[0176]
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0177] In various embodiments, the invention provides a compound of any of formula II-a, II-b, II-c, or II-d:

[0178]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0179] According to another embodiment, the present invention provides a compound of formula III:

[0180]
or a pharmaceutically acceptable salt thereof,
wherein, each of Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0181] According to another embodiment, the present invention provides a compound of any of formula III-a, III-b, III-c, or III-d:

[0182]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0183] According to another embodiment, the present invention provides a compound of formula IV:

[0184]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, R′, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0185] According to another embodiment, the present invention provides a compound of any of formula IV-a, IV-b, IV-c, or IV-d:

[0186]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, R′, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0187] According to another embodiment, the present invention provides a compound of formula V:

[0188]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0189] According to another embodiment, the present invention provides a compound of any of formula V-a, V-b, V-c, or V-d:

[0190]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0191] According to another embodiment, the present invention provides a compound of formula VI:

[0192]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring A, Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0193] According to another embodiment, the present invention provides a compound of any of formula VI-a, VI-b, VI-c, or VI-d:

[0194]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0195] According to another embodiment, the present invention provides a compound of formula VII:

[0196]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring A, Ring B, R¹, R², R³, R′, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0197] According to another embodiment, the present invention provides a compound of any of formula VII-a, VII-b, VII-c, or VII-d:

[0198]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring B, R¹, R², R³, R′, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0199] In certain embodiments, the present invention provides a compound of any of formula I, II, III, IV, V, VI, or VII wherein Ring B is phenyl. In other embodiments, the present invention provides a compound of any of formula I, II, III, IV, V, VI, or VII wherein Ring B is pyridyl. In other embodiments, the present invention provides a compound of any of formula I, II, III, IV, V, VI, or VII wherein Ring B is piperdinyl. In other embodiments, the present invention provides a compound of any of formula I, II, III, IV, V, VI, or VII wherein Ring B is cyclohexyl.

[0200] In some embodiments, the present invention provides a compound of formula VIII:

[0201]
or a pharmaceutically acceptable salt thereof,
wherein each of Ring A, R¹, R², R³, R^y, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0202] In some embodiments, the present invention provides a compound of formula VIII wherein R^y is haloaliphatic. In certain embodiments, the present invention provides a compound of formula VIII wherein R^y is —CF₃.

[0203] In some embodiments, the present invention provides a compound of formula VIII wherein R^y is halogen. In certain embodiments, the present invention provides a compound of formula VIII wherein R^y is —Cl.

[0204] In certain embodiments, the present invention provides a compound of formula VIII wherein at least one R³ is —OMe.

[0205] In some embodiments, the present invention provides a compound of any of formula VIII-a, VIII-b, VIII-c, or VIII-d:

[0206]
or a pharmaceutically acceptable salt thereof,
wherein each of R¹, R², R³, R^y, m and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

[0207] In some embodiments, the present invention provides a compound of any of formula VIII-a, VIII-b, VIII-c, or VIII-d wherein R^y is haloaliphatic. In certain embodiments, the present invention provides a compound of formula VIII wherein R^y is —CF₃.

[0208] In some embodiments, the present invention provides a compound of any of formula VIII-a, VIII-b, VIII-c, or VIII-d wherein R^y is halogen. In certain embodiments, the present invention provides a compound of formula VIII wherein R^y is —Cl.

[0209] In certain embodiments, the present invention provides a compound of any of formula VIII-a, VIII-b, VIII-c, or VIII-d wherein at least one R³ is —OMe.

[0210] As defined generally above, the R¹ group of any of formula I, II, III, IV, V, VI, VII, or VIII is a warhead group. In certain embodiments, R¹ is -L-Y, wherein:

• [0211] L is a covalent bond or a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N₂)—;
• [0212] Y is hydrogen, C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R^e groups; and
• [0213] each R^e is independently selected from -Q-Z, oxo, NO₂, halogen, CN, a suitable leaving group, or a C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, wherein:
• [0214] Q is a covalent bond or a bivalent C_1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, or —SO₂N(R)—; and
  • [0215] Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

[0216] In certain embodiments, L is a covalent bond.

[0217] In certain embodiments, L is a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain. In certain embodiments, L is —CH₂—.

In certain embodiments, L is a covalent bond, —CH₂—, —NH—, —CH₂NH—, —NHCH₂—, —NHC(O)—, —NHC(O)CH₂OC(O)—, —CH₂NHC(O)—, —NHSO₂—, —NHSO₂CH₂—, —NHC(O)CH₂OC(O)—, or —SO₂NH—.

[0218] In certain embodiments, L is a bivalent C_1-8 hydrocarbon chain wherein at least one methylene unit of L is replaced by —C(O)—. In certain embodiments, L is a bivalent C_1-8 hydrocarbon chain wherein at least two methylene units of L are replaced by —C(O)—. In some embodiments, L is —C(O)CH₂CH₂C(O)—, —C(O)CH₂NHC(O)—, —C(O)CH₂NHC(O)CH₂CH₂C(O)—, or —C(O)CH₂CH₂CH₂NHC(O)CH₂CH₂C(O)—.

[0219] In certain embodiments, L is a bivalent C_1-8 hydrocarbon chain wherein at least one methylene unit of L is replaced by —S(O)₂—. In certain embodiments, L is a bivalent C_1-8 hydrocarbon chain wherein at least one methylene unit of L is replaced by —S(O)₂— and at least one methylene unit of L is replaced by —C(O)—. In certain embodiments, L is a bivalent C_1-8 hydrocarbon chain wherein at least one methylene unit of L is replaced by —S(O)₂— and at least two methylene units of L are replaced by —C(O)—. In some embodiments, L is —S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)— or —S(O)₂CH₂CH₂NHC(O)—.

[0220] In some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0221] In certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0222] In some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0223] As described above, in certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond. One of ordinary skill in the art will recognize that such a double bond may exist within the hydrocarbon chain backbone or may be “exo” to the backbone chain and thus forming an alkylidene group. By way of example, such an L group having an alkylidene branched chain includes —CH₂C(═CH₂)CH₂—. Thus, in some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond. Exemplary L groups include —NHC(O)C(═CH₂)CH₂—.

[0224] In certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—. In certain embodiments, L is —C(O)CH═CH(CH₃)—, —C(O)CH═CHCH₂NH(CH₃)—, —C(O)CH═CH(CH₃)—, —C(O)CH═CH—, —CH₂C(O)CH═CH—, —CH₂C(O)CH═CH(CH₃)—, —CH₂CH₂C(O)CH═CH—, —CH₂CH₂C(O)CH═CHCH₂—, —CH₂CH₂C(O)CH═CHCH₂NH(CH₃)—, or —CH₂CH₂C(O)CH═CH(CH₃)—, or —CH(CH₃)OC(O)CH═CH—.

[0225] In certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—.

[0226] In some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. In some embodiments, L is —CH2OC(O)CH═CHCH2-, —CH2-OC(O)CH═CH—, or —CH(CH═CH2)OC(O)CH═CH—.

[0227] In certain embodiments, L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH2N(CH3)-, —NRC(O)CH═CHCH2O—, —CH2NRC(O)CH═CH—, —NRSO2CH═CH—, —NRSO2CH═CHCH2-, —NRC(O)(C═N₂)C(O)—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRC(O)CH═CHCH₂O—, —NRC(O)C(═CH₂)CH₂—, —CH₂NRC(O)—, —CH₂CH₂NRC(O)—, or —CH₂NRC(O)cyclopropylene-, wherein each R is independently hydrogen or optionally substituted C_1-6 aliphatic.

[0228] In certain embodiments, L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHC(O)CH═CHCH₂O—, —CH₂NHC(O)CH═CH—, —NHSO₂CH═CH—, —NHSO₂CH═CHCH₂—, —NHC(O)(C═N₂)C(O)—, —NHC(O)C(═CH₂)CH₂—, —CH₂NHC(O)—, —CH₂CH₂NHC(O)—, or —CH₂NHC(O)cyclopropylene-.

[0229] In some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond. In certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO₂—, —C(═S)—, —C(═NR)—, —O—, —N(R)—, or —C(O)—. In some embodiments, L has at least one triple bond and at least one methylene unit of L is replaced by —N(R)—, —N(R)C(O)—, —C(O)—, —C(O)O—, or —OC(O)—, or —O—.

[0230] Exemplary L groups include —C≡C—, —C≡CCH₂N(isopropyl)-, —NHC(O)C≡CCH₂CH₂—, —CH₂—C≡C—CH₂—, —C≡CCH₂O—, —CH₂C(O)C≡C—, —C(O)C≡C—, or —CH₂OC(═O)C≡C—.

[0231] In some embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

[0232] In certain embodiments, L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, or —SO₂N(R)—. Exemplary L groups include —NHC(O)-cyclopropylene-SO₂— and —NHC(O)— cyclopropylene-.

[0233] As defined generally above, Y is hydrogen, C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 R^e groups, each R^e is independently selected from -Q-Z, oxo, NO₂, halogen, CN, a suitable leaving group, or C_1-6 aliphatic, wherein Q is a covalent bond or a bivalent C_1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, or —SO₂N(R)—; and, Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

[0234] In certain embodiments, Y is hydrogen.

[0235] In certain embodiments, Y is C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN. In some embodiments, Y is C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN. In other embodiments, Y is C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN. In some embodiments, Y is C_2-6 alkenyl. In other embodiments, Y is C_2-4 alkynyl. In certain embodiments, Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

[0236] In other embodiments, Y is C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN. Such Y groups include —CH₂F, —CH₂Cl, —CH₂CN, and —CH₂NO₂.

[0237] In certain embodiments, Y is a saturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Y is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein.

[0238] In some embodiments, Y is a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein. Exemplary such rings are epoxide and oxetane rings, wherein each ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein.

[0239] In other embodiments, Y is a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. Such rings include piperidine and pyrrolidine, wherein each ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In certain embodiments, Y is

[0240]
or

[0241]
wherein each R, Q, Z, and R^e is as defined above and described herein. In certain embodiments, Y is piperazine.

[0242] In some embodiments, Y is a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In certain embodiments, Y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In certain embodiments, Y is

[0243]
wherein R^e is as defined above and described herein. In certain embodiments, Y is cyclopropyl optionally substituted with halogen, CN or NO₂.

[0244] In certain embodiments, Y is a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein.

[0245] In some embodiments, Y is a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In some embodiments, Y is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl wherein each ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In certain embodiments, Y is

[0246]
wherein each R^e is as defined above and described herein.

[0247] In certain embodiments, Y is a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein. In certain embodiments, Y is selected from:

[0248]
wherein each R and R^e is as defined above and described herein.

[0249] In certain embodiments, Y is a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein. In certain embodiments, Y is phenyl, pyridyl, or pyrimidinyl, wherein each ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein.

[0250] In some embodiments, Y is selected from:

[0251]
wherein each R^e is as defined above and described herein.

[0252] In other embodiments, Y is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein. In some embodiments, Y is a 5 membered partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein. Exemplary such rings are isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, triazole, thiadiazole, and oxadiazole, wherein each ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein. In certain embodiments, Y is selected from:

[0253]
wherein each R and R^e is as defined above and described herein.

[0254] In certain embodiments, Y is an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein. According to another aspect, Y is a 9-10 membered bicyclic, partially unsaturated, or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein. Exemplary such bicyclic rings include 2,3-dihydrobenzo[d]isothiazole, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein.

[0255] As defined generally above, each R^e group is independently selected from -Q-Z, oxo, NO₂, halogen, CN, a suitable leaving group, or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, wherein Q is a covalent bond or a bivalent C_1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, or —SO₂N(R)—; and Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

[0256] In certain embodiments, R^e is C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN. In other embodiments, R^e is oxo, NO₂, halogen, or CN.

[0257] In some embodiments, R^e is -Q-Z, wherein Q is a covalent bond and Z is hydrogen (i.e., R^e is hydrogen). In other embodiments, R^e is -Q-Z, wherein Q is a bivalent C_1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO₂—. In other embodiments, Q is a bivalent C_2-6 straight or branched, hydrocarbon chain having at least one double bond, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO₂—. In certain embodiments, the Z moiety of the R^e group is hydrogen. In some embodiments, -Q-Z is —NHC(O)CH═CH₂ or —C(O)CH═CH₂.

[0258] In certain embodiments, each R^e is independently selected from oxo, NO₂, CN, fluoro, chloro, —NHC(O)CH═CH₂, —C(O)CH═CH₂, —CH₂CH═CH₂, —C(O)OCH₂Cl, —C(O)OCH₂F, —C(O)OCH₂CN, —C(O)CH₂Cl, —C(O)CH₂F, —C(O)CH₂CN, or —CH₂C(O)CH₃.

[0259] In certain embodiments, R^e is a suitable leaving group, ie a group that is subject to nucleophilic displacement. A “suitable leaving” is a chemical group that is readily displaced by a desired incoming chemical moiety such as the thiol moiety of a cysteine of interest. Suitable leaving groups are well known in the art, e.g., see, “Advanced Organic Chemistry,” Jerry March, 5^th Ed., pp. 351-357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyloxy, and diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).

[0260] In certain embodiments, the following embodiments and combinations of -L-Y apply:

[0261] (a) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(b) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(c) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(d) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(e) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(f) L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRC(O)CH═CHCH₂O—, —CH₂NRC(O)CH═CH—, —NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—, —NRC(O)(C═N₂)—, —NRC(O)(C═N₂)C(O)—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—, —NRC(O)CH═CHCH₂O—, —NRC(O)C(═CH₂)CH₂—, —CH₂NRC(O)—, —CH₂NRC(O)CH═CH—, —CH₂CH₂NRC(O)—, or —CH₂NRC(O)cyclopropylene-; wherein R is H or optionally substituted C_1-6 aliphatic; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(g) L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHC(O)CH═CHCH₂O—, —CH₂NHC(O)CH═CH—, —NHSO₂CH═CH—, —NHSO₂CH═CHCH₂—, —NHC(O)(C═N₂)—, —NHC(O)(C═N₂)C(O)—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHSO₂CH═CH—, —NHSO₂CH═CHCH₂—, —NHC(O)CH═CHCH₂O—, —NHC(O)C(═CH₂)CH₂—, —CH₂NHC(O)—, —CH₂NHC(O)CH═CH—, —CH₂CH₂NHC(O)—, or —CH₂NHC(O)cyclopropylene-; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(h) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(i) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(j) L is —C≡C—, —C≡CCH₂N(isopropyl)-, —NHC(O)C≡CCH₂CH₂—, —CH₂—C≡C—CH₂—, —C≡CCH₂O—, —CH₂C(O)C≡C—, —C(O)C≡C—, or —CH₂OC(═O)C≡C—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(k) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or
(l) L is a covalent bond and Y is selected from:
(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN;
(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(vi)

[0262]
or

[0263]
wherein each R, Q, Z, and R^e is as defined above and described herein; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(x)

[0264]
wherein each R^e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(xii)

[0265]
or

[0266]
wherein each R and R^e is as defined above and described herein; or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein; or
(xiv)

[0267]

[0268] wherein each R^e is as defined above and described herein; or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein; or

[0269]

[0270] wherein each R and R^e is as defined above and described herein; or

[0271] (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein;
(m) L is —C(O)— and Y is selected from:
(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN; or
(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(vi)

[0272]
or

[0273]
wherein each R, Q, Z, and R^e is as defined above and described herein; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(x)

[0274]
wherein each R^e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(xii)

[0275]
or

[0276]

[0277] wherein each R and R^e is as defined above and described herein; or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein; or

(xiv)

[0278]
wherein each R^e is as defined above and described herein; or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein; or
(xvi)

[0279]

[0280] wherein each R and R^e is as defined above and described herein; or

[0281] (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN; or
(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(vi)

[0282]
or

[0283]
wherein each R, Q, Z, and R^e is as defined above and described herein; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(x)

[0284]
wherein each R^e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(xii)

[0285]
or

[0286]

[0287] wherein each R and R^e is as defined above and described herein; or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein; or

(xiv)

[0288]

[0289] wherein each R^e is as defined above and described herein; or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein; or

[0290]

[0291] wherein each R and R^e is as defined above and described herein; or

[0292] (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein;
(o) L is a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from:
(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN;
(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(vi)

[0293]
or

[0294]
wherein each R, Q, Z, and R^e is as defined above and described herein; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(x)

[0295]
wherein each R^e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(xii)

[0296]
or

[0297]

[0298] wherein each R and R^e is as defined above and described herein; or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein; or

(xiv)

[0299]
wherein each R^e is as defined above and described herein; or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein; or
(xvi)

[0300]

[0301] wherein each R and R^e is as defined above and described herein; or

[0302] (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein;
(p) L is a covalent bond, —CH₂—, —NH—, —C(O)—, —CH₂NH—, —NHCH₂—, —NHC(O)—, —NHC(O)CH₂OC(O)—, —CH₂NHC(O)—, —NHSO₂—, —NHSO₂CH₂—, —NHC(O)CH₂OC(O)—, or —SO₂NH—; and Y is selected from:
(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN; or
(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups, wherein each R^e is as defined above and described herein; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(vi)

[0303]
or

[0304]
wherein each R, Q, Z, and R^e is as defined above and described herein; or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(x)

[0305]
wherein each R^e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein each R^e is as defined above and described herein; or
(xii)

[0306]
or

[0307]

[0308] wherein each R and R^e is as defined above and described herein; or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R^e groups, wherein each R^e group is as defined above and described herein; or

(xiv)

[0309]
wherein each R^e is as defined above and described herein; or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R^e groups, wherein each R^e group is as defined above and described herein; or
(xvi)

[0310]

[0311] wherein each R and R^e is as defined above and described herein; or

[0312] (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R^e groups, wherein R^e is as defined above and described herein.
(q) L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein two or three methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.
(r) L-Y is “pro-warhead” that is converted in vitro or in vivo to an irreversible warhead.

[0313] In certain embodiments, L-Y is

[0314]
wherein LG is a leaving group as understood by one of ordinary skill in the art. In certain embodiments, L-Y is

[0315]
or

[0316]
wherein R is as defined and described above and herein. In certain embodiments, the “pro-warhead” is converted to a warhead group (e.g., an acrylamide group) according to the following:

[0317]
or

[0318]
Such “pro-warheads” are applicable to any α,β unsaturated system, e.g.,

[0319]
or

[0320]

[0321] In certain embodiments, R¹ is -L-Y, wherein:

• [0322] L is a covalent bond or a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by —N(R)C(O)—, —N(R)SO₂—, —O—, —C(O)—, or —SO₂—; and
• [0323] Y is hydrogen, or C_1-6 aliphatic optionally substituted with oxo, halogen, N(R)₂, NO₂, or CN.

[0324] In certain embodiments, the Y group of R¹ group, -L-Y, is selected from those set forth in Table 1, below, wherein each wavy line indicates the point of attachment to the rest of the molecule.

[0325]

TABLE 1
Exemplary Y groups:
		a
		b
		c
		d
		e
		f
		g
		h
		i
		j
		k
		l
		m
		n
		o
		p
		q
		r
		s
		t
		u
		v
		w
		x
		y
		z
		aa
		bb
		cc
		dd
		ee
		ff
		gg
		hh
		ii
		jj
		kk
		ll
		mm
		nn
		oo
		pp
		qq
		rr
		ss
		tt
		uu
		vv
		ww
		xx
		yy
		zz
		aaa
		bbb
		ccc
		ddd
		eee
		fff
		ggg
		hhh
		iii
		jjj
		kkk
		lll
		mmm
		nnn
		ooo
		ppp
		qqq
		rrr
		sss
		ttt
		uuu
		vvv
		qqq
		www
		xxx
		yyy
		zzz
		aaaa
		bbbb
		cccc
		dddd
		eeee
		ffff
		gggg
		hhhh
		iiii
		jjjj
		kkkk
		llll
		mmmm
		nnnn
		oooo
		pppp
		qqqq
		rrrr
		ssss
		tttt
		uuuu
		vvvv
		wwww
		xxxx
		yyyy
		zzzz
		aaaaa
		bbbbb
		ccccc

wherein each R^e is independently a suitable leaving group, NO₂, CN, or oxo.

[0326] In certain embodiments, R¹ is —C≡CH, —C≡CCH₂NH(isopropyl), —NHC(O)C≡CCH₂CH₃, —CH₂—C≡C—CH₃, —C≡CCH₂OH, —CH₂C(O)C≡CH, —C(O)C≡CH, or —CH₂OC(═O)C≡CH. In some embodiments, R¹ is selected from —NHC(O)CH═CH₂, —NHC(O)CH═CHCH₂N(CH₃)₂, or —CH₂NHC(O)CH═CH₂.

[0327] In some embodiments, R¹ is 6-12 atoms long. In certain embodiments, R¹ is 6-9 atoms long. In certain embodiments, R¹ is 10-12 atoms long. In certain embodiments, R¹ is at least 8 atoms long.

[0328] In certain embodiments, R¹ is —C(O)CH₂CH₂C(O)CH═C(CH₃)₂, —C(O)CH₂CH₂C(O)CH═CH(cyclopropyl), —C(O)CH₂CH₂C(O)CH═CHCH₃, C(O)CH₂CH₂C(O)CH═CHCH₂CH₃, or —C(O)CH₂CH₂C(O)C(═CH₂)CH₃. In certain embodiments, R¹ is —C(O)CH₂NHC(O)CH═CH₂, —C(O)CH₂NHC(O)CH₂CH₂C(O)CH═CHCH₃, or —C(O)CH₂NHC(O)CH₂CH₂C(O)C(═CH₂)CH₃. In certain embodiments, R¹ is —S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═C(CH₃)₂, —S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═CHCH₃, or —S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═CH₂. In certain embodiments, R¹ is —C(O)(CH₂)₃NHC(O)CH₂CH₂C(O)CH═CHCH₃ or —C(O)(CH₂)₃NHC(O)CH₂CH₂C(O)CH═CH₂.

[0329] In certain embodiments, R¹ is selected from those set forth in Table 2, below, wherein each wavy line indicates the point of attachment to the rest of the molecule.

[0330]

TABLE 2
Exemplary R1 Groups
	a
	b
	c
	d
	e
	f
	g
	h
	i
	j
	k
	l
	m
	n
	o
	p
	q
	r
	s
	t
	u
	v
	w
	x
	y
	z
	aa
	bb
	cc
	dd
	ee
	ff
	gg
	hh
	ii
	jj
	kk
	ll
	mm
	nn
	oo
	pp
	qq
	rr
	ss
	tt
	uu
	vv
	ww
	xx
	yy
	zz
	aaa
	bbb
	ccc
	ddd
	eee
	fff
	ggg
	hhh
	iii
	jjj
	kkk
	lll
	mmm
	nnn
	ooo
	ppp
	qqq
	rrr
	sss
	ttt
	uuu
	vvv
	www
	xxx
	yyy
	zzz
	aaaa
	bbbb
	cccc
	dddd
	eeee
	ffff
	gggg
	hhhh
	iiii
	jjjj
	kkkk
	llll
	mmmm
	nnnn
	oooo
	pppp
	qqqq
	rrrr
	ssss
	tttt
	uuuu
	vvvv
	wwww
	xxxx
	yyyy
	zzzz
	aaaaa
	bbbbb
	ccccc
	ddddd
	eeeee
	fffff
	ggggg
	hhhhh
	iiiii
	jjjjj
	kkkkk
	lllll
	mmmmm
	nnnnn
	ooooo
	ppppp
	qqqqq
	rrrrr
	sssss
	ttttt
	uuuuu
	vvvvv
	wwwww
	xxxxx
	yyyyy
	zzzzz
	aaaaaa
	bbbbbb
	cccccc
	dddddd
	eeeeee
	ffffff
	gggggg
	hhhhhh
	iiiiii
	jjjjjj
	kkkkkk
	llllll
	mmmmmm
	nnnnnn
	oooooo
	pppppp
	qqqqqq
	rrrrrr
	ssssss
	tttttt
	uuuuuu
	vvvvvv
	wwwwww
	xxxxxx
	yyyyyy
	zzzzzz
	aaaaaaa
	bbbbbbb
	ccccccc
	ddddddd
	eeeeeee
	fffffff
	ggggggg
	hhhhhhh
	iiiiiii
	jjjjjjj
	kkkkkkk
	lllllll
	mmmmmmm
	nnnnnnn
	ooooooo
	ppppppp
	qqqqqqq
	rrrrrrr
	sssssss
	ttttttt
	uuuuuuu
	vvvvvvv
	wwwwwww
	xxxxxxx
	yyyyyyy
	zzzzzzz
	aaaaaaaa
	bbbbbbbb
	cccccccc
	dddddddd
	eeeeeeee
	ffffffff
	gggggggg
	hhhhhhhh
	llllllll
	iiiiiiii
	jjjjjjjj
	kkkkkkkk
	mmmmmmmm
	nnnnnnnn
	oooooooo
	pppppppp
	qqqqqqqq
	rrrrrrrr
	ssssssss
	tttttttt
	uuuuuuuu
	vvvvvvvv
	wwwwwwww
	xxxxxxxx
	yyyyyyyy
	zzzzzzzz
	aaaaaaaaa
	bbbbbbbbb
	ccccccccc
	ddddddddd
	eeeeeeeee
	fffffffff
	ggggggggg
	hhhhhhhhh
	iiiiiiiii
	jjjjjjjjj

wherein each R^e is independently a suitable leaving group, NO₂, CN, or oxo.

[0331] In certain embodiments, R¹ is selected from:

[0332]

[0333] In certain embodiments, R¹ is selected from:

[0334]

[0335] In certain embodiments, R¹ is selected from

[0336]
and

[0337] In certain embodiments, R¹ is selected from:

[0338]
In some embodiments, R¹ is selected from those depicted in Table 3, below.

[0339] In certain embodiments, the invention provides a compound selected from the group consisting of those set forth in Table 3, below:

[0340]

TABLE 3
Exemplary Compounds of Formula I
	I-1
	I-2
	I-3
	I-4
	I-5
	I-6
	I-7
	I-8
	I-9
	I-10
	I-11
	I-12
	I-13
	I-14
	I-15
	I-16
	I-17
	I-18
	I-19
	I-20
	I-21
	I-22
	I-23
	I-24
	I-25
	I-26
	I-27
	I-28
	I-29
	I-30
	I-31
	I-32
	I-33
	I-34
	I-35
	I-36
	I-37
	I-38
	I-39
	I-40
	I-41
	I-42
	I-43
	I-44
	I-45
	I-46
	I-47
	I-48
	I-49
	I-50
	I-51
	I-52
	I-53
	I-54
	I-55
	I-56
	I-57
	I-58
	I-59
	I-60
	I-61
	I-62
	I-63
	I-64
	I-65
	I-66
	I-67
	I-68
	I-69
	I-70
	I-71
	I-72
	I-73
	I-74
	I-75
	I-76
	I-77
	I-78
	I-79
	I-80
	I-81
	I-82
	I-83
	I-84
	I-85
	I-86
	I-87
	I-88
	I-89
	I-90
	I-91
	I-92
	I-93
	I-94
	I-95
	I-96
	I-97
	I-98
	I-99
	I-100
	I-101
	I-102
	I-103
	I-104
	I-105
	I-106
	I-107
	I-108
	I-109
	I-110
	I-111
	I-112
	I-113
	I-114
	I-115
	I-116
	I-117
	I-118
	I-119
	I-120
	I-121
	I-122
	I-123
	I-124
	I-125
	I-126
	I-127
	I-128
	I-129
	I-130
	I-131
	I-132
	I-133
	I-134
	I-135
	I-136
	I-137
	I-138
	I-139
	I-140
	I-141
	I-142
	I-143
	I-144
	I-145
	I-146
	I-147
	I-148
	I-149
	I-150
	I-151
	I-152
	I-153
	I-154
	I-155
	I-156
	I-157
	I-158
	I-159
	I-160
	I-161
	I-162
	I-163
	I-164
	I-165
	I-166
	I-167
	I-168
	I-169
	I-170
	I-171
	I-172
	I-173
	I-174
	I-175
	I-176
	I-177
	I-178
	I-179
	I-180
	I-181
	I-182
	I-183
	I-184
	I-185
	I-186
	I-187
	I-188
	I-189
	I-190
	I-191
	I-192
	I-193
	I-194
	I-195
	I-196
	I-197
	I-198
	I-199
	I-200
	I-201
	I-202
	I-203
	I-204
	I-205
	I-206
	I-207
	I-208
	I-209
	I-210
	I-211
	I-212
	I-213
	I-214
	I-215
	I-216
	I-217
	I-218
	I-219
	I-220
	I-221
	I-222
	I-223
	I-224
	I-225
	I-226
	I-227
	I-228
	I-229
	I-230
	I-231
	I-232
	I-233
	I-234
	I-235
	I-236
	I-237
	I-238
	I-239
	I-240
	I-241
	I-242
	I-243
	I-244
	I-245
	I-246
	I-247
	I-248
	I-249
	I-250
	I-251
	I-252
	I-253
	I-254
	I-255
	I-256
	I-257
	I-258
	I-259
	I-260
	I-261
	I-262
	I-263
	I-264
	I-265
	I-266
	I-267
	I-268
	I-269
	I-270
	I-271
	I-272
	I-273
	I-274
	I-275
	I-276
	I-277
	I-278
	I-279
	I-280
	I-281
	I-282
	I-283
	I-284
	I-285
	I-286
	I-287
	I-288
	I-289
	I-290
	I-291
	I-292
	I-293
	I-294
	I-295
	I-296
	I-297
	I-298
	I-319
	I-320
	I-321
	I-322
	I-323
	I-324
	I-325
	I-326
	I-327
	I-328
	I-329
	I-330
	I-331
	I-332
	I-333
	I-334
	I-335
	I-336
	I-337
	I-338
	I-339
	I-340
	I-341
	I-342
	I-343
	I-344
	I-345
	I-346
	I-347
	I-348
	I-349
	I-350
	I-351
	I-354
	I-355
	I-356
	I-357
	I-358
	I-359
	I-360
	I-361
	I-362
	I-363
	I-364
	I-365
	I-366
	I-367

[0341] In some embodiments, the present invention provides a compound set forth in Table 3, above, or a pharmaceutically acceptable salt thereof.

[0342] Other compounds contemplated by the invention are selected from those depicted in Table 4, below:

[0343]

TABLE 4
Additional Exemplary Compounds
	I-307
	I-308
	I-309
	I-310
	I-311
	I-312
	I-313
	I-314
	I-315
	I-316
	I-317
	I-318
	I-352
	I-353

[0344] Compounds according to the invention can be conjugated to biological molecules, such as antibodies or other biological carriers. In certain embodiments, the present invention provides a conjugate comprising one or both of ERK1 and ERK2 kinase having a cysteine residue, Cys183 (ERK1) and/or Cys166 (ERK2), wherein the Cys183 and/or Cys166 is covalently, and irreversibly, bonded to an inhibitor, such that inhibition of the kinase is maintained. Cys166 of ERK2 is the same positional amino acid as Cys183 of ERK1. Thus, the below discussion regarding Cys183 of ERK1 also applies to Cys166 of ERK2 (and vice versa).

[0345] In certain embodiments, the present invention provides a conjugate of the formula A:
Cys183-modifier-inhibitor moiety  A
wherein:
the Cys183 is Cys183 of ERK1;
the modifier is a bivalent group resulting from covalent bonding of a warhead group with the Cys183 of ERK1 kinase;
the warhead group is a functional group capable of covalently binding to Cys183; and
the inhibitor moiety is a moiety that binds in the ATP binding site of the ERK1 kinase.

[0346] In certain embodiments, the inhibitor moiety of conjugate A is of formula I-i:

[0347]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where W is attached; and wherein each of Ring A, Ring B, R², R³, R^y, W, m and p, of formula I-i is as defined for formula I above and as defined and described in embodiments herein.

[0348] In certain embodiments, the inhibitor moiety of conjugate A is of formula I-a-i:

[0349]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, R^y, m and p, of formula I-a-i is as defined for formula I-a above and as defined and described in embodiments herein.

[0350] In certain embodiments, the inhibitor moiety of conjugate A is any one of formulae I-b-i, I-c-i, I-d-i, and I-e-i:

[0351]
wherein each wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein each of Ring B, R², R³, R^y, m and p, of formulae I-b-i, I-c-i, I-d-i, and I-e-i is as defined for formulae I-b, I-c, I-d, and I-e above and as defined and described in embodiments herein.

[0352] In certain embodiments, the inhibitor moiety of conjugate A is of formula I-f-i:

[0353]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, R^y, m and p, of formula I-f-i is as defined for formula I-f above and as defined and described in embodiments herein.

[0354] In certain embodiments, the inhibitor moiety of conjugate A is of any one of formulae I-g-i, I-h-i, I-j-i, and I-k-i:

[0355]
wherein each wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein each of Ring B, R², R³, R^y, m and p, of formulae I-g-i, I-h-i, I-j-i, and I-k-i: is as defined for formula I-g, I-h, I-j, and I-k above and as defined and described in embodiments herein.

[0356] In certain embodiments, the inhibitor moiety of conjugate A is of formula II-i:

[0357]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula II-i is as defined for formula II above and as defined and described in embodiments herein.

[0358] In certain embodiments, the inhibitor moiety of conjugate A is of formula III-i:

[0359]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula III-i is as defined for formula III above and as defined and described in embodiments herein.

[0360] In certain embodiments, the inhibitor moiety of conjugate A is of formula IV-i:

[0361]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, R′, m and p, of formula IV-i is as defined for formula IV above and as defined and described in embodiments herein.

[0362] In certain embodiments, the inhibitor moiety of conjugate A is of formula V-i:

[0363]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula V-i is as defined for formula V above and as defined and described in embodiments herein.

[0364] In certain embodiments, the inhibitor moiety of conjugate A is of formula VI-i:

[0365]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula VI-i is as defined for formula VI above and as defined and described in embodiments herein.

[0366] In certain embodiments, the inhibitor moiety of conjugate A is of formula VII-i:

[0367]
wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, R′, m and p, of formula VII-i is as defined for formula VII above and as defined and described in embodiments herein.

[0368] In certain embodiments, the inhibitor moiety of conjugate A is of formula VIII-i:

[0369]

[0370] wherein the wavy bond indicates the point of attachment to Cys183 of conjugate A via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, R^y, m and p, of formula VIII-i is as defined for formula VIII above and as defined and described in embodiments herein.

[0371] In certain embodiments, the present invention provides a conjugate of the formula B:
Cys166-modifier-inhibitor moiety  B
wherein:
the Cys166 is Cys166 of ERK2;
the modifier is a bivalent group resulting from covalent bonding of a warhead group with the Cys166 of ERK2 kinase;
the warhead group is a functional group capable of covalently binding to Cys166; and
the inhibitor moiety is a moiety that binds in the ATP binding site of the ERK2 kinase.

[0372] In certain embodiments, the inhibitor moiety of conjugate B is of formula I-i:

[0373]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where W is attached; and wherein each of Ring A, Ring B, R², R³, R^y, W, m and p, of formula I-i is as defined for formula I above and as defined and described in embodiments herein.

[0374] In certain embodiments, the inhibitor moiety of conjugate B is of formula I-a-i:

[0375]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, R^y, m and p, of formula I-a-i is as defined for formula I-a above and as defined and described in embodiments herein.

[0376] In certain embodiments, the inhibitor moiety of conjugate B is any one of formulae I-b-i, I-c-i, I-d-i, and I-e-i:

[0377]
wherein each wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein each of Ring B, R², R³, R^y, m and p, of formulae I-b-i, I-c-i, I-d-i, and I-e-i is as defined for formula I-b, I-c, I-d, and I-e above and as defined and described in embodiments herein.

[0378] In certain embodiments, the inhibitor moiety of conjugate B is of formula I-f-i:

[0379]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, R^y, m and p, of formula I-f-i is as defined for formula I-f above and as defined and described in embodiments herein.

[0380] In certain embodiments, the inhibitor moiety of conjugate B is of any one of formulae I-g-i, I-h-i, I-j-i, and I-k-i:

[0381]
wherein each wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein each of Ring B, R², R³, R^y, m and p, of formulae I-g-i, I-h-i, I-j-i, and I-k-i: is as defined for formula I-g, I-h, I-j, and I-k above and as defined and described in embodiments herein.

[0382] In certain embodiments, the inhibitor moiety of conjugate B is of formula II-i:

[0383]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula II-i is as defined for formula II above and as defined and described in embodiments herein.

[0384] In certain embodiments, the inhibitor moiety of conjugate B is of formula III-i:

[0385]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula III-i is as defined for formula III above and as defined and described in embodiments herein.

[0386] In certain embodiments, the inhibitor moiety of conjugate B is of formula IV-i:

[0387]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, Ring B, R², R³, R′, m and p, of formula IV-i is as defined for formula IV above and as defined and described in embodiments herein.

[0388] In certain embodiments, the inhibitor moiety of conjugate B is of formula V-i:

[0389]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula V-i is as defined for formula V above and as defined and described in embodiments herein.

[0390] In certain embodiments, the inhibitor moiety of conjugate B is of formula VI-i:

[0391]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, m and p, of formula VI-i is as defined for formula VI above and as defined and described in embodiments herein.

[0392] In certain embodiments, the inhibitor moiety of conjugate B is of formula VII-i:

[0393]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where O is attached; and wherein each of Ring A, Ring B, R², R³, R′, m and p, of formula VII-i is as defined for formula VII above and as defined and described in embodiments herein.

[0394] In certain embodiments, the inhibitor moiety of conjugate B is of formula VIII-i:

[0395]
wherein the wavy bond indicates the point of attachment to Cys166 of conjugate B via the modifier, wherein when Ring A is a five or six member ring, then the wavy bond is attached to an atom adjacent to where NH is attached; and wherein each of Ring A, R², R³, R^y, m and p, of formula VIII-i is as defined for formula VIII above and as defined and described in embodiments herein.

[0396] In certain embodiments, the present invention provides a conjugate of any of the formulae below:

[0397]
wherein each of Cys183, Cys166, Modifier, Ring A, Ring B, R², R³, R^y, W, m and p, with respect to the above formulae is as defined and described in embodiments herein for formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-l, II, III, IV, V, VI, VII and VIII. In some embodiments, when Ring A is a five or six member ring, then modifier is attached to an atom adjacent to where W, N, or O is attached.

[0398] In other embodiments, the modifier moiety of any of conjugate described above is selected from those set forth in Table 5, below. Exemplary modifiers further include any bivalent group resulting from covalent bonding of a warhead moiety found in Table 1 or Table 2 with a cysteine of the kinases recited herein. It will be understood that the exemplary modifiers below are shown as conjugated to the sulfhydryl of CysX.

[0399]

TABLE 5
Exemplary Modifiers Conjugated to Cys 183 or Cys166:
	a
	b
	c
	d
	e
	f
	g
	h
	i
	j
	k
	l
	m
	n
	o
	p
	q
	r
	s
	t
	u
	v
	w
	x
	y
	z
	aa
	bb
	cc
	dd
	ee
	ff
	gg
	hh
	ii
	jj
	kk
	ll
	mm
	nn
	oo
	pp
	qq
	rr
	ss
	tt
	uu
	vv
	ww
	xx
	yy
	zz
	aaa
	bbb
	ccc
	ddd
	eee
	fff
	ggg
	hhh
	iii
	jjj
	kkk
	lll
	mmm
	nnn
	ooo
	ppp
	qqq
	rrr
	sss
	ttt
	uuu
	vvv
	www
	xxx
	yyy
	zzz
	aaaa
	bbbb
	cccc
	dddd
	eeee
	ffff
	gggg
	hhhh
	iiii
	jjjj
	kkkk
	llll
	mmmm
	nnnn
	oooo
	pppp
	qqqq
	rrrr
	ssss
	tttt
	uuuu
	vvvv
	wwww
	xxxx
	yyyy
	zzzz
	aaaaa
	bbbbb
	ccccc
	ddddd
	eeeee
	fffff
	ggggg
	hhhhh
	iiiii
	jjjjj
	kkkkk
	lllll
	mmmmm
	nnnnn
	ooooo
	ppppp
	qqqqq
	rrrrr
	sssss
	ttttt