CLAIM OF PRIORITY

This application claims priority to U.S. Ser. No. 61/927,793, filed on Jan. 15, 2014, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, pharmaceutical compositions, and methods of using such compounds and compositions to inhibit the activity of FGFR-4.

BACKGROUND

Fibroblast growth factor receptor 4 (FGFR-4) is a protein that in humans is encoded by the FGFR-4 gene. This protein is a member of the fibroblast growth factor receptor family, where amino acid sequence was highly conserved between members throughout evolution. FGFR family members 1-4 differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. The genomic organization of the FGFR-4 gene encompasses 18 exons. Although alternative splicing has been observed, there is no evidence that the C-terminal half of the IgIII domain of this protein varies between three alternate forms, as indicated for FGFR 1-3.

Ectopic mineralization, characterized by inappropriate calcium-phosphorus deposition in soft tissue, has been observed in rats treated with an FGFR-1 inhibitor (Brown, A P et al. (2005), Toxicol. Pathol., p. 449-455). This suggests that selective inhibition of FGFR-4 without inhibition of other isoforms of FGFR, including FGFR-1, may be desirable in order to avoid certain toxicities. FGFR-4 preferentially binds fibroblast growth factor 19 (FGF19) and has recently been associated with the progression of certain sarcomas, renal cell cancer, breast cancer, and liver cancer.

SUMMARY OF THE INVENTION

Described herein are inhibitors of FGFR-4. Further described herein are pharmaceutical compositions and pharmaceutical formulations that include an inhibitor of FGFR-4.

In one aspect, the invention features a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein:

[Image Omitted]

[Image Omitted] denotes a single or double bond;

Warhead is a moiety capable of forming a covalent bond with a nucleophile;

Ring A is a 5-8 membered aryl, 5-12 membered heteroaryl, 3-7 member heterocyclyl or 3-12 membered cycloalkyl group;

W is C or N, X and Z are each independently CH or N;

Y is CH or Nâ€”R⁴wherein R⁴is H, C_1-6alkyl, or 3-12 membered cycloalkyl;

each of R¹-R³is, independently, halo, cyano, optionally substituted C_1-6alkyl, optionally substituted C_1-6alkoxy, hydroxy, oxo, amino, amido, alkyl urea, optionally substituted 3-7 member heterocyclyl;

R⁷is hydrogen or C_1-6alkyl; or R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-5 occurrences of R¹;

m is 0-5;

n is 0-5; and

p is 0-2.

In the compounds disclosed herein, a warhead is a moiety that is reactive with a nucleophile, for example, capable of forming a covalent bond with a nucleophile. Examples of warheads include, without limitation, alkyl halides, alkyl sulfonates, heteroaryl halides, epoxides, haloacetamides, maleimides, sulfonate esters, alpha-beta unsaturated ketones, alpha-beta unsaturated esters, vinyl sulfones, propargyl amides, acrylamides. In some of these instances, e.g., acrylamide and propargyl amide, the N of the warhead is the adjacent N in the formulae shown above. Structures of exemplary warheads are shown below:

[Image Omitted]

wherein X is a leaving group such as halo, or an activated hydroxyl moiety (e.g., triflate); and each of R^a, R^b, and R^cis, independently, H, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4cycloalkyl, or cyano.

In the formulae shown above, the warheads are typically attached to a N atom on the inhibitor. In other embodiments, the warhead can alternatively be attached to an atom other than N. Examples of exemplary warheads include, without limitation,

[Image Omitted]

Other examples of warheads can be found, e.g., in WO 2010/028236 and WO 2011/034907.

In another aspect, the invention features a method for treating a condition mediated by FGFR-4, a condition characterized by overexpression of FGFR-4, a condition characterized by amplification of FGFR4, a condition mediated by FGF19, a condition characterized by amplified FGF-19, or a condition characterized by overexpression of FGF19, any of these methods comprising administering a therapeutically effective amount of a compound disclosed herein to a subject.

In another aspect, the invention features a method of treating any of the following conditions by administering a therapeutically effective amount of a compound disclosed herein to a subject: hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, a sarcoma, or hyperlipidemia.

The invention includes all possible combinations of the embodiments described above and below.

DETAILED DESCRIPTION

The compounds disclosed herein can form a covalent bond with FGFR-4 protein; for example, the compounds can form a covalent bond with a cysteine residue of FGFR-4, for example, the cysteine at residue 552. FGFRs1-3 do not contain this cysteine. The ability to form a covalent bond between the compound and FGFR-4 is therefore an important factor in the selectivity of the compounds disclosed herein for FGFR-4.

The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Other embodiments and different ways to practice the invention are expressly included. Also, the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting. The use of â€œincluding,â€ â€œincludes,â€ â€œinclude,â€ â€œcomprising,â€ or â€œhaving,â€ â€œcontainingâ€ , â€œinvolvingâ€ , and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

DEFINITIONS

â€œAliphatic groupâ€ , as used herein, refers to a straight-chain, branched-chain, or cyclic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, and an alkynyl group.

â€œAlkenylâ€ , as used herein, refers to an aliphatic group containing at least one double bond.

â€œAlkoxylâ€ or â€œalkoxyâ€ , as used herein, refers to an alkyl group having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.

â€œAlkylâ€ , as used herein, refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. â€œAlkyleneâ€ refers to a double radical, that is, an aliphatic group substituted on two ends. In some embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀for straight chains, C₃-C₃₀for branched chains), and in other embodiments can have 20 or fewer, or 10 or fewer. Likewise, certain cycloalkyls may have from 3-10 carbon atoms in their ring structure, and in some embodiments may have 5, 6 or 7 carbons in the ring structure. The term â€œalkenylâ€ , as used herein, refers to an aliphatic group containing at least one double bond; the term â€œalkynylâ€ , as used herein, refers to an aliphatic group containing at least one triple bond.

â€œAlkylthioâ€ , as used herein, refers to a hydrocarbyl group having a sulfur radical attached thereto. In some embodiments, the â€œalkylthioâ€ moiety is represented by one of â€”S-alkyl, â€”S-alkenyl, or â€”S-alkynyl. Representative alkylthio groups include methylthio, ethylthio, and the like.

â€œAmidoâ€ , as used herein, refers to â€”C(â• O)â€”N(R¹)(R²) or â€”N(R¹)â€”C(â• O)â€”R²wherein each of R¹and R²is independently hydrogen, hydroxyl, C₁-C₆alkyl, or C₁-C₆alkoxyl, e.g., methoxyl.

â€œAminoâ€ , as used herein, refers to â€”NH₂, â€”NH(alkyl), or â€”N(alkyl)(alkyl).

â€œAmplifiedâ€ , as used herein, means additional copies of a gene or chromosome segment are produced in cancer cells that may confer a growth or survival advantage.

â€œAralkylâ€ , as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

â€œArylâ€ , as used herein, refers to 5-, 6-, and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as â€œaryl heterocyclesâ€ or â€œheteroaromatics.â€ The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, â€”CF₃, â€”CN, or the like. The term â€œarylâ€ also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are â€œfused ringsâ€ ) wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. Each ring can contain, e.g., 5-7 members.

The term â€œcarbocycleâ€ as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term â€œcycloalkylâ€ as used herein, includes cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). The cycloalkyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

â€œCovalent inhibitor,â€ as used herein, means an inhibitor that can form a covalent bond with a protein.

The â€œenantiomeric excessâ€ or â€œ% enantiomeric excessâ€ of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S-enantiomer, and 10% of the other enantiomer, i.e., the R-enantiomer.

ee=(90âˆ’10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein contain an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the S-enantiomer. In other words, the compositions contain an enantiomeric excess of the S-enantiomer over the R-enantiomer. In some embodiments, the compositions described herein contain an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the R-enantiomer. In other words, the compositions contain an enantiomeric excess of the R-enantiomer over the S-enantiomer.

â€œFGFR-4â€ or â€œFGFR-4 proteinâ€ refers to any form of the FGFR-4 protein, including wild type and all variant forms (including, without limitation, mutant forms and splice variants). The FGFR-4 protein is a product of the FGFR-4 gene, and the FGFR-4 protein therefore includes any protein encoded by any form of the FGFR-4 gene, including all aberrations, e.g., point mutations, indels, translocation fusions, and focal amplifications.

â€œHaloâ€ refers to a radical of any halogen, e.g., â€”F, â€”Cl, â€”Br, or â€”I.

â€œHaloalkylâ€ and â€œhaloalkoxyâ€ refers to alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms â€œfluoroalkylâ€ and â€œfluoroalkoxyâ€ include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

â€œHeteroarylalkylâ€ refers to an alkyl group substituted with a heteroaryl group.

â€œHeterocyclylâ€ or â€œheterocyclic groupâ€ refers to a ring structure, such as a 3- to 14-membered ring structure, whose ring(s) include one or more heteroatoms. Heterocyclyl can also include polycycles, with each group having, e.g., 3-7 ring members. The term â€œheterocyclylâ€ or â€œheterocyclic groupâ€ includes â€œheteroarylâ€ and â€œsaturated or partially saturated heterocyclylâ€ structures. The term â€œsaturated or partially saturated heterocyclylâ€ refers to a non-aromatic cyclic structure that includes at least one heteroatom. The term â€œheterocyclylâ€ can also include 8-12 membered bicyclic heterocyclyls, e.g., wherein a saturated or partially saturated heterocyclyl is fused to an aromatic or heteroaromatic ring. The term â€œheterocyclylâ€ can also include 8-12 membered bicyclic heterocyclyls, e.g., wherein a saturated or partially saturated cycloalkyl is fused to an aromatic or heteroaromatic ring. The point of attachment of the heterocyclyl to the rest of the molecule can be through the saturated or partially saturated heterocyclyl or cycloalkyl, or through the aromatic or heteroaromatic ring.

â€œHeteroarylâ€ refers to a 5-14 membered (i.e., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic) aromatic ring system having 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatoms if bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring heteroatoms independently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any ring atom can be substituted (e.g., by one or more substituents).

Heterocyclyl groups include, for example, thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiin, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, â€”CF₃, â€”CN, or the like.

â€œHeterocyclylalkylâ€ refers to an alkyl group substituted with a heterocycle group.

â€œHydroxyâ€ or â€œhydroxylâ€ refers to the chemical group â€”OH.

â€œInhibitorâ€ refers to a compound that inhibits an enzyme such that a reduction in activity of the enzyme can be observed, e.g., in a biochemical assay. In certain embodiments, an inhibitor has an IC₅₀of less than about 1 Î¼M, less than about 500 nM, less than about 250 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM. An inhibitor of FGFR-4 refers to a compound that inhibits FGFR-4.

â€œNucleophileâ€ refers to a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. In some embodiments, a nucleophile can be an oxygen nucleophile, e.g., water or hydroxyl, a nitrogen nucleophile, e.g., amine, or a sulfur nucleophile, e.g., thiol, such as, for example, the thiol in the side chain of a cysteine residue.

â€œOverexpressed,â€ as used herein, means there is production of a gene product in a sample that is substantially higher than that observed in a population of control samples (e.g. normal tissue).

â€œOxoâ€ refers to (â• O).

â€œSelectiveâ€ refers to a compound that inhibits the activity of a target protein, e.g., FGFR-4, more potently than it inhibits activity of other proteins. In this instance, the isoforms FGFR-1, FGFR-2, FGFR-3, and FGFR-4 are all considered distinct proteins. In some embodiments, a compound can inhibit the activity of the target protein, e.g., FGFR-4, at least 1.5, at least 2, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 200, at least 500, or at least 1000 or more times potently than it inhibits the activity of a non-target protein.

â€œSubstitutedâ€ refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that â€œsubstitutionâ€ or â€œsubstituted withâ€ includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term â€œsubstitutedâ€ is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), â€”CF₃, â€”CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, â€”CF₃, â€”CN, and the like. Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

â€œWarhead moietyâ€ or â€œwarheadâ€ refers to a moiety of an inhibitor which participates, either reversibly or irreversibly, with the reaction of a donor, e.g., a protein, with a substrate. Warheads may, for example, form covalent bonds with the protein, or may create stable transition states, or be a reversible or an irreversible alkylating agent. For example, the warhead moiety can be a functional group on an inhibitor that can participate in a bond-forming reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein. In embodiments, the warhead is an electrophile and the â€œdonorâ€ is a nucleophile such as the side chain of a cysteine residue. Examples of suitable warheads include, without limitation, the groups shown below:

[Image Omitted]

wherein X is a leaving group such as halo, or an activated hydroxyl moiety (e.g., triflate); and each of R^a, R^b, and R^cis, independently, H, substituted or unsubstituted C_1-4alkyl, substituted or unsubstituted C_1-4cycloalkyl, or cyano.

As used herein, the term â€œpatientâ€ or â€œsubjectâ€ refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

As used herein, the term â€œeffective amountâ€ refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term â€œtreatingâ€ includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term â€œmodulateâ€ or â€œmodulatingâ€ refers to an increase or decrease, e.g., in the activity of an enzyme in response to exposure to a compound or composition described herein, e.g., the inhibition of FGFR-4, in at least a sub-population of cells in a subject such that a desired end result is achieved (e.g., a therapeutic result). In some embodiments, a compound as described herein inhibits a target described herein, e.g., FGFR-4.

Compounds

The compounds described herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H) or carbon-14 (¹⁴C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, deuterated compounds or compounds containing ¹³C are intended to be encompassed within the scope of the invention.

Certain compounds can exist in different tautomeric forms, and all possible tautomeric forms of all of the compounds described herein are intended to be encompassed within the scope of the invention.

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.

The compounds described herein can be useful as the free base or as a salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) â€œPharmaceutical Saltsâ€ , J. Pharm. Sci. 66:1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

In one aspect, the invention provides a compound having structural Formula I:

[Image Omitted]

wherein:

[Image Omitted] denotes a single or double bond;

Warhead is a moiety capable of forming a covalent bond with a nucleophile;

Ring A is a 5-8 membered aryl, 5-12 membered heteroaryl, 3-7 member heterocyclyl or 3-12 membered cycloalkyl group;

W is C or N, X and Z are each independently CH or N;

Y is CH or Nâ€”R⁴where R⁴is H, C_1-6alkyl, or 3-12 membered cycloalkyl;

each of R¹-R³is, independently, halo, cyano, optionally substituted C_1-6alkyl, optionally substituted C_1-6alkoxy, hydroxy, oxo, amino, amido, alkyl urea, optionally substituted 3-7 member heterocyclyl;

R⁷is hydrogen or C_1-6alkyl; or R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-5 occurrences of R¹;

m is 0-5;

n is 0-5; and

p is 0-2.

In some embodiments, [Image Omitted] denotes a single bond. In some embodiments, denotes a double bond. In some embodiments, is a single bond and the other is a double bond.

In some embodiments, Ring A is aryl. In some embodiments, Ring A is phenyl substituted with 0-3 R¹. In some embodiments, R¹is selected from the group consisting of halo, optionally substituted C_1-6alkyl, and optionally substituted C_1-6alkoxy.

In some embodiments, R⁷is hydrogen or C_1-6alkyl. In some embodiments, R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-5 occurrences of R¹. In some embodiments, R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-3 occurrences of R¹.

In some embodiments, X is N. In some embodiments, X is CH.

In some embodiments, Y is Nâ€”R⁴wherein R⁴is C_1-6alkyl or 3-12 membered cycloalkyl. In some embodiments, R⁴is methyl, ethyl or isopropyl. In some embodiments, R⁴is ethyl. In some embodiments, R⁴is 3-12 membered cycloalkyl. In some embodiments, R⁴is cyclopentyl.

In some embodiments, Y is Nâ€”R⁴wherein R⁴is C_1-6alkyl or 3-12 membered cycloalkyl and R³is oxo. In some embodiments, R⁴is methyl, ethyl or isopropyl. In some embodiments, R⁴is ethyl. In some embodiments, R⁴is 3-12 membered cycloalkyl. In some embodiments, R⁴is cyclopentyl.

In some embodiments, q is 0.

In some embodiments, the warhead moiety is selected from the group consisting of

[Image Omitted]

wherein each of R^a, R^b, and R^cis, independently, hydrogen, optionally substituted C_1-4alkyl, optionally substituted 3-12 membered cycloalkyl, or cyano.

In some embodiments, R²is alkoxy or halo. In some embodiments, R²is methoxy or chloro. In some embodiments, two R²are chloro and two R²are methoxy.

In one embodiment, the invention features a compound of Formula I(a) or a pharmaceutically acceptable salt thereof:

[Image Omitted]

wherein X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

In one embodiment, the invention features a compound of Formula I(b) or a pharmaceutically acceptable salt thereof:

[Image Omitted]

wherein X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

In one embodiment, the invention features a compound of Formula I(b) or a pharmaceutically acceptable salt thereof:

[Image Omitted]

wherein X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

In one embodiment, the invention features a compound of Formula I(d) or a pharmaceutically acceptable salt thereof:

[Image Omitted]

In some embodiments, the Warhead moiety is

[Image Omitted]

Ring A is phenyl, and R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-5 occurrences of R¹; R⁴is C_1-6alkyl or 3-12 membered cycloalkyl; R²is C_1-6alkoxy or halo; and n is 4. In some embodiments, R⁷together with Ring A forms an 8-12 membered bicyclic heterocyclyl optionally substituted with 1-3 occurrences of R¹.

In some embodiments, Ring A together with R⁷forms an 8-10 membered heterocyclyl. In some embodiments, Ring A together with R⁷forms:

[Image Omitted]

wherein V is CH₂or O; r is 0 or 1; and R¹and m are as defined herein.