FGFR inhibitors and methods of use thereof

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 846,991, filed on May 13, 2019; U.S. Provisional Application No. 62 / 993,957, filed on March 24, 2020; and U.S. Provisional Application No. 63 / 011,469, filed on April 17, 2020.BACKGROUND

[0002] Fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4) are receptor tyrosine kinases consisting of an extracellular ligand binding domain and an intracellular tyrosine kinase domain. Binding of FGF ligands leads to receptor dimerization and a conformational change in the intracellular domain resulting in intermolecular transphosphorylation of the kinase domain and intracellular tail. Phosphorylated residues serve as docking sites for adaptor proteins that promote downstream signaling cascades leading to cellular behaviors including proliferation, survival, differentiation, migration, and angiogenesis. Deregulated FGFR signaling can occur via FGFR gene amplification or fusion, FGFR missense mutations, receptor overexpression resulting from dysregulation of epigenetic and / or transcriptional regulators, or upregulation of FGF ligands in the tumor microenvironment. FGFRs are expressed on many cell types; thus, aberrant FGFR signaling has been implicated in oncogenesis, tumor progression, and resistance to therapy across many tumor types. (For a review of FGFR signaling, see N. Turner and R. Grose, Nat. Rev. Cancer 2010, 10:116-129; and references cited therein.).

[0003] EP 2 657 233 describes a 3,5-disubstituted benzene alkynyl compound and a salt thereof that have fibroblast growth factor receptor inhibitory effects; a pharmaceutical composition, an FGFR inhibitor, and an antitumor agent, each comprising the 3,5-disubstituted benzene alkynyl compound or a salt thereof as an active ingredient; a method for treating a tumor; and use of the compound in the treatment of a tumor. Pan-FGFR1-3 inhibitors have generated clinical responses in numerous FGFR-altered cancers, however on-target toxicity limits dosing of these inhibitors. One of the most common adverse effects of pan-FGFR inhibition is hyperphosphatemia. Regulation of phosphate reabsorption is mediated by FGFR3 and FGFR1. Thus, there is a need for FGFR-selective inhibitors that spare FGFR1. (J. Gattineni et al., Am. J. Physiol. Renal Physiol. 2014, 306:F351-F358; X. Han et al., PLoS One 2016, 11:e0147845.) Cancers harboring FGFR2 gene fusions as well as those with FGFR2 amplification and / or FGFR2 activating mutations have demonstrated responses to pan-FGFR inhibition, however the low rates and duration of responses suggest they were limited by toxicities. Thus, there is a need for FGFR2-selective inhibitor compounds and methods for treating cancers and other disorders with these compounds. (For reviews of pan-FGFR1-3 inhibitors and clinical responses, see I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; and references cited therein.).SUMMARY

[0004] All embodiments in the subsequent paragraphs that do not fall within the claims are provided for context / reference. The invention is as defined in the appended set of claims. The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for the human (or animal) body by therapy (or for diagnosis).DETAILED DESCRIPTION 1. General Description of Certain Embodiments of the Invention

[0005] Compounds of the present invention, and pharmaceutical compositions thereof as claimed, are useful as inhibitors of FGFR2. In some embodiments, the present disclosure provides a compound of formula I-1: or a pharmaceutically acceptable salt thereof, wherein: Cy A< is wherein represents a bond to R 5< and represents a bond to Cy 6< ; R 5< is -R 5A< -L 5< -R 5B< . R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< ; R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; Cy 6< is phenylene; a bivalent saturated or partially unsaturated 3-14 membered carbocyclic ring; a bivalent saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< ; R W< is halogen, -CN, each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , an instance of R 6< and an instance of R L< , an instance of R 6< and an instance of R WA< , or an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< ; R 8< is H, -NR 2 , halogen, -OH, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 9< is H, -NR 2 , halogen, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 10< is H or C 1-6 aliphatic optionally substituted with 1-3 halogens; each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; wherein each of said C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R A< or C 1-6 aliphatic; each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with w instances of R C< ; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; or two instances of R 5C< , one instance of R 5C< and one instance of R 5D< , or two instances of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; each of m, n, p, q, r, t, u, v, and w is independently 0, 1, 2, 3, or 4.

[0006] In some embodiments, the present disclosure provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 5< is -R 5A< -L 5< -R 5B< ; R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< ; R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; Cy 6< is phenylene or a 6-membered heteroarylene having 1-3 nitrogen atoms, wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< ; R W< is halogen, -CN, or each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4. 2. Compounds and Definitions

[0007] Compounds of the present disclosure include those described generally herein, 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 disclosure, 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", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.

[0008] 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" or "cycloaliphatic"), 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, "cycloaliphatic" (or "carbocycle") refers to a monocyclic C 3 -C 6 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.

[0009] The term "alkyl", unless otherwise indicated, as used herein, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C 1 -C 10 alkyl. Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0010] 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.

[0011] The term "lower haloalkyl" refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0012] 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)).

[0013] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0014] As used herein, the term "C 1-8 (or C 1-6 , or C 1-4 ) bivalent saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0015] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) 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.

[0016] 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.

[0017] The term "halogen" means F, Cl, Br, or I.

[0018] 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 disclosure, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.

[0019] The terms "heteroaryl" or "heteroaromatic", unless otherwise defined, as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring. A heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.:

[0020] The terms "heterocyclyl" or "heterocyclic group", unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings, and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen.

[0021] The term "partially unsaturated" in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. Where a partially unsaturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.:

[0022] The term "saturated" in the context of rings, unless otherwise defined, refers to a 3-10 membered monocyclic ring, or a 7-14 membered polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. Where a saturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.:

[0023] The terms "alkylene", "arylene", "cycloalkylene", "heteroarylene", "heterocycloalkylene", and the other similar terms with the suffix "-ylene" as used herein refers to a divalently bonded version of the group that the suffix modifies. For example, "alkylene" is a divalent alkyl group connecting the groups to which it is attached.

[0024] 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:

[0025] As described herein, compounds of the disclosure 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. 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 disclosure 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.

[0026] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH 2 ) 0-4 R°; -(CH 2 ) 0-4 OR°; -O(CH 2 ) 0-4 R°, - O-(CH 2 ) 0-4 C(O)OR°; -(CH 2 ) 0-4 CH(OR°) 2 ; -(CH 2 ) 0-4 SR°; -(CH 2 ) 0-4 Ph, which may be substituted with R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R°; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R°) 2 ; -(CH 2 ) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH 2 ) 0-4 N(R°)C(O)NR° 2 ; -N(R°)C(S)NR° 2 ; -(CH 2 ) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR° 2 ; -N(R°)N(R°)C(O)OR°; -(CH 2 ) 0-4 C(O)R°; -C(S)R°; =(CH 2 ) 0-4 C(O)OR°; -(CH 2 ) 0-4 C(O)SR°; -(CH 2 ) 0-4 C(O)OSiR° 3 ; -(CH 2 ) 0-4 OC(O)R°; -OC(O)(CH 2 ) 0-4 SR°; -SC(S)SR°; -(CH 2 ) 0-4 SC(O)R°; -(CH 2 ) 0-4 C(O)NR° 2 ; -C(S)NR° 2 ; -C(S)SR°; -SC(S)SR°, -(CH 2 ) 0-4 OC(O)NR° 2 ; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH 2 C(O)R°; -C(NOR°)R°; -(CH 2 ) 0-4 SSR°; -(CH 2 ) 0-4 S(O) 2 R°; -(CH 2 ) 0-4 S(O) 2 OR°; -(CH 2 ) 0-4 OS(O) 2 R°; -S(O) 2 NR° 2 ; -(CH 2 ) 0-4 S(O)R°; -N(R°)S(O) 2 NR° 2 ; -N(R°)S(O) 2 R°; -N(OR°)R°; -C(NH)NR° 2 ; -P(O)(OR°)R°; -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, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(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.

[0027] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, - (CH 2 ) 0-2 R ●< , -(haloR ●< ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ●< , -(CH 2 ) 0-2 CH(OR ●< ) 2 ; -O(haloR ●< ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ●< , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ●< , -(CH 2 ) 0-2 SR ●< , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ●< , -(CH 2 ) 0-2 NR ●< 2 , -NO 2 , -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, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0028] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR *< 2 , =NNHC(O)R *< , =NNHC(O)OR *< , =NNHS(O) 2 R *< , =NR*, =NOR *< , -O(C(R *< 2 )) 2-3 O-, or -S(C(R *< 2 )) 2-3 S-, 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 ) 2-3 O-, 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.

[0029] Suitable substituents on the aliphatic group of R *< include halogen, -R ●< , -(haloR ●< ), -OH, -OR ●< , -O(haloR*), -CN, -C(O)OH, -C(O)OR ●< , -NH 2 , -NHR ●< , -NR ●< 2 , or -NO 2 , 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, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] 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)CH 2 C(O)R †< , -S(O) 2 R †< , -S(O) 2 NR †< 2 , -C(S)NR †< 2 , -C(NH)NR †< 2 , or -N(R †< )S(O) 2 R †< ; 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.

[0031] Suitable substituents on the aliphatic group of R †< are independently halogen, -R ●< , -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR ●< , -NH 2 , -NHR ●< , -NR ●< 2 , or -NO 2 , 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, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] The term "isomer" as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term "stereoisomer" as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and / or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are within the scope of the disclosure.

[0033] The term "tautomer" as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the disclosure are within the scope of the disclosure.

[0034] The term "isotopic substitution" as used herein refers to the substitution of an atom with its isotope. The term "isotope" as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen. Examples of the isotope of a hydrogen atom include 2< H (also represented as D) and 3< H. Examples of the isotope of a carbon atom include 13< C and 14< C. Examples of the isotope of an oxygen atom include 18< O. Unless otherwise stated, all isotopic substitution of the compounds of the disclosure are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. In certain embodiments, for example, a warhead moiety, R W< , of a provided compound comprises one or more deuterium atoms.

[0035] 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. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217.

[0036] Pharmaceutically acceptable salts of the compounds of this disclosure 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.

[0037] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N +< (C 1-4 alkyl) 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, loweralkyl sulfonate and aryl sulfonate.

[0038] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2: 1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

[0039] As used herein the term "about" is used herein to mean approximately, roughly, around, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).

[0040] An "effective amount", "sufficient amount" or "therapeutically effective amount" as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and / or duration of afflictions related to FGFR2 signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to FGFR2 signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

[0041] As used herein and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0042] The phrase "in need thereof" refers to the need for symptomatic or asymptomatic relief from conditions related to FGFR2 signaling activity or that may otherwise be relieved by the compounds and / or compositions of the disclosure.3. Description of Exemplary Embodiments

[0043] As described above, in some embodiments, the present disclosure provides a compound of formula I-1: or a pharmaceutically acceptable salt thereof, wherein: Cy A< is wherein represents a bond to R 5< and represents a bond to Cy 6< ; R 5< is -R 5A< -L 5< -R 5B< ; R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< ; R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; Cy 6< is phenylene; a bivalent saturated or partially unsaturated 3-14 membered carbocyclic ring; a bivalent saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< ; R W< is halogen, -CN, each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , an instance of R 6< and an instance of R L< , an instance of R 6< and an instance of R WA< , or an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< ; R 8< is H, -NR 2 , halogen, -OH, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 9< is H, -NR 2 , halogen, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 10< is H or C 16 aliphatic optionally substituted with 1-3 halogens; each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; wherein each of said C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R A< or C 1-6 aliphatic; each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with w instances of R C< ; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; or two instances of R 5C< , one instance of R 5C< and one instance of R 5D< , or two instances of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; each of m, n, p, q, r, t, u, v, and w is independently 0, 1, 2, 3, or 4.

[0044] As defined generally above, Cy A< is wherein represents a bond to R 5< and represents a bond to Cy 6< . In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is In some embodiments, Cy A< is

[0045] In some embodiments, Cy A< is In some embodiments, Cy A< is or In some embodiments, Cy A< is or In some embodiments, Cy A< is selected from the groups depicted in the compounds in Table 1.

[0046] As defined generally above, Cy 6< is phenylene; a bivalent saturated or partially unsaturated 3-14 membered carbocyclic ring; a bivalent saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0047] In some embodiments, Cy 6< is phenylene; a bivalent saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring; a bivalent saturated or partially unsaturated 8-14 membered bicyclic carbocyclic ring; a bivalent saturated or partially unsaturated 3-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a bivalent saturated or partially unsaturated 8-14 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0048] In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-14 membered carbocyclic ring; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring, or a bivalent saturated or partially unsaturated 8-14 membered bicyclic carbocyclic ring; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 8-14 membered bicyclic carbocyclic ring; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0049] In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a bivalent saturated or partially unsaturated 8-14 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0050] In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 3-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent saturated or partially unsaturated 5-6 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a bivalent pyrrolidine or dihydropyrrolidine ring; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0051] In some embodiments, Cy 6< is a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0052] In some embodiments, Cy 6< is a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 5-6 membered monocyclic heteroarylene having 1-2 nitrogen atoms; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 5-membered monocyclic heteroarylene having 1-2 nitrogen atoms; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0053] In some embodiments, Cy 6< is a 9-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 9-10 membered bicyclic heteroarylene having 1-3 nitrogen atoms; wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< .

[0054] In some embodiments, Cy 6< is selected from the groups depicted in the compounds in Table 1.

[0055] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein.

[0056] As defined generally above, each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , an instance of R 6< and an instance of R L< , an instance of R 6< and an instance of R WA< , or an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< .

[0057] In some embodiments, two instances of R 6< , an instance of R 6< and an instance of R L< , an instance of R 6< and an instance of R WA< , or an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< .

[0058] In some embodiments, an instance of R 6< and an instance of R WA< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< . In some embodiments, an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< .

[0059] In some embodiments, an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< . In some embodiments, an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated ring having one nitrogen atom; wherein said ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -(C 1-4 alkyl) ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated ring. In some embodiments, an instance of R 6< and an instance of R 7a< are taken together with their intervening atoms to form a 4-8 membered partially unsaturated ring having one nitrogen atom.

[0060] In some embodiments, each R 6< is selected from the groups depicted in the compounds in Table 1.

[0061] As defined generally above, R 8< is H, -NR 2 , halogen, -OH, or C 1-6 aliphatic optionally substituted with 1-3 halogens. In some embodiments, R 8< is H. In some embodiments, R 8< is - NR 2 . In some embodiments, R 8< is halogen. In some embodiments, R 8< is -OH. In some embodiments, R 8< is C 1-6 aliphatic optionally substituted with 1-3 halogens.

[0062] In some embodiments, R 8< is -NH 2 . In some embodiments, R 8< is C 1-4 alkyl. In some embodiments, R 8< is methyl. In some embodiments, R 8< is -NH 2 or methyl. In some embodiments, R 8< is selected from the groups depicted in the compounds in Table 1.

[0063] As defined generally above, R 9< is H, -NR 2 , halogen, or C 1-6 aliphatic optionally substituted with 1-3 halogens. In some embodiments, R 9< is H. In some embodiments, R 9< is - NR 2 . In some embodiments, R 9< is -NH 2 . In some embodiments, R 9< is halogen. In some embodiments, R 9< is C 1-6 aliphatic optionally substituted with 1-3 halogens. In some embodiments, R 9< is C 1-4 alkyl. In some embodiments, R 9< is selected from the groups depicted in the compounds in Table 1.

[0064] As defined generally above, R 10< is H or C 1-6 aliphatic optionally substituted with 1-3 halogens. In some embodiments, R 10< is H. In some embodiments, R 10< is C 1-6 aliphatic optionally substituted with 1-3 halogens. In some embodiments, R 10< is C 1-4 alkyl. In some embodiments, R 10< is methyl. In some embodiments, R 10< is H or methyl. In some embodiments, R 10< is selected from the groups depicted in the compounds in Table 1.

[0065] As defined generally above, L 6< is a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; wherein each of said C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R A< or C 1-6 aliphatic.

[0066] In some embodiments, L 6< is a C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one instance of R A< or C 1-6 aliphatic. In some embodiments, L 6< is a C 3-6 cycloalkylene, 3-6 membered heterocycloalkylene, or 5-6 membered heteroarylene.

[0067] In some embodiments, L 6< is selected from the groups depicted in the compounds in Table 1.

[0068] As defined generally above, each instance of R 5C< and R 5D< is independently R A< or R B< , and is substituted by u instances of R C< ; or two instances of R 5C< , one instance of R 5C< and one instance of R 5D< , or two instances of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< .

[0069] In some embodiments, two instances of R 5C< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< .

[0070] In some embodiments, one instance of R 5C< and one instance of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< . In some embodiments, one instance of R 5C< and one instance of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring substituted with v instances of R C< .

[0071] In some embodiments, two instances of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with v instances of R C< . In some embodiments, two instances of R 5D< are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring substituted with v instances of R C< .

[0072] In some embodiments, each instance of R 5C< and R 5D< is selected from the groups depicted in the compounds in Table 1.

[0073] As defined generally above, v is 0, 1, 2, 3, or 4. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 0 or 1. In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0, 1, 2, or 3. In some embodiments, v is 1 or 2. In some embodiments, v is 1, 2, or 3. In some embodiments, v is 1, 2, 3, or 4. In some embodiments, v is 2 or 3. In some embodiments, v is 2, 3, or 4. In some embodiments, v is 3 or 4. In some embodiments, v is selected from the values represented in the compounds in Table 1.

[0074] As defined generally above, w is 0, 1, 2, 3, or 4. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 0 or 1. In some embodiments, w is 0, 1, or 2. In some embodiments, w is 0, 1, 2, or 3. In some embodiments, w is 1 or 2. In some embodiments, w is 1, 2, or 3. In some embodiments, w is 1, 2, 3, or 4. In some embodiments, w is 2 or 3. In some embodiments, w is 2, 3, or 4. In some embodiments, w is 3 or 4. In some embodiments, w is selected from the values represented in the compounds in Table 1.

[0075] In some embodiments, the present disclosure provides a compound of Formula I-1, wherein each of the variables is as defined in the description of Formula I or Formula I-2, below, and described in embodiments herein, both singly and in combination.

[0076] As described above, in some embodiments, the present disclosure provides a compound of formula I-2: or a pharmaceutically acceptable salt thereof, wherein: R 5< is -R 5A< -L 5< -R 5B< ; R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< ; R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; Cy 6< is phenylene or a 6-membered heteroarylene having 1-3 nitrogen atoms, wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< ; R W< is halogen, -CN, or each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0077] As defined generally above, each of R WA< , R WB< and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , or -C(O)N(R)OR. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, or optionally substituted C 1-6 aliphatic. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, -C 1-4 alkyl, -(C 1-4 alkyl)-O-(C 1-4 alkyl), or -(C 1-4 alkyl)-N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, or - C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, or -C 1-4 alkyl. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, or -CH 3 . In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or deuterium. In some embodiments, each of R WA< , R WB< , and R WC< is deuterium.

[0079] In some embodiments, the present disclosure provides a compound of Formula I-2, wherein each of the variables is as defined in the description of Formula I, below, and described in embodiments herein, both singly and in combination.

[0080] As described above, in some embodiments, the present disclosure provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 5< is -R 5A< -L 5< -R 5B< ; R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< ; R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; Cy 6< is phenylene or a 6-membered heteroarylene having 1-3 nitrogen atoms, wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< ; R W< is halogen, -CN, or each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< ; each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(o) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0081] As defined generally above, R 5A< is a bivalent radical of R B< , wherein R 5A< is substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is a bivalent C 1-6 aliphatic substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is phenylene substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is a 5-6 membered monocyclic heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is an 8-10 membered bicyclic heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is a bivalent 3-7 membered saturated or partially unsaturated carbocyclic ring substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is a bivalent 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is a bivalent 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with m instances of R 5C< in addition to -L 5< -R 5B< . In some embodiments, R 5A< is selected from the groups depicted in the compounds in Table 1.

[0082] As defined generally above, L 5< is a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -. In some embodiments L 5< is a covalent bond. In some embodiments L 5< is a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.

[0083] In some embodiments, L 5< is a C 1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -. In some embodiments, L 5< is a C 1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L< )-.

[0084] In some embodiments, L 5< is -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L< )-. In some embodiments, L 5< is -O-. In some embodiments, L 5< is -C(O)-. In some embodiments, L 5< is -C(O)NH-. In some embodiments, L 5< is -C(O)N(R L< )-. In some embodiments, L 5< is selected from the groups depicted in the compounds in Table 1.

[0085] As defined generally above, R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< . In some embodiments, R 5B< is hydrogen. In some embodiments, R 5B< is R B< substituted with n instances of R 5D< . In some embodiments, R 5B< is C 1-6 aliphatic substituted with n instances of R 5D< . In some embodiments, R 5B< is phenyl substituted with n instances of R 5D< . In some embodiments, R 5B< is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is a 3-7 membered saturated or partially unsaturated carbocyclic ring substituted with n instances of R 5D< . In some embodiments, R 5B< is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D<

[0086] In some embodiments, R 5B< is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is a 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is a 6-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; substituted with n instances of R 5D< . In some embodiments, R 5B< is selected from the groups depicted in the compounds in Table 1.

[0087] As defined generally above, each instance of R 5C< is independently R A< or R B< , and is substituted by u instances of R C< . In some embodiments, each instance of R 5C< is R A< . In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -OR, -S(O) 2 NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -OC(O)R, and -N(R)C(O)R. In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -OR, and -C(O)NR 2 . In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 .

[0088] In some embodiments, each instance of R 5C< is R B< , wherein R 5C< is substituted by u instances of R C< . In some embodiments, each instance of R 5C< is R B< , wherein R 5C< is substituted by one instance of R C< . In some embodiments, each instance of R 5C< is independently selected from C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by u instances of R C< .

[0089] In some embodiments, each instance of R 5C< is independently selected from C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by u instances of R C< . In some embodiments, each instance of R 5C< is independently selected from C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 5C< is independently selected from C 1-4 alkyl optionally substituted by one instance of - OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom; each of which is optionally substituted with 1, 2, or 3 fluoro or chloro.

[0090] In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -OR, -C(O)NR 2 , and the following groups, each of which is optionally substituted by u instances of R C< : C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, and the following groups, each of which is optionally substituted with 1, 2, or 3 halogens: -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 5C< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , and the following groups, each of which is optionally substituted with 1, 2, or 3 fluoro or chloro: C 1-4 alkyl optionally substituted by one instance of -OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 5C< is selected from the groups depicted in the compounds in Table 1.

[0091] As defined generally above, each instance of R 5D< is independently R A< or R B< , and is substituted by u instances of R C< . In some embodiments, each instance of R 5D< is R A< . In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -OR, -S(O) 2 NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -OC(O)R, and -N(R)C(O)R. In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -OR, and -C(O)NR 2 . In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 .

[0092] In some embodiments, each instance of R 5D< is R B< , wherein R 5D< is substituted by u instances of R C< . In some embodiments, each instance of R 5D< is R B< , wherein R 5D< is substituted by one instance of R C< . In some embodiments, each instance of R 5D< is independently selected from C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by u instances of R C< .

[0093] In some embodiments, each instance of R 5D< is independently selected from C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by u instances of R C< . In some embodiments, each instance of R 5D< is independently selected from C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 5D< is independently selected from C 1-4 alkyl optionally substituted by one instance of - OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom; each of which is optionally substituted with 1, 2, or 3 fluoro or chloro.

[0094] In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -OR, -C(O)NR 2 , and the following groups, each of which is optionally substituted by u instances of R C< : C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, and the following groups, each of which is optionally substituted with 1, 2, or 3 halogens: -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 5D< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , and the following groups, each of which is optionally substituted with 1, 2, or 3 fluoro or chloro: C 1-4 alkyl optionally substituted by one instance of -OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 5D< is selected from the groups depicted in the compounds in Table 1.

[0095] As defined generally above, in some embodiments, the present disclosure provides a compound of Formula I wherein R 5< is -R 5A< -L 5< -R 5B< . In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of L 5< , R 5B< , R 5C< , and m is as defined in embodiments and classes and subclasses herein.

[0096] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< R 5C< , and m is as defined in embodiments and classes and subclasses herein.

[0097] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< , R 5C< , and m is as defined in embodiments and classes and subclasses herein.

[0098] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< , R 5C< , and m is as defined in embodiments and classes and subclasses herein.

[0099] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< R 5C< , and m is as defined in embodiments and classes and subclasses herein.

[0100] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< and R 5C< is as defined in embodiments and classes and subclasses herein.

[0101] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is: wherein each of R 5B< and R 5C< is as defined in embodiments and classes and subclasses herein.

[0102] In some embodiments, R 5< (i.e. -R 5A< -L 5< -R 5B< taken together) is selected from the groups depicted in the compounds in Table 1.

[0103] As defined generally above, Cy 6< is phenylene or a 6-membered heteroarylene having 1-3 nitrogen atoms, wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is phenylene substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 1-3 nitrogen atoms, wherein Cy 6< is substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 1-2 nitrogen atoms, substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 1 nitrogen atom, substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 2 nitrogen atoms, substituted with p instances of R 6< in addition to -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 2 nitrogen atoms, substituted only with -L 6< -R W< . In some embodiments, Cy 6< is a 6-membered heteroarylene having 1-2 nitrogen atoms, substituted with p instances of R 6< in addition to -L 6< -R W< , wherein L 6< is a covalent bond, and -R W< is -CN or In some embodiments, Cy 6< is selected from the groups depicted in the compounds in Table 1.

[0104] As defined generally above, each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< . In some embodiments, each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< .

[0105] In some embodiments, two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< . In some embodiments, two instances of R 6< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< .

[0106] In some embodiments, an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< . In some embodiments, an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having one nitrogen atom; wherein said ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -(C 1-4 alkyl) ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having one nitrogen atom.

[0107] In some embodiments, each instance of R 6< is R A< . In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -OR, -S(O) 2 NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -OC(O)R, and -N(R)C(O)R. In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -OR, and -C(O)NR 2 . In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -C(O)N(C 1-4 alkyl) 2 .

[0108] In some embodiments, each instance of R 6< is R B< , wherein R 6< is substituted by q instances of R C< . In some embodiments, each instance of R 6< is R B< , wherein R 6< is substituted by one instance of R C< . In some embodiments, each instance of R 6< is independently selected from C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by q instances of R C< .

[0109] In some embodiments, each instance of R 6< is independently selected from C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by q instances of R C< . In some embodiments, each instance of R 6< is independently selected from C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 halogens. In some embodiments, each instance of R 6< is independently selected from C 1-4 alkyl optionally substituted by one instance of - OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom; each of which is optionally substituted with 1, 2, or 3 fluoro or chloro.

[0110] In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -OR, -C(O)NR 2 , and the following groups, each of which is optionally substituted by q instances of R C< : C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 6< is independently selected from halogen, -CN, and the following groups, each of which is optionally substituted with 1, 2, or 3 halogens: -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , C 1-4 aliphatic optionally substituted by one instance of R C< ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R 6< is independently selected from halogen, -CN, -O-(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , and the following groups, each of which is optionally substituted with 1, 2, or 3 fluoro or chloro: C 1-4 alkyl optionally substituted by one instance of -OH, -O-(C 1-4 alkyl), or -N(C 1-4 alkyl) 2 ; a 3-5 membered saturated carbocyclic ring; and a 3-5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 6< is selected from the groups depicted in the compounds in Table 1.

[0111] As defined generally above, L 6< is a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -. In some embodiments, L 6< is a covalent bond. In some embodiments, L 6< is a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.

[0112] In some embodiments, L 6< is a C 1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -. In some embodiments, L 6< is a C 1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -NH- or -N(R L< )-.

[0113] In some embodiments, L 6< is -NH- or -N(R L< )-. In some embodiments, L 6< is -NH-. In some embodiments, L 6< is -N(R L< )-. In some embodiments, L 6< is -NH- or -N(CH 3 )-. In some embodiments, L 6< is -N(CH 3 )-. In some embodiments, L 6< is selected from the groups depicted in the compounds in Table 1.

[0114] As defined generally above, R W< is halogen, -CN, In some embodiments, R W< is halogen, -CN,

[0115] In some embodiments, R W< is halogen. In some embodiments, R W< is -CN. In some embodiments R W< is In some embodiments R W< is or In some embodiments R W< is In some embodiments R W< is In some embodiments R W< is In some embodiments R W< is In some embodiments R W< is

[0116] In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is In some embodiments, R W< is

[0117] In some embodiments, R W< is -CN, In some embodiments, R W< is In some embodiments, R W< is or

[0118] In some embodiments, R W< is and R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0119] In some embodiments, R W< is and R WA< and R WB< or R WB< and R WC< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 0-1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R W< is and R WA< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R W< is and R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R W< is selected from the groups depicted in the compounds in Table 1.

[0120] Without wishing to be bound by any particular theory, it is believed that R W< is a warhead group, particularly suitable for covalently binding to the sulfhydryl side chain moiety of a protein kinase, for example Cys491 of FGFR2. Thus, in some embodiments, R W< is characterized in that it is capable of covalently binding to a cysteine residue, thereby irreversibly inhibiting a protein kinase. In some embodiments, the protein kinase is an FGFR. In certain embodiments, the protein kinase is FGFR2. In certain embodiments, the protein kinase is FGFR2, and the cysteine residue is Cys491.

[0121] As defined generally above, each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0122] In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0123] In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , or -C(O)N(R)OR. In some embodiments, each of R WA< , R WB< and R WC< is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0124] In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, each of R WA< , R WB< and R WC< is independently hydrogen, -C 1-4 alkyl, -(C 1-4 alkyl)-O-(C 1-4 alkyl), or - (C 1-4 alkyl)-N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or -C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or -C 1-4 alkyl. In some embodiments, each of R WA< , R WB< , and R WC< is independently hydrogen or -CH 3 .

[0125] In some embodiments, R WA< and R WB< or R WB< and R WC< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 0-1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WA< and R WB< or R WB< and R WC< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated carbocyclic ring. In some embodiments, R WA< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WC< and an instance of R L< are taken together with their intervening atoms to form a 5-6 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each of R WA< , R WB< , and R WC< is selected from the groups depicted in the compounds in Table 1.

[0126] As defined generally above, R WD< is halogen or -OS(O) 2 R. In some embodiments, R WD< is halogen. In some embodiments, R WD< is chloro or bromo. In some embodiments, R WD< is chloro. In some embodiments, R WD< is -OS(O) 2 R. In some embodiments, R WD< is -OS(O) 2 -(optionally substituted C 1-3 alkyl). In some embodiments, R WD< is -OS(O) 2 CH 3 or -OS(O) 2 CF 3 . In some embodiments, R WD< is -OS(O) 2 -(optionally substituted phenyl). In some embodiments, R WD< is selected from the groups depicted in the compounds in Table 1.

[0127] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< and R W< is as defined in embodiments and classes and subclasses herein.

[0128] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein.

[0129] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< and R W< is as defined in embodiments and classes and subclasses herein.

[0130] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< and R W< is as defined in embodiments and classes and subclasses herein.

[0131] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , R W< , and p is as defined in embodiments and classes and subclasses herein.

[0132] In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< , R 6< , and R W< is as defined in embodiments and classes and subclasses herein. In some embodiments, -Cy 6< -L 6< -R W< taken together is: wherein each of L 6< and R W< is as defined in embodiments and classes and subclasses herein.

[0133] In some embodiments, -Cy 6< -L 6< -R W< is selected from the groups depicted in the compounds in Table 1.

[0134] As defined generally above, R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< . In some embodiments, R 7< is H. In some embodiments, R 7< is R B< , wherein R 7< is substituted with t instances of R 7A< . In some embodiments, R 7< is C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with t instances of R 7A< . In some embodiments, R 7< is C 1-6 aliphatic; a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with t instances of R 7A< .

[0135] In some embodiments, R 7< is C 1-6 alkyl; a 3-7 membered saturated carbocyclic ring; or a 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen; each of which is substituted with 0-1 instances of R 7A< and 0-3 halogens. In some embodiments, R 7< is C 1-6 alkyl substituted with 0-1 instances of R 7A< and 0-3 halogens. In some embodiments, R 7< is -C 1-4 alkyl, -(C 1-4 alkyl)-OH, -(C 1-4 alkyl)-O-(C 1-4 alkyl), or -(C 1-4 alkyl)-N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, R 7< is -C 1-4 alkyl, optionally substituted with 1, 2, or 3 fluoro. In some embodiments, R 7< is -CH 3 . In some embodiments, R 7< is C 1-6 alkyl substituted with 0-1 instances of R B< and 0-3 halogens.

[0136] In some embodiments, R 7< is a 3-7 membered saturated carbocyclic ring substituted with 0-1 instances of R 7A< and 0-3 halogens. In some embodiments, R 7< is a 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen; which is substituted with 0-1 instances of R 7A< and 0-3 halogens. In some embodiments, R 7< is a 5-6 membered saturated monocyclic heterocyclic ring having 1 oxygen atom; which is substituted with 0-1 instances of R 7A< and 0-3 halogens. In some embodiments, R 7< is a 5-6 membered saturated monocyclic heterocyclic ring having 1 oxygen atom; which is substituted with 0-3 halogens and 0-1 group selected from -C 1-4 alkyl, -OH, - O-(C 1-4 alkyl), or N(C 1-4 alkyl) 2 ; wherein each C 1-4 alkyl is optionally substituted with 1, 2, or 3 fluoro. In some embodiments, R 7< is a 5-6 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 7< is selected from the groups depicted in the compounds in Table 1.

[0137] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2 or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from the values represented in the compounds in Table 1.

[0138] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 3 or 4. In some embodiments, n is selected from the values represented in the compounds in Table 1.

[0139] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0 or 1. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 3 or 4. In some embodiments, p is selected from the values represented in the compounds in Table 1.

[0140] As defined generally above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0 or 1. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 2 or 3. In some embodiments, q is 2, 3, or 4. In some embodiments, q is 3 or 4. In some embodiments, q is selected from the values represented in the compounds in Table 1.

[0141] As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4. In some embodiments, r is 3 or 4. In some embodiments, r is selected from the values represented in the compounds in Table 1.

[0142] As defined generally above, t is 0, 1, 2, 3, or 4. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 0 or 1. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 2 or 3. In some embodiments, t is 2, 3, or 4. In some embodiments, t is 3 or 4. In some embodiments, t is selected from the values represented in the compounds in Table 1.

[0143] As defined generally above, u is 0, 1, 2, 3, or 4. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 0 or 1. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 0, 1, 2, or 3. In some embodiments, u is 1 or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 1, 2, 3, or 4. In some embodiments, u is 2 or 3. In some embodiments, u is 2, 3, or 4. In some embodiments, u is 3 or 4. In some embodiments, u is selected from the values represented in the compounds in Table 1.

[0144] In some embodiments, the present disclosure provides a compound of formula I-1 comprising a pyrrolopyrimidine, pyrrolotriazine, pyrazolopyrazine, pyrrolopyridine, furopyrimidine, thienopyrimidine, or pyrrolopyridazinone thereby forming a compound of formulas Ia, Ib, Ic, Id, Ie, If, Ig, or Ih : or a pharmaceutically acceptable salt thereof, wherein each of Cy 6< , L 6< , R W< , R 5< , R 7< , R 8< , R 9< , and R 10< is as defined in embodiments and classes and subclasses herein.

[0145] In some embodiments, the present disclosure provides a compound of formula I-1 wherein R 5A< is phenylene, pyridinylene, or cyclohexenylene, thereby forming a compound of formulas II-1, III-1, IV-1, or V-1 : or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , Cy 6< , L 5< , L 6< , R 5B< , R 5C< , R W< , and m is as defined in embodiments and classes and subclasses herein.

[0146] In some embodiments, the present disclosure provides a compound of formula I-1 wherein Cy 6< is phenylene, pyridinylene, or pyrimidinylene, thereby forming a compound of formulas VI-1, VII-1, VIII-1, or IX-1: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 6< , R 5< , R W< , R 6< , and p is as defined in embodiments and classes and subclasses herein.

[0147] In some embodiments, the present disclosure provides a compound of formulas II-1, III-1, IV-1, or V-1 wherein Cy 6< is phenylene, thereby forming a compound of formulas X-1, XI-1, XII-1, or XIII-1, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , m, and p is as defined in embodiments and classes and subclasses herein.

[0148] For example, in some embodiments, the present disclosure provides a compound of formula X-1, XI-1, XII-1, or XIII-1: or a pharmaceutically acceptable salt thereof, wherein: Cy A< is wherein the of Cy A< represents a bond to of Cy A< represents a bond to R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; R W< is halogen, -CN, or each instance of R 6< is independently R A< or R B< , wherein R\ 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< R 8< is H, -NR 2 , halogen, -OH, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 9< is H, -NR 2 , halogen, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 10< is H or C 1-6 aliphatic optionally substituted with 1-3 halogens; each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; each of R WA< , R WB< , and R WC< is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0149] In some embodiments, the present disclosure provides a compound of formula X-1, XI-1, XII-1, or XIII-1: or a pharmaceutically acceptable salt thereof, wherein: Cy A< is wherein the of Cy A< represents a bond to and of Cy A< represents a bond to R 5B< is hydrogen or R B< , wherein R 5B< is substituted with n instances of R 5D< ; R W< is halogen, -CN, or each instance of R 6< is independently R A< or R B< , wherein R 6< is substituted by q instances of R C< ; or two instances of R 6< , or an instance of R 6< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R C< ; R 7< is H or R B< , wherein R 7< is substituted with t instances of R 7A< ; R 8< is H, -NR 2 , halogen, -OH, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 9< is H, -NR 2 , halogen, or C 1-6 aliphatic optionally substituted with 1-3 halogens; R 10< is H or C 1-6 aliphatic optionally substituted with 1-3 halogens; each of L 5< and L 6< is independently a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L< )-, -C(R L< ) 2 -, C 3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(R L< )-, -NHC(O)-, -N(R L< )C(O)-, -C(O)NH-, -C(O)N(R L< )-, -NHS(O) 2 -, -N(R L< )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L< )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -; each of R WA< , R WB< , and R WC< is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA< and R WB< , R WB< and R WC< , R WA< and an instance of R L< , or R WC< and an instance of R L< are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R WD< is halogen or -OS(O) 2 R; each instance of R 5C< , R 5D< , R 7A< , and R L< is independently R A< or R B< , and is substituted by u instances of R C< ; each instance of R A< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , or -N(R)S(O) 2 R; each instance of R B< is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R C< is independently oxo, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F, -OS(O) 2 F, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0150] In some embodiments, the present disclosure provides a compound of formulas II-1, III-1, IV-1, or V-1 wherein Cy 6< is pyridinylene, thereby forming a compound of formulas XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, or XXI-1 respectively: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , m, and p is as defined in embodiments and classes and subclasses herein.

[0151] In some embodiments, the present disclosure provides a compound of formulas II-1, III-1, IV-1, or V-1 wherein Cy 6< is pyrimidinylene, thereby forming a compound of formulas XXII-1, XXIII-1, XXIV-1, or XXV-1 respectively: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , m, and p is as defined in embodiments and classes and subclasses herein.

[0152] In some embodiments, the present disclosure provides a compound of formula I-1 , II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1 wherein Cy A< is wherein represents a bond to R 5< and represents a bond to Cy 6< .

[0153] In some embodiments, the present disclosure provides a compound of formula I-1 , II- 1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1 wherein Cy A< is wherein represents a bond to R 5< and represents a bond to Cy 6< .

[0154] In some embodiments, the present disclosure provides a compound of 1-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 5< is -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L< )-. In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1 wherein L 5< is -O-. In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 5< is -C(O)-. In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 5< is -C(O)NH-. In some embodiments, the present disclosure provides a compound of I-1 , Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 5< is -C(O)N(R L< )-.

[0155] In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 6< is -NH- or -N(R L< )-. In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1 , IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein L 6< is -NH-.

[0156] In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein m is 0 or 1. In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein m is 0. In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein m is 1.

[0157] In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein p is 0 or 1. In some embodiments, the present disclosure provides a compound of I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein p is 0. In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein p is 1.

[0158] In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein R W< is In some embodiments, the present disclosure provides a compound of formula I-1, Ia , Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein R W< is In some embodiments, the present disclosure provides a compound of formula I-1, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, XXI-1, XXII-1, XXIII-1, XXIV-1, or XXV-1, wherein R W< is

[0159] In some embodiments, the present disclosure provides a compound of formula I wherein R 5A< is phenylene, pyridinylene, or cyclohexenylene, thereby forming a compound of formulas II, III, IV, or V: or a pharmaceutically acceptable salt thereof, wherein each of Cy 6< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 7< , and m is as defined in embodiments and classes and subclasses herein.

[0160] In some embodiments, the present disclosure provides a compound of formula I wherein Cy 6< is phenylene, pyridinylene, or pyrimidinylene, thereby forming a compound of formulas VI, VII, VIII, or IX: or a pharmaceutically acceptable salt thereof, wherein each of L 6< , R 5< , R W< , R 6< , R 7< , and p is as defined in embodiments and classes and subclasses herein.

[0161] In some embodiments, the present disclosure provides a compound of formulas II, III, IV, or V wherein Cy 6< is phenylene, thereby forming a compound of formulas X, XI, XII, or XIII, respectively: or a pharmaceutically acceptable salt thereof, wherein each of L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , R 7< , m, and p is as defined in embodiments and classes and subclasses herein.

[0162] In some embodiments, the present disclosure provides a compound of formulas II, III, IV, or V wherein Cy 6< is pyridinylene, thereby forming a compound of formulas XIV, XV, XVI, XVII, XVIII, XIX, XX, or XXI respectively: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , m, and p is as defined in embodiments and classes and subclasses herein.

[0163] In some embodiments, the present disclosure provides a compound of formulas II, III, IV, or V wherein Cy 6< is pyrimidinylene, thereby forming a compound of formulas XXII, XXIII, XXIV, or XXV respectively: or a pharmaceutically acceptable salt thereof, wherein each of Cy A< , L 5< , L 6< , R 5B< , R 5C< , R W< , R 6< , m, and p is as defined in embodiments and classes and subclasses herein.

[0164] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5< is -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L< )-. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5< is -O-. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5< is -C(O)-. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5< is -C(O)NH-. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5< is -C(O)N(R L< )-.

[0165] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 6< is -NH- or -N(R L< )-. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 6< is -NH-.

[0166] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein m is 0 or 1. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein m is 0. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein m is 1.

[0167] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein p is 0 or 1. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein p is 0. In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein p is 1.

[0168] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W< is In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W< is In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W< is

[0169] In some embodiments, the present disclosure provides a compound of XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 5< is -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L< )-. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 5< is -O-. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 5< is -C(O)-. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 5< is -C(O)NH-. In some embodiments, the present disclosure provides a compound of XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 5< is -C(O)N(R L< )-.

[0170] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 6< is -NH- or -N(R L< )-. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein L 6< is -NH-.

[0171] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein m is 0 or 1. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein m is 0. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein m is 1.

[0172] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein p is 0 or 1. In some embodiments, the present disclosure provides a compound of XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein p is 0. In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein p is 1.

[0173] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W< is In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W< is In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W< is

[0174] Examples of compounds of the present disclosure include those listed in the Tables and exemplification herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure comprises a compound selected from those depicted in Table 1, below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below.

[0175] In chemical structures in Table 1, above, when a stereocenter is depicted with a dashed or wedged bond and labeled "abs" (or unlabeled), the compound is essentially a single isomer at that stereocenter (rather than an equimolar mixture), and the absolute stereochemistry is as shown in the chemical structure. (See, for example, the structure of Example 146.) When a stereocenter is depicted with a dashed or wedged bond and also labeled "or 1", the compound is a single isomer at that stereocenter, but the absolute stereochemistry at that stereocenter has not been determined. (See, for example, the structures of Examples 397 and 398.) When a stereocenter is depicted with a dashed or wedged bond and also labeled "and1" or "&1", the compound is a mixture of two isomers at that stereocenter: the structure as drawn, and the isomer in which that stereogenic center has the opposite configuration. (See, for example, the structure of Example 581.)

[0176] Certain compounds depicted in Table 1, above, exist in solution at room temperature as non-interconverting atropisomers across a biaryl bond. When one of the atoms of a biaryl bond is labeled as "or 1", this signifies that the compound exists in solution at room termperature as non-interconverting atropisomers, and the compound is essentially a single atropisomer (rather than an equimolar mixture). (See, for example, the structures of Examples 516 and 517.)

[0177] In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical FGFR2 Caliper IC 50 of "A". In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical FGFR2 Caliper IC 50 of "A" or "B". In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical FGFR2 Caliper IC 50 of "A" or "B" or "C".

[0178] In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell SNU-16 IC 50 of "A". In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell SNU-16 IC 50 of "A" or "B". In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell SNU-16 IC 50 of "A" or "B" or "C".4. General Methods of Providing the Present Compounds

[0179] The compounds of this disclosure may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.5. Uses, Formulation, and Administration Pharmaceutically Acceptable Compositions

[0180] According to another embodiment, the disclosure provides a composition comprising a compound of this disclosure, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of this disclosure, and a pharmaceutically acceptable carrier. The amount of compound in compositions of this disclosure is such that is effective to measurably inhibit a FGFR2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit a FGFR2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.

[0181] The terms "subject" and "patient," as used herein, means an animal (i.e., a member of the kingdom animal), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

[0182] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0183] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure.

[0184] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of a FGFR2 protein kinase, or a mutant thereof.

[0185] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0186] Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0187] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0188] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0189] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0190] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0191] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0192] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0193] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0194] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0195] Preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0196] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0197] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

[0198] The precise dose to be employed in the compositions will also depend on the route of administration and should be decided according to the judgment of the practitioner and each subject's circumstances. In specific embodiments of the disclosure, suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg / day to about 1000 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 800 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 500 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 250 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 100 mg / day. In some embodiments, the oral dose is about 5 mg / day to about 50 mg / day. In some embodiments, the oral dose is about 5 mg / day. In some embodiments, the oral dose is about 10 mg / day. In some embodiments, the oral dose is about 20 mg / day. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 40 mg / day. In some embodiments, the oral dose is about 50 mg / day. In some embodiments, the oral dose is about 60 mg / day. In some embodiments, the oral dose is about 70 mg / day. In some embodiments, the oral dose is about 100 mg / day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

[0199] In some embodiments, pharmaceutically acceptable compositions contain a provided compound and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt%, about 0.01 to about 80 wt%, about 0.01 to about 70 wt%, about 0.01 to about 60 wt%, about 0.01 to about 50 wt%, about 0.01 to about 40 wt%, about 0.01 to about 30 wt%, about 0.01 to about 20 wt%, about 0.01 to about 2.0 wt%, about 0.01 to about 1 wt%, about 0.05 to about 0.5 wt%, about 1 to about 30 wt%, or about 1 to about 20 wt%. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying ingredients and the like.

[0200] Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.

[0201] Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)).

[0202] The pharmaceutically acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0203] Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N +< R'R"R‴RʺʺY -< , in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y -< is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N +< R'R"R‴, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0204] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain wetting or emulsifying agents, or pH buffering agents.

[0205] Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0206] Compounds and compositions described herein are generally useful for the inhibition of a kinase or a mutant thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a fibroblast growth factor receptor (FGFR). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of FGFR1, FGFR2, FGFR3, and FGFR4. In some embodiments, the kinase inhibited by the compounds and compositions described herein is FGFR2.

[0207] Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of FGFR2 enzymes. For example, FGFR2 inhibitors of the present disclosure are useful for the treatment of proliferative diseases generally.

[0208] Activating FGFR2 gene fusions have been detected in numerous cancers including intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, and ovarian cancer. (I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; Y-M Wu, et al. Cancer Discov. 3:636-647; and references cited therein.)

[0209] FGFR2 amplification has been described in gastric cancer, breast cancer, triple negative breast cancer, and rectal cancer. (I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; and references cited therein.)

[0210] Activating FGFR2 mutations have been detected in endometrial carcinoma, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, breast cancer, and urothelial cancers. The most common mutations include those in the intracellular kinase domain (e.g., N549K and K659N / M) and those in the extracellular domain (S252W and P253R). Resistance mutations that occur in FGFR2 from treatment with pan-FGFR1-3 inhibitors can also be targeted with FGFR2 inhibitors. These include V564F, E565A, N549K / H / T, and L617V. (I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; R. Porta, et al. Crit. Rev. Oncol. Hematol. 2017, 113:256-267; and references cited therein).

[0211] Inhibition of FGFR2 also has anti-tumor activity in tumors with increased expression of FGFR2 ligands (FGFs1-4, 7, 8, 10, 21-23) (N. Turner and R. Grose, Nat. Rev. Cancer 2010, 10:116-129; and references cited therein).

[0212] Inhibition of FGFR2 also has anti-tumor activity in tumors with amplification or overexpression of the FGFR adaptor protein FRS2. (I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; and references cited therein.)

[0213] Selective inhibition of FGFR2 can generally be effective in indications where pan-FGFR1-3 inhibitors are effective. Such indications are described in I. S. Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; R. Porta, et al. Crit. Rev. Oncol. Hematol. 2017, 113:256-267; and references cited therein.

[0214] Activating mutations in FGFR2 have also been detected in craniosynostotic syndromes including Crouzon, Apert, Pfeiffer, Antley-Bixler, Beare-Stevenson cutis gyrate, Jackson-Weiss, Bent Bone Dysplasia, and Seathre-Chotzen-like syndromes which result in the premature fusion of cranial sutures. (S.C. Azoury, et al. Int. J. Biol. Sci. 2017, 13:1479-1488; and references cited therein.) Inhibition of FGFR2 is also effective in such craniosynostotic syndromes.

[0215] The activity of a compound utilized in this disclosure as an inhibitor of an FGFR kinase, for example, FGFR2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or the subsequent functional consequences, or ATPase activity of activated FGFR2, or a mutant thereof. Alternative in vitro assays quantitate the ability of the inhibitor to bind to FGFR2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / FGFR2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with FGFR2 bound to known radioligands. Representative in vitro and in vivo assays useful in assaying an FGFR2 inhibitor include those described and disclosed in the patent and scientific publications described herein. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of FGFR2, or a mutant thereof, are set forth in the Examples below.Treatment of Disorders

[0216] Provided compounds are inhibitors of FGFR2 and are therefore useful for treating one or more disorders associated with activity of FGFR2 or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating an FGFR2-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof. in certain embodiments, the present disclosure provides a method of treating an FGFR2-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.

[0217] As used herein, the term "FGFR2-mediated" disorders, diseases, and / or conditions means any disease or other deleterious condition in which FGFR2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which FGFR2, or a mutant thereof, is known to play a role. Such FGFR2-mediated disorders include but are not limited to proliferative disorders (e.g. cancer) and craniosynostotic syndromes.

[0218] In some embodiments, the present disclosure provides a method for treating one or more disorders, wherein the disorders are selected from proliferative disorders and craniosynostotic syndromes, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating one or more disorders, wherein the disorders are selected from proliferative disorders and craniosynostotic syndromes, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0219] In some embodiments, the present disclosure provides a method of treating a disorder in a subject, said method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, to a subject in need thereof, wherein the disorder is bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, or urothelial cancer. In some embodiments, the disorder is intrahepatic cholangiocarcinoma. In some embodiments, the disorder is hepatocellular carcinoma. In some embodiments, the disorder is lung squamous cell carcinoma or non-small cell lung cancer.

[0220] In some embodiments, the disorder is bile duct cancer. In some embodiments, the bile duct cancer is intrahepatic cholangiocarcinoma. In some embodiments, the disorder is liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the disorder is lung cancer. In some embodiments, the lung cancer is lung squamous cell carcinoma or non-small cell lung cancer.

[0221] In some embodiments, the present disclosure provides a method of treating intrahepatic cholangiocarcinoma in a subject, said method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating hepatocellular carcinoma in a subject, said method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating lung squamous cell carcinoma or non-small cell lung cancer in a subject, said method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, to a subject in need thereof.

[0222] In some embodiments, the disorder is associated with FGFR2 signaling. FGFR2 and other receptor tyrosine kinases (RTKs) are known to have multiple upstream and downstream signaling pathways (see Turner and Grose, Nat. Rev. Cancer (2010)10, 116), and inhibition of FGFR2 can be used to treat disorders associated with aberrant signaling within those pathways. In some embodiments, the disorder is associated with FGF signaling, JAK-STAT signaling, PI3K-Akt signaling, PLC-gamma signaling, or MAPK signaling.

[0223] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment.

[0224] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment.

[0225] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein.Proliferative Disorders

[0226] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is leukemia, breast cancer, lung cancer, colorectal cancer, or a combination thereof. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the proliferative disorder is breast cancer. In some embodiments, the proliferative disorder is lung cancer. In some embodiments, the proliferative disorder is colorectal cancer.

[0227] In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial carcinoma, non-small cell lung cancer, or urothelial cancer. In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, or ovarian cancer. In some embodiments, the proliferative disorder is gastric cancer, breast cancer, triple negative breast cancer, or rectal cancer. In some embodiments, the proliferative disorder is endometrial carcinoma, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, breast cancer, or urothelial cancer.

[0228] In some embodiments, the proliferative disorder is associated with one or more activating mutations in FGFR2. In some embodiments, the activating mutation in FGFR2 is a mutation to one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in FGFR2 is a mutation to the intracellular kinase domain. In some embodiments, the activating mutation in FGFR2 is a mutation to the extracellular domain. In some embodiments the activating mutation in FGFR2 is selected from N549K, K659N / M, S252W, P253R, and combinations thereof. In some embodiments the activating mutation in FGFR2 is N549K or K659N / M. In some embodiments the activating mutation in FGFR2 is N549K. In some embodiments the activating mutation in FGFR2 is K659N / M. In some embodiments the activating mutation in FGFR2 is S252W or P253R. In some embodiments the activating mutation in FGFR2 is S252W. In some embodiments the activating mutation in FGFR2 is P253R.

[0229] In some embodiments the proliferative disorder is associated with one or more resistance mutations in FGFR2. In some embodiments the resistance mutation in FGFR2 is selected from V564F, E565A, N549K / H / T, and L617V, and combinations thereof. In some embodiments the resistance mutation in FGFR2 is V564F. In some embodiments the resistance mutation in FGFR2 is E565A. In some embodiments the resistance mutation in FGFR2 is N549K / H / T. In some embodiments the resistance mutation in FGFR2 is L617V.Routes of Administration and Dosage Forms

[0230] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder (e.g. a proliferative disorder or craniosynostotic syndrome). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0231] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0232] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0233] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of inj ectables.

[0234] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0235] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0236] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0237] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0238] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0239] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0240] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.Dosage Amounts and Regimens

[0241] In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein.

[0242] In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 30 mg / kg body weight, at least about 40 mg / kg body weight, at least about 50 mg / kg body weight, at least about 75 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 250 mg / kg body weight, at least about 300 mg / kg body weight, at least about 350 mg / kg body weight, at least about 400 mg / kg body weight, at least about 450 mg / kg body weight, at least about 500 mg / kg body weight, at least about 550 mg / kg body weight, at least about 600 mg / kg body weight, at least about 650 mg / kg body weight, at least about 700 mg / kg body weight, at least about 750 mg / kg body weight, at least about 800 mg / kg body weight, at least about 900 mg / kg body weight, or at least about 1000 mg / kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

[0243] In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg / kg body weight, about 0.1 mg to about 6 mg / kg body weight, about 0.1 mg to about 4 mg / kg body weight, or about 0.1 mg to about 2 mg / kg body weight.

[0244] In some embodiments the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg.

[0245] In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades.

[0246] The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and / or dosing regimens.Inhibition of Protein Kinases

[0247] According to one embodiment, the disclosure relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound.

[0248] According to another embodiment, the disclosure relates to a method of inhibiting activity of FGFR2, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. In certain embodiments, the disclosure relates to a method of reversibly inhibiting FGFR2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. In certain embodiments, the disclosure relates to a method of irreversibly inhibiting FGFR2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound.

[0249] In some embodiments, the disclosure relates to a method of irreversibly inhibiting FGFR2, or a mutant thereof, wherein a compound of this disclosure forms a covalent bond with FGFR2, or a mutant thereof. In some embodiments, the disclosure relates to a method of irreversibly inhibiting FGFR2, or a mutant thereof, wherein a compound of this disclosure forms a covalent bond between R W< of the compound and a cysteine of the FGFR2, or a mutant thereof. In some embodiments, the disclosure relates to a method of irreversibly inhibiting FGFR2, or a mutant thereof, wherein a compound of this disclosure forms a covalent bond between R W< of the compound and Cys491 of the FGFR2, or a mutant thereof.

[0250] According to another embodiment, the disclosure relates to an FGFR2, or a mutant thereof, irreversibly inhibited by a compound of this disclosure. In some embodiments, the disclosure relates to an FGFR2, or a mutant thereof, covalently bonded to a compound of this disclosure. In some embodiments, the disclosure relates to an FGFR2, or a mutant thereof, covalently bonded to a compound of this disclosure, wherein the covalent bond is between R W< of the compound and a cysteine of the FGFR2, or a mutant thereof. In some embodiments, the disclosure relates to an FGFR2, or a mutant thereof, covalently bonded to a compound of this disclosure, wherein the covalent bond is between R W< of the compound and Cys491 of the FGFR2, or a mutant thereof.

[0251] In another embodiment, the disclosure provides a method of selectively inhibiting FGFR2 over one or more of FGFR1, FGFR3, and FGFR4. In some embodiments, a compound of the present disclosure is more than 5-fold selective over FGFR1, FGFR3, and FGFR4. In some embodiments, a compound of the present disclosure is more than 10-fold selective over FGFR1, FGFR3, and FGFR4. In some embodiments, a compound of the present disclosure is more than 50-fold selective over FGFR1, FGFR3, and FGFR4. In some embodiments, a compound of the present disclosure is more than 100-fold selective over FGFR1, FGFR3, and FGFR4. In some embodiments, a compound of the present disclosure is more than 200-fold selective over FGFR1, FGFR3, and FGFR4.

[0252] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0253] Inhibition of activity of FGFR2 (or a mutant thereof) in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0254] Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.

[0255] According to another embodiment, the disclosure relates to a method of inhibiting activity of FGFR2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. According to certain embodiments, the disclosure relates to a method of reversibly or irreversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the disclosure relates to a method of reversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the disclosure relates to a method of irreversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.

[0256] In some embodiments, the disclosure relates to a method of irreversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient, comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound, wherein the compound forms a covalent bond with the FGFR2, or a mutant thereof. In some embodiments, the disclosure relates to a method of irreversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient, comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound, wherein the compound forms a covalent bond between R W< of the compound and a cysteine of the FGFR2, or a mutant thereof. In some embodiments, the disclosure relates to a method of irreversibly inhibiting activity of one or more of FGFR2, or a mutant thereof, in a patient, comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound, wherein the compound forms a covalent bond between R W< of the compound and Cys491 of the FGFR2, or a mutant thereof.

[0257] According to another embodiment, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits the FGFR2, or a mutant thereof.

[0258] In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound irreversibly inhibits the FGFR2, or a mutant thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound forms a covalent bond with the FGFR2, or a mutant thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound forms a covalent bond between R W< of the compound and a cysteine of the FGFR2, or a mutant thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound forms a covalent bond between R W< of the compound and Cys491 of the FGFR2, or a mutant thereof.

[0259] According to another embodiment, the present disclosure provides a method of inhibiting signaling activity of FGFR2, or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting FGFR2 signaling activity in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.

[0260] In some embodiments, the present disclosure provides a method for treating a disorder mediated by FGFR2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits the FGFR2, or a mutant thereof.

[0261] The compounds described herein can also inhibit FGFR2 function through incorporation into agents that catalyze the destruction of FGFR2. For example, the compounds can be incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of FGFR2 to the E3 ligase will thus result in the destruction of the FGFR2 protein. The variable chain of atoms can include, for example, rings, heteroatoms, and / or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.Combination Therapies

[0262] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0263] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more additional therapeutic agents. In certain other embodiments, the methods of treatment comprise administering the compound or composition of the disclosure as the only therapeutic agent.

[0264] In some embodiments, the one or more additional therapeutic agents is selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. In some embodiments, the one or more additional therapeutic agent is selected from the following agents, or a pharmaceutically acceptable salt thereof: BCR-ABL inhibitors: e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (see Dardaei et al, 2018, Nat Med.; 24(4):512-517): e.g. crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, lorlatinib; BRAF inhibitors (see Prahallad et al, 2015, Cell Rep. 12, 1978-1985): e.g. vemurafenib, dabrafenib; FGFR inhibitors: e.g. infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547; FLT3 inhibitors: e.g. sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, and crenolanib; MEK Inhibitors (see Fedele et al, 2018, BioRxiv 307876; Torres-Ayuso et al, 2018, Cancer Discov. 8, 1210-1212; and Wong et al, 2016, Oncotarget. 2016 Oct 4; 7(40): 65676-65695) : e.g. trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g. ulixertinib, MK-8353, LY-3214996; VEGF receptor inhibitors: e.g. bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, sorafenib; Tyrosine kinase inhibitors: e.g. erlotinib, linifanib, sunitinib, pazopanib; Epidermal growth factor receptor (EGFR) inhibitors: gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: e.g. trastuzumab, neratinib, lapatinib, lapatinib; MET inhibitors: e.g. crizotinib, cabozantinib; CD20 antibodies: e.g. rituximab, tositumomab, ofatumumab; DNA Synthesis inhibitors: e.g. capecitabine, gemcitabine, nelarabine, hydroxycarbamide; Antineoplastic agents: e.g. oxaliplatin, cisplatin; HER dimerization inhibitors: e.g. pertuzumab; Human Granulocyte colony-stimulating factor (G-CSF) modulators: e.g. filgrastim; Immunomodulators: e.g. afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g. dacetuzumab; Pro-apoptotic receptor agonists (PARAs): e.g. dulanermin; Heat Shock Protein (HSP) inhibitors: e.g. tanespimycin (17-allylamino-17-desmethoxygeldanamycin); Hedgehog antagonists: e.g. vismodegib; Proteasome inhibitors: e.g. bortezomib; PI3K inhibitors: e.g. pictilisib, dactolisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; Phospholipase A2 inhibitors: e.g. anagrelide; BCL-2 inhibitors: e.g. venetoclax; Aromatase inhibitors: exemestane, letrozole, anastrozole, faslodex, tamoxifen; Topoisomerase I inhibitors: e.g. irinotecan, topotecan; Topoisomerase II inhibitors: e.g. etoposide, teniposide; mTOR inhibitors: e.g. temsirolimus, ridaforolimus, everolimus, sirolimus; Osteoclastic bone resorption inhibitors: e.g. zoledronic acid; CD33 Antibody Drug Conjugates: e.g. gemtuzumab ozogamicin; CD22 Antibody Drug Conjugates: e.g. inotuzumab ozogamicin; CD20 Antibody Drug Conjugates: e.g. ibritumomab tiuxetan; Somatostain analogs: e.g. octreotide; Interleukin-11 (IL-11): e.g. oprelvekin; Synthetic erythropoietin: e.g. darbepoetin alfa; Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: e.g. denosumab; Thrombopoietin mimetic peptides: e.g. romiplostim; Cell growth stimulators: e.g. palifermin; Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: e.g. figitumumab; Anti-CSl antibodies: e.g. elotuzumab; CD52 antibodies: e.g. alemtuzumab; CTLA-4 inhibitors: e.g. tremelimumab, ipilimumab; PD1 inhibitors: e.g. nivolumab, pembrolizumab; an immunoadhesin; e.g. pidilizumab, AMP-224; PDL1 inhibitors: e.g. MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105; LAG-3 inhibitors: e.g. BMS-986016; GITR agonists; GITR fusion proteins and anti-GITR antibodies; Histone deacetylase inhibitors (HDI): e.g. voninostat; Anti-CTLA4 antibodies: e.g. tremelimumab, ipilimumab; Alkylating agents: e.g. temozolomide, dactinomycin, melphalan, altretamine carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine , altretamine, ifosfamide, procarbazine , mechlorethamine, mustine and mechloroethamine, streptozocin, thiotepa; Biologic response modifiers: e.g. bacillus calmette-guerin, denileukin diftitox; Anti-tumor antibiotics: e.g. doxorubicin, bleomycin, daunorubicin , daunorubicin liposomal, mitoxantrone, epirubicin, idarubicin, mitomycin C; Anti-microtubule agents: e.g. estramustine; Cathepsin K inhibitors: e.g. odanacatib; Epothilone analogs: e.g. ixabepilone; TpoR agonists: e.g. eltrombopag; Anti-mitotic agents: e.g. docetaxel; Adrenal steroid inhibitors: e.g. aminoglutethimide; Anti-androgens: e.g. nilutamide; Androgen Receptor inhibitors: e.g. enzalutamide, abiraterone acetate, orteronel, galeterone, and seviteronel, bicalutamide, flutamide; Androgens: e.g. fluoxymesterone; CDK1 inhibitors: e.g. alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib; Gonadotropin-releasing hormone (GnRH) receptor agonists: e.g. leuprolide or leuprolide acetate; Taxane anti-neoplastic agents: e.g. cabazitaxel, larotaxel; 5-HTla receptor agonists: e.g. xaliproden; HPV vaccines: e.g. Cervarix ®< sold by GlaxoSmithKline, Gardasil ®< sold by Merck; Iron Chelating agents: e.g. deferasirox; Anti-metabolites: e.g. claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin; Bisphosphonates: e.g. pamidronate; Demethylating agents: e.g. 5-azacitidine, decitabine; Anti-tumor Plant Alkaloids: e.g. paclitaxel protein-bound; vinblastine, vincristine, vinorelbine, paclitaxel; Retinoids: e.g. alitretinoin, tretinoin, isotretinoin, bexarotene; Glucocorticosteroids: e.g. hydrocortisone, dexamethasone, prednisolone, prednisone, methylprednisolone; Cytokines: e.g. interleukin-2, interleukin-11 (oprevelkin), alpha interferon alfa (IFN-alpha); estrogen receptor downregulators: fulvestrant; Anti-estrogens: e.g. tamoxifen, toremifene; Selective estrogen receptor modulators (SERMs): e.g. raloxifene; Luteinizing hormone releasing hormone (LHRH) agonists: e.g. goserelin; Progesterones: e.g. megestrol; cytotoxic agents: arsenic trioxide, asparaginase (also known as L-asparaginase, Erwinia L-asparaginase; Anti-nausea drugs: e.g. NK-1 receptor antagonists (e.g. casopitant); Cytoprotective agents: e.g. amifostine, leucovorin; and Immune checkpoint inhibitors. The term "immune checkpoints" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present disclosure, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and / or TGFR beta.

[0265] In some embodiments, the one or more additional therapeutic agent is selected from the following agents: anti-FGFR antibodies; cytotoxic agents; Estrogen Receptor-targeted or other endocrine therapies, immune-checkpoint inhibitors, CDK inhibitors, other Receptor Tyrosine Kinase inhibitors, BRAF inhibitors, MEK inhibitors, PI3K inhibitors, SHP2 inhibitors, and SRC inhibitors. (See M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; Y.K. Chae, et al. Oncotarget 2017, 8:16052-16074; L. Formisano et al., Nat. Comm. 2019, 10:1373-1386; and references cited therein.)

[0266] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[0267] A compound of the current disclosure may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0268] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0269] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0270] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0271] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered.

[0272] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 µg / kg body weight / day of the additional therapeutic agent can be administered.

[0273] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0274] The compounds of this disclosure, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure.

[0275] Any of the compounds and / or compositions of the disclosure may be provided in a kit comprising the compounds and / or compositions. Thus, in some embodiments, the compound and / or composition of the disclosure is provided in a kit.

[0276] The disclosure is further described by the following non-limiting Examples.EXAMPLES

[0277] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only.

[0278] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds of the disclosure were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art.

[0279] In the description of the synthetic methods described below, unless otherwise stated, it is to be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration, and workup procedures) are selected from the standard conditions for that reaction, unless otherwise indicated. In the general schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0280] At least some of the compounds identified as "Intermediates" herein are contemplated as compounds of the disclosure.

[0281] In some embodiments, compounds of formula I are prepared according to the general procedure depicted in Scheme 1, below.

[0282] In some embodiments, Step 1 comprises the condensation of Int-1 with a compound of formula X-R 7< , thereby forming a compound of formula Int-2, wherein R 7< is defined in embodiments herein and X is a leaving group.

[0283] In some embodiments, Step 2 comprises the iodination of a compound of formula Int-2. In some embodiments the reagent used is N-iodosuccinimide.

[0284] In some embodiments, Step 3 comprises the coupling of a compound of formula Int-3 with a synthon comprising Cy 6< -L 6< -R W< functionalized with a suitable reactive group, thereby forming a compound of formula Int-4. In some embodiments the suitable reactive group is a boronate ester. In some embodiments, the suitable reactive group is a pinacol boronate.

[0285] In some embodiments, Step 4 comprises the coupling of a compound of formula Int-4 with a synthon comprising R 5< functionalized with a suitable reactive group, thereby forming a compound of formula I. In some embodiments, the suitable reactive group is a boronic acid or boronate ester.Example 1 N-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0286] 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0287]

[0288] Step 1: A round bottomed flask was charged with 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3 g, 14.0 mmol), Cs 2 CO 3 (9.10 g, 28.0 mmol), DMF (50 mL) and a stirbar. The mixture was cooled to 0 °C and iodomethane (1.98 g, 14.0 mmol) was added, and the solution was stirred for 3 h at 0 °C. The reaction mixture was diluted with H 2 O (300 mL), and the aqueous phase was extracted with EA (300 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (eluting with MeOH / DCM=1 / 80). Concentration in vacuo resulted in 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.20 g, 70%) as a yellow crystalline solid.5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0289]

[0290] Step 2: A round bottomed flask was charged with 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3 g, 13.2 mmol), TFA (7.52 g, 66.0 mmol), DCM (50 mL) and a stirbar. The mixture was cooled to 0 °C and 1-iodopyrrolidine-2,5-dione (2.96 g, 13.2 mmol) was added, and the solution was stirred for 2 h at room temperature. The reaction mixture was diluted with saturated Na 2 SO 3 solution (100 mL). The pH of the solution was adjusted to 7~8 with saturated NaHCO 3 solution. The solid was filtered and washed with H 2 O, then washed with a small amount of DCM and resulted in 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.70 g, 80%) as a white amorphous solid.N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0291]

[0292] Step 3: A resealable reaction vial was charged with 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.7 g, 10.51 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (3.7 g, 12.61 mmol), Pd(PPh 3 ) 4 (1.21 g, 1.05 mmol), K 3 PO 4 (6.68 g, 31.53 mmol), DMF (50 mL), H 2 O (3 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 50 °C. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (eluting with MeOH / DCM=1 / 100~1 / 20). Concentration in vacuo resulted in N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (2.2 g, 54%) as an off-white amorphous solid.N-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0293]

[0294] Step 4: A resealable reaction vial was charged with N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (120 mg, 0.31 mmol), 2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (122 mg, 0.373 mmol), Pd(DtBPF)Cl 2 (20.1 mg, 0.031 mmol), CsF (240 mg, 0.930 mmol), DMF(4 mL), H 2 O (0.5 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 2 h at 90 °C. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by TLC (eluting with MeOH / DCM=1 / 15). Concentration in vacuo resulted in N-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (13.9 mg, 9%) as a white amorphous solid.Example 2 Alternative route for N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0295] 6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0296]

[0297] Step 1: A round bottomed flask was charged with tert-butyl-4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenylcarbamate (20 g, 47.8 mmol), DCM (240 mL) and a stirbar. TFA (60 mL) was added. The solution was stirred for 4 h at room temperature. The reaction mixture was basified with saturated Na 2 CO 3 aqueous solution (40 mL), and the solids were filtered out and concentrated in vacuo. This resulted in 6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (14 g, 92.1%) as a off-white amorphous solid.N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0298]

[0299] Step 2: A resealable reaction vial was charged with 6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g, 31.4 mmol), DMF / Pyridine (4:1, 200 mL) and a stirbar before being evacuated and purged with nitrogen three times. And the solution was cooled to 0°C. Then methacryloyl chloride (4.0 g, 37.7 mmol) was dissolved in DMF (10 mL) and added to the above solution, and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with H 2 O (200 mL), and the aqueous phase was extracted with ethyl acetate (200 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was recrystallized with MeCN. Concentration in vacuo resulted in N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo [2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (8.8 g, 73%) as an off-white amorphous solid.Example 3 4-(4-amino-6-(4-methacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(oxetan-2-ylmethyl)benzamide

[0300] Methyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate

[0301]

[0302] Step 1: A resealable reaction vial was charged with 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 g, 72.9 mmol), [4-(methoxycarbonyl)phenyl]boronic acid (15.7 g, 87.4 mmol), Pd(DtBPF)Cl 2 (4.74 g, 7.29 mmol), CsF (33.1 g, 218 mmol), DMF (200 mL), H 2 O (25 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 90 °C.The reaction mixture was diluted with H 2 O (500 mL), and the aqueous phase was extracted with DCM (200 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The reaction mixture was added MeCN (10 mL) and filtered through a pad of Celite ®< , the pad was washed with MeCN. The filtrate was concentrated in vacuo and the resulting solid was methyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl }benzoate (11.0 g, 38.9 mmol), obtained as a yellow amorphous solid.Methyl 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate

[0303]

[0304] Step 2: A round bottomed flask was charged with methyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoate (10.9 g, 38.6 mmol), DCM (200 mL), TFA (13.1 g, 115 mmol) and a stirbar. The mixture was cooled to 0 °C, NIS (9.53 g, 42.4 mmol) was added, and the solution was stirred for 1 h at room temperature. The reaction mixture was diluted with Na 2 SO 3 solution, and the aqueous phase was extracted with DCM (300 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. DCM (20 mL) was added and the reaction mixture was filtered through a pad of Celite ®< , the pad was washed with little DCM. The filtrate was concentrated in vacuo and the resulting solid was methyl 4-{4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl }benzoate (12.0 g, 29.3 mmol), obtained as an off-white amorphous solidMethyl 4-(4-amino-6-(4-methacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]|pyrimidin-5-yl)benzoate

[0305]

[0306] Step 3: A resealable reaction vial was charged with methyl 4-{4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl }benzoate (11.9 g, 29.1 mmol), 2-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-enamide (10.0 g, 34.9 mmol), Pd(dppf)Cl 2 (2.12 g, 2.91 mmol), K 3 PO 4 (18.5 g, 87.3 mmol), DMF (100 mL), H 2 O (12.5 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 90 °C. The reaction mixture was diluted with H 2 O (500 mL), and the aqueous phase was extracted with DCM (300 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (eluting with MeOH / DCM=1 / 40). Concentration in vacuo resulted in methyl 4-{4-amino-7-methyl-6-[4-(2-methylprop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoate (7.70 g, 17.4 mmol) as a yellow amorphous solid.4-(4-amino-6-(4-methacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoic acid

[0307]

[0308] Step 4: A round bottomed flask was charged with methyl 4-{4-amino-7-methyl-6-[4-(2-methylprop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoate (7.65 g, 17.3 mmol), MeOH (40 mL), NaOH (2 N, 40 mL) and a stirbar. The solution was stirred for overnight at room temperature. The pH of the reaction mixture was adjusted to 6~7 with HCl (2 M). The reaction mixture was filtered through a pad of Celite ®< , the pad was washed with H 2 O. The filtrate was concentrated in vacuo and the resulting solid was 4-{4-amino-7-methyl-6-[4-(2-methylprop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic acid (6.50 g, 15.2 mmol), obtained as a off-white amorphous solid.4-(4-amino-6-(4-methacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(oxetan-2-ylmethyl)benzamide

[0309]

[0310] Step 5: A round bottomed flask was charged with 4-{4-amino-7-methyl-6-[4-(2-methylprop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic acid (60 mg, 0.14 mmol), 1-(oxetan-2-yl)methanamine (13.4 mg, 0.15 mmol), HATU (58.7 mg, 0.15 mmol) DIEA (54.2 mg, 0.42 mmol) and a stirbar. Dimethylformamide (3 mL) was added, and the solution was stirred at 25 °C for 2 h. The resulting crude material was purified by HPLC (Column: XBridge Prep Phenyl OBD Column, 19×150mm, 5um, 13nm). Lyophilization yielded 4-{4-amino-7-methyl-6-[4-(2-methylprop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-N-[(oxetan-2-yl)methyl]benzamide (20.0 mg, 0.040 mmol) as a off-white amorphous solid.

[0311] Additional compounds prepared according to the methods of Examples 1-3 are depicted in Table 2 below. Example 4 N-(4-(4-amino-7-methyl-5-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[0312] tert-butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0313]

[0314] Step 1: A round bottomed flask was charged with N-(4-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}phenyl)prop-2-enamide (200 mg, 537 µmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (199 mg, 644 µmol), Pd(dtbpf)Cl2 (34.9 mg, 53.7 µmol), K3PO4 (341 mg, 1.61 mmol), 5 mL of DMF and a stirbar. The solution was stirred at 90 °C for 2h.The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (2 g column; eluting with heptanes / ethyl acetate; 3:1). Concentration in vacuo resulted in tert-butyl 4-{4-amino-7-methyl-6-[4-(prop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate (121 mg, 48%) as a yellow oil.N-(4-(4-amino-7-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[0315]

[0316] Step 2: A round bottomed flask was charged with tert-butyl 4-{4-amino-7-methyl-6-[4-(prop-2-enamido)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate (30 mg, 63.2 µmol), 0.2 mL of TFA , 0.8 mL of DCM and a stirbar. The solution was stirred at room temperature for 1h.The reaction mixture was filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC (acetonitrile / water / 0.1% formic acid). Lyophilization yielded N-{4-[4-amino-7-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylphenyl}prop-2-enamide (16.8 mg, 71%) as a white amorphous solid.N-(4-(4-amino-7-methyl-5-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[0317]

[0318] Step 3: A round bottomed flask was charged with N-{4-[4-amino-7-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}prop-2-enamide (40 mg, 106 µmol), TEA (32.1 mg, 318 µmol), DMAP (1.29 mg, 10.6 µmol), 5 mL of DCM and a stir bar. TFAA was added dropwise at 0 °C. The solution was stirred at room temperature for 1h.The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with dichloromethane (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC (acetonitrile / water / 0.1% formic acid). Lyophilization yielded N-(4-{4-amino-7-methyl-5-[1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl }phenyl)prop-2-enamide (27.9 mg, 37%) as a white amorphous solid.

[0319] Additional compounds prepared according to the methods of Example 4 are depicted in Table 3 below. Table 3. Additional Exemplary Compounds Compound Structure Proton NMR MS [M+1] N-(4-(4-amino-7-methyl-5-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide 1< H NMR (400 MHz, DMSO-d6) δ 10.33 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.87 - 7.68 (m, 2H), 7.47 - 7.39 (m, 2H), 6.49 - 6.28 (m, 3H), 5.85 - 5.70 (m, 2H), 4.30 - 4.09 (m, 2H), 3.65 - 3.52 (m, 5H), 2.09 (s, 2H).471.1N-(4-(4-amino-7-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide 1< H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 28.0 Hz, 1H), 8.21 - 8.08 (m, 1H), 7.80 - 7.56 (m, 2H), 7.44-7.39 (m, 2H), 6.56 - 6.05 (m, 2H), 5.80 (d, J = 10.4 Hz, 1H), 3.57-3.46 (m, 4H), 3.16 (d, J = 46.0 Hz, 2H), 2.77 - 2.63 (m, 2H), 2.00 (m, J = 46.4 Hz, 2H).375.2 Example 5 N-(4-(4-amino-7-methyl-5-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0320] tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0321]

[0322] Step 1: A round bottomed flask was charged with 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.00 g, 10.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.01 g, 13.0 mmol), Pd(dtbpf)Cl2 (710 mg, 1.09 mmol), K 3 PO 4 (6.91 g, 32.6 mmol) and a stirbar. DMF (45 mL) and H 2 O(3 mL) was added, and the solution was stirred for 3 h at 90 °C. The mixture was diluted with EtOAc(300 mL) and washed with water (3*100 mL), the organic phase was concentrated and the crude product was purified by silica gel column with DCM:MeOH= 25 :1 to afford tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate (2.97 g, 83%) as brown oil.tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-car - boxylate

[0323]

[0324] Step 2: A round bottomed flask was charged with tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate (1.70 g, 5.16 mmol), Pd / C (326 mg, 154 µmol), and a stirbar. MeOH (50 mL) was added, and the solution was stirred at 50 °C for 48 h under H 2 . The mixture was filtered and washed with MeOH for 5times, the filtration was concentrated and obtained tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidine-1-carboxylate (900 mg, 53%) as brown oil.tert-butyl 4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperi dine-1-carboxylate

[0325]

[0326] Step 3: A round bottomed flask was charged with tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidine-1-carboxylate (800 mg, 2.41 mmol), NBS (428 mg, 2.41 mmol and a stirbar. ACN (20 mL) was added, and the solution was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure and obtained the product tert-butyl 4-{4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidine-1-carboxylate (500 mg, 51%) as brown solid. The crude product was used next step without further purification.6-bromo-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0327]

[0328] Step 4: A round bottomed flask was charged with tert-butyl 4-{4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidine-1-carboxylate (500 mg, 1.21 mmol), DCM (5 mL) and a stirbar. TFA (0.5 mL) was added, and the solution was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure, and diluted with DCM (30 mL), washed with saturated NaHCO 3 aq. (3* 15 mL), the organic phase was concentrated and obtained the product 6-bromo-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (310 mg, 83%) as brown oil.(4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)(pyrrolidin-1-yl)methanone

[0329]

[0330] Step 5: A round bottomed flask was charged with 6-bromo-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (280 mg, 902 µmol), DIEA (580 mg, 4.50 mmol), DCM (10 mL) and a stirbar. triphosgene (106 mg, 360 µmol) was added, and the solution was stirred for 1h at room temperature, then pyrrolidine (512 mg, 7.21 mmol) was added and stirred for 1h at room temperature. The solvent was removed and the crude product was purified by C18 Flash to afford 6-bromo-7-methyl-5-[1-(pyrrolidine-1-carbonyl)piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160 mg, 21%) as off-white solid.N-(4-(4-amino-7-methyl-5-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0331]

[0332] Step 6: A resealable reaction vial was charged with 6-bromo-7-methyl-5-[1-(pyrrolidine-1-carbonyl)piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140 mg, 0.34mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (112 mg, 0.41 mmol), Pd(dppf)Cl 2 (25.1 mg, 34.3 µmol), K 3 PO 4 (216 mg, 1.02 mmol), and a stirbar before being evacuated and purged with nitrogen three times. DMF (1mL) and H2O (0.1 mL) was added, and the mixture was stirred 3 h at 90 °C. The resulted mixture was purified through C18 Column. The resulting crude material was purified by HPLC. Lyophilization yielded N-(4-{4-amino-7-methyl-5-[1-(pyrrolidine-1-carbonyl)piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}phenyl)-2-methylprop-2-enamide (24.3 mg, 15%) as a white amorphous solid.

[0333] Additional compounds prepared according to the methods of Example 5 are depicted in Table 4 below. Table 4. Exemplary Compound Compound Structure Proton NMR MS [M+1] N-(4-(4-amino-7-methyl-5-(1-(pyrrolidine-1-carbonyl)piperidi n-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methac rylamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.11 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.38 (s, 2H), 5.83 (s, 1H), 5.56 (s, 1H), 3.58 - 3.61 (m, 2H), 3.55 (s, 3H), 3.26 - 3.38 (m, 4H), 3.02 - 3.05 (m, 1H), 2.68 - 2.76 (m, 2H), 2.08 (s, 3H), 1.63 - 1.66 (m, 4H), 1.48 - 1.57 (m, 4H).488.3 Example 6 N-(4-(4-amino-7-methyl-5-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[0334] tert-butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[0335]

[0336] Step 1: A round bottomed flask was charged with tert-butyl 4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (700 mg, 1.7 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (559 mg, 2.0 mmol), Pd(dtbpf)Cl2 (124 mg, 0.17 mmol), K 3 PO 4 (1.08 g, 5.1 mmol) and a stirbar. DMF (10 mL) and H 2 O(1 mL) was added, and the solution was stirred for 3 h at 90 °C. The mixture was diluted with EtOAc(100 mL) and washed with water (3*100 mL), the organic phase was concentrated and the crude product was purified by silica gel column with DCM:MeOH= 25 :1 to afford tert-butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (340 mg, 42%) as yellow solid.tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-car - boxylate

[0337]

[0338] Step 2: A round bottomed flask was charged with tert-butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (340 mg, 0.71 mmol), DCM (5 mL) and a stirbar. TFA(0.5 mL) was added, and the solution was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure, and diluted with DCM (30 mL), washed with saturated NaHCO 3 aq. (3* 15 mL), the organic phase was concentrated and obtained the product tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (240 mg, 89%) as brown oil.N-(4-(4-amino-7-methyl-5-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6 yl)phenyl) acrylamide

[0339]

[0340] Step 3: A round bottomed flask was charged with tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-car -boxylate (120 mg, 0.32 mmol), NaBH(OAc) 3 (81 mg, 0.38 mmol), (CH 2 O)n (20 mg, 0.64 mmol) and a stirbar. DCM (5 mL) and AcOH (0.5 mL) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with DCM (20 mL) three times. The combined organic layers dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC. Lyophilization yielded N-(4-{4-amino-7-methyl-5-[1-(pyrrolidine-1-carbonyl)piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}phenyl)-2-methylprop-2-enamide (8 mg, 6%) as a white amorphous solid.

[0341] Additional compounds prepared according to the methods of Example 6 are depicted in Table 5 below. Table 5. Exemplary Compound Compound Structure Proton NMR MS [M+1] N-(4-(4-amino-7-methyl-5-(1-methylpiperidin -4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acryl amide 1< H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.11 (s, 1H), 7.85 - 7.78 (m, 2H), 7.40 - 7.29 (m, 2H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.37-6.28 (m, 3H), 5.81 (dd, J = 10.0, 2.0 Hz, 1H), 3.37 (s, 3H), 2.75 (d, J = 10.9 Hz, 3H), 2.50-2.31 (m, 3H), 2.14 (s, 3H), 1.93-1.91 (m, 2H), 1.65 (s, 4H).391.2 Example 7 N-(4-(4-amino-7-methyl-5-(1-((methylcarbamoyl)glycyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[0342]

[0343] A resealable reaction vial was charged with N-{4-[4-amino-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}prop-2-enamide (100 mg, 0.265 mmol), 2-[(methylcarbamoyl)amino]acetic acid (35.0 mg, 0.265 mmol), HATU (121 mg, 0.32 mmol), DIEA (68.5 mg, 0.53 mmmol), and a stirbar. Dimethylformamide (5 mL) was added, and the mixture was stirred for 1 h at r.t. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with dichloromethane (15 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC (acetonitrile / water / 0.1% formic acid). Lyophilization yielded N-{4-[4-amino-7-methyl-5-(1-{2-[(methylcarbamoyl)amino]acetyl } piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}prop-2-enamide (6.00 mg, 5%) as a white amorphous solid.

[0344] Additional compounds prepared according to the methods of Example 7 are depicted in Table 6 below. Table 6. Additional Exemplary Compounds Compound Structure Proton NMR MS [M+1] N-(4-(4-amino-7-methyl-5-(1-((methylcarbamo yl)glycyl)piperidi n-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide 1< H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.39 (s, 2H), 6.30 (d, J = 16.8 Hz, 1H), 6.10 (s, 1H), 5.92 (s, 1H), 5.80 (d, J = 10.5 Hz, 1H), 3.78-3.66 (m, 3H), 3.45-3.37 (m, 1H), 3.31 (s, 3H), 3.21-3.08 (m, 2H), 2.55-2.53 (m, 1H), 2.51 (s, 3H), 1.86-1.73 (m, 2H), 1.45-1.24 (m, 2H).491.2(R)-N-(4-(4-amino-5-(1-(4-(dimethylamino)-2-methylbutanoyl) piperidin-4-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acryla mide 1< H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 6.53 - 6.42 (m, 3H), 6.30 (dd, J = 16.8, 2.1 Hz, 1H), 5.80 (dd, J = 10.0, 2.0 Hz, 1H), 4.37 (s, 1H), 3.88 (s, 1H), 3.28 (s, 3H), 3.09 (t, J = 13.6 Hz, 1H), 2.75-2.61 (m, 2H), 2.06 (s, 4H), 2.01 (s, 4H), 1.76-1.48 (m, 4H), 1.29-1.22 (m, 3H), 0.91-0.82 (m, 3H).504.4 Example 8

[0345] 5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0346]

[0347] Step 1: A resealable reaction vial was charged with 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 g, 72.9 mmol), (4-methoxyphenyl)boronic acid (13.3 g, 87.5 mmol), Pd(DtBPF)Cl 2 (4.74 g, 7.29 mmol), CsF (33.1 g, 218 mmol), DMF (200 mL), H 2 O (25 mL) and a stir bar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 90 °C. The reaction mixture was diluted with H 2 O (500 mL), and the aqueous phase was extracted with DCM (200 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The reaction mixture was added MeCN (10 mL) and filtered through a pad of Celite ®< , the pad was washed with MeCN. The filtrate was concentrated in vacuo and the resulting solid was 5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.2 g, 55%), obtained as a yellow amorphous solid.6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0348]

[0349] Step 2: A round bottomed flask was charged with 5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.8 g, 38.5 mmol), DCM (200 mL), TFA (13.1 g, 115 mmol) and a stir bar. The mixture was cooled to 0 °C, NIS (9.53 g, 42.4 mmol) was added, and the solution was stirred for 1 h at room temperature. The reaction mixture was diluted with Na 2 SO 3 solution, and the aqueous phase was extracted with DCM (300 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. DCM (20 mL) was added and the reaction mixture was filtered through a pad of Celite ®< , the pad was washed with little DCM. The filtrate was concentrated in vacuo and the resulting solid was 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.9 g, 74%), obtained as an off-white amorphous solid.tert-butyl 4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin 6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0350]

[0351] Step 3: A resealable reaction vial was charged with 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 g, 2.63 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.2 g, 3.16 mmol), Pd(dppf)Cl 2 (190 mg, 0.26 mmol), K 3 PO 4 (1.5 g, 6.9 mmol), DMF (20 mL), H 2 O (2 mL) and a stir bar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 90 °C. The reaction mixture was diluted with H 2 O (100 mL), and the aqueous phase was extracted with DCM (100 mL) three times. The combined organic layers were washed with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (eluting with MeOH / DCM=1 / 40). Concentration in vacuo resulted in tert-butyl 4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate ( 800 mg, 61%) as a yellow solid.5-(4-methoxyphenyl)-7-methyl-6-(1 (piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine trifluoroacetate salt

[0352]

[0353] Step 4: A round bottomed flask was charged with tert-butyl 4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (800 mg, 1.6 mmol), DCM (20 mL) and a stir bar. TFA (5 mL) was added. The reaction mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo resulted in 5-(4-methoxyphenyl)-7 methyl-6-(1 (piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine trifluoracetate salt (795 mg, 100%) as a dark oil.1-(4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one

[0354]

[0355] Step 5: A round bottomed flask was charged with 5-(4-methoxyphenyl)-7-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate salt (120 mg, 0.24 mmol), Et 3 N (72.9 mg, 0.72 mmol) DCM (10 mL) and a stir bar. The mixture was cooled to -30 °C, prop-2-enoyl chloride (21.6 mg, 0.24 mmol) was added dropwise and the solution was stirred for 0.5 h at -30 °C. The reaction mixture was quenched with MeOH, and concentrated in vacuo. The resulting crude material was purified by prep-HPLC. Lyophilization yielded 1-(4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one (33 mg, 30 %) as a white amorphous solid.

[0356] Additional compounds prepared according to the methods of Example 8 are depicted in Table 7 below. Table 7. Additional Exemplary Compounds Compound Structure Proton NMR MS [M+1] 1-(4-(4-(4-amino-7-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propan-1-one 1< H NMR (400 MHz, DMSO-d6) δ 1.63 - 1.88 (m, 2H), 2.01 (t, J = 14.8 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 2.73 (t, J = 12.4 Hz, 1H), 3.16 (t, J = 12.8 Hz, 1H), 3.70 (s, 3H), 3.93 (d, J = 14.0 Hz, 1H), 4.43 (td, J = 5.6, 11.5 Hz, 2H), 5.85 (s, 1H), 7.02 - 7.07 (m, 2H), 7.07 - 7.12 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.39 - 7.46 (m, 3H), 7.89 (s, 1H), 8.15 (s, 1H).522.231-(4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.95 (s, 1H), 7.36 (s, 1H), 7.29 - 7.21 (m, 2H), 7.04 - 6.96 (m, 2H), 6.85 (m, 1H), 6.12 (m, 1H), 5.70 (m, 1H), 4.47 (t, J = 7.2 Hz, 2H), 4.13 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.24 (d, J = 13.6 Hz, 1H), 2.83 (t, J = 12.4 Hz, 1H), 2.04 (d, J = 12.4 Hz, 2H), 1.79 (d, J = 16.8 Hz, 2H).458.221-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-2-methylpiperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.80 - 7.72 (m, 1H), 7.48 (s, 1H), 7.38 - 7.25 (m, 2H), 7.16 - 7.10 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.82 (d,J = 8.2 Hz, 1H), 6.66 (s, 1H), 6.01 (d, J = 16.4 Hz, 1H), 5.60 (d, J = 10.4 Hz, 1H), 5.01 (s, 1H), 4.38 (s, 1H), 4.07 (s, 1H), 3.66 (s, 3H), 3.32 (s, 1H), 3.07 (s, 1H), 2.37 (s, 3H), 2.15 (s, 2H), 1.49 (s, 1H), 1.38 (s, 1H), 1.31 (d, J = 6.8 Hz, 3H).549.251-(3-(4-(4-amino-7-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-2-methylpiperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.80 - 7.72 (m, 1H), 7.48 (s, 1H), 7.38 - 7.25 (m, 2H), 7.16 - 7.10 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.66 (s, 1H), 6.01 (d, J= 16.4 Hz, 1H), 5.60 (d, J = 10.4 Hz, 1H), 5.01 (s, 1H), 4.38 (s, 1H), 4.07 (s, 1H), 3.66 (s, 3H), 3.32 (s, 1H), 3.07 (s, 1H), 2.15 (s, 2H), 1.49 (s, 1H), 1.38 (s, 1H), 1.31 (d, J = 6.8 Hz, 3H).534.251-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.96 (s, 1H), 7.79 - 7.71 (m, 1H), 7.47 (s, 1H), 7.38 - 7.31 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.38 - 5.91 (m, 1H), 5.67 (dd, J = 10.4, 32.3 Hz, 1H), 4.51 - 3.93 (m, 3H), 3.70 (s, 3H), 3.56 (s, 0H), 3.17 (s, 1H), 2.98 (s, 0H), 2.36 (s, 3H), 2.09 (d, J = 17.2 Hz, 2H), 1.77 (s, 1H), 1.50 (s, 1H).535.251-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.95 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 5.00 (s, 1H), 4.46 (t, J = 11.6 Hz, 1H), 3.94 (s, 1H), 3.70 (s, 3H), 2.84 (s, 1H), 2.35 (s, 3H), 2.04 (d, J = 12.8 Hz, 2H), 1.86 (s, 3H), 1.79 (d, J = 12.8 Hz, 2H).549.26(E)-1-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-(dimethylamino) but-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.95 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 2.8 Hz, 2H), 4.45 (s, 2H), 4.13 (s, 1H), 3.69 (s, 3H), 3.02 (d, J = 4.0 Hz, 2H), 2.80 (s, 2H), 2.35 (s, 3H), 2.14 (s, 6H), 2.03 (s, 2H), 1.78 (s, 3H).592.411-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.98 (d, J = 18.1 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.50 - 7.44 (m, 1H), 7.37 - 7.30 (m, 2H), 7.14 (dd, J = 8.6, 1.9 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.57 (dt, J = 16.7, 10.6 Hz, 1H), 6.14 (ddd, J = 16.7, 5.5, 2.4 Hz, 1H), 5.66 (ddd, J = 12.8, 10.3, 2.4 Hz, 1H), 5.09 - 4.96 (m, 1H), 3.92 - 3.78 (m, 1H), 3.70 (s, 5H), 3.62 - 3.42 (m, 3H), 2.36 (s, 4H).521.201-(4-(3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.05 (d,J = 7.4 Hz, 1H), 6.79 (dd, J = 17.3, 9.7 Hz, 2H), 6.09 (dd, J = 16.6, 2.5 Hz, 1H), 5.66 (dd, J = 10.3, 2.5 Hz, 1H), 4.15 (d, J = 13.0 Hz, 1H), 3.92 (s, 2H), 3.22 (d, J = 45.6 Hz, 4H), 3.03 (d, J = 12.4 Hz, 1H), 2.37 (s, 3H), 2.12 - 1.96 (m, 2H), 1.64 (s, 2H).537.401-(4-(5-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.41 - 1.68 (m, 2H), 1.80 - 1.92 (m, 2H), 2.38 (s, 3H), 2.92 - 3.00 (m, 1H), 3.10 - 3.26 (m, 2H), 3.85 - 3.98 (m, 1H), 4.04 (s, 3H), 4.04 - 4.09 (m, 1H), 5.63 (dd, J = 2.8 Hz, 1H), 6.07 (dd, J = 2.4 Hz, 1H), 6.70 - 6.77 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 11.2 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.79 (t, J = 15.6 Hz, 1H), 8.28 (s, 1H)537.401-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 8.01 (s, 1H), 7.77 - 7.70 (m, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 6.89 - 6.75 (m, 2H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 - 5.66 (m, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.39 (d,J = 11.2 Hz, 1H), 4.14 (d, J = 13.5 Hz, 1H), 3.55 (s, 3H), 3.32 (s, 2H), 3.23 (s, 1H), 2.83 (t, J = 13.1 Hz, 1H), 2.34 (s, 3H), 2.07 (d, J = 10.1 Hz, 2H), 1.88 - 1.75 (m, 2H), 1.70 (s, 3H).549.401-(4-(4-(4-amino-7-methyl-5-(4-((5-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.03 (dd, J = 2.1, 1.1 Hz, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.71 (dd, J = 8.2, 2.5 Hz, 1H), 7.45 (d, J = 0.7 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.17 - 7.09 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.14 (d, J = 13.9 Hz, 1H), 3.70 (s, 3H), 3.23 (t, J = 12.9 Hz, 1H), 2.84 (t, J = 12.5 Hz, 1H), 2.27 (s, 3H), 2.04 (s, 2H), 1.78 (t, J = 13.6 Hz, 2H).535.31-(4-(4-(4-amino-7-methyl-5-(4-((4-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 8.05 (d, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.36 - 7.31 (m, 2H), 7.16 - 7.12 (m, 2H), 7.02 - 6.99 (m, 1H), 6.91 (s, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.46 (t, J = 10.8 Hz, 1H), 4.14 (d, J = 13.7 Hz, 1H), 3.70 (s, 3H), 3.21 (d, J = 12.9 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.35 (s, 4H), 2.04 (s, 2H), 1.80 (d, J = 13.6 Hz, 2H).535.401-(4-(4-(4-amino-5-(4-((6-fluoropyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (q, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.42 - 7.34 (m, 2H), 7.27 7.19 (m, 2H), 6.97 (dd, J = 7.9, 1.7 Hz, 1H), 6.92 (dd, J = 7.9, 2.4 Hz, 1H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.85 (s, 2H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.46 (ddd, J = 15.3, 11.3, 3.9 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.22 (t, J = 12.9 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.05 (d, J = 12.4 Hz, 2H), 1.79 (t, J = 12.8 Hz, 2H).539.31-(4-(4-(4-amino-5-(4-((6-methoxypyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.98 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.25 - 7.16 (m, 2H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.55 (dd, J = 7.9, 5.0 Hz, 2H), 6.12 (dd, J = 16.6, 2.5 Hz, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.47 (td,J = 12.2, 11.3, 6.8 Hz, 2H), 4.14 (d, J = 13.6 Hz, 1H), 3.69 (d, J = 15.3 Hz, 6H), 3.21 (d, J = 13.0 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.04 (d, J = 12.5 Hz, 2H), 1.89 - 1.65 (m, 2H).551.351-(4-(4-(4-amino-7-methyl-5-(4-(pyridin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.25 - 8.13 (m, 2H), 7.94 (s, 1H), 7.88 (ddd, J = 8.2, 7.2, 2.0 Hz, 1H), 7.46 (s, 1H), 7.38 - 7.30 (m, 2H), 7.22 - 7.11 (m, 3H), 7.07 (dd, J = 8.3, 1.0 Hz, 1H), 6.84 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.86 (s, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.47 (td, J = 11.1, 5.5 Hz, 2H), 4.14 (d, J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.23 (t, J = 12.9 Hz, 1H), 2.83 (t, J = 12.7 Hz, 1H), 2.12 - 1.98 (m, 2H), 1.78 (t, J = 12.9 Hz, 2H).521.351-(4-(4-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.8 Hz, 2H), 8.17 (s, 1H), 7.96 (s, 1H), 7.48 (d, J = 0.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 - 7.23 (m, 3H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.6, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 4.49 (d, J = 12.4 Hz, 2H), 4.15 (d, J = 13.7 Hz, 1H), 3.70 (s, 3H), 3.24 (s, 1H), 2.84 (t, J = 12.3 Hz, 1H), 2.07 (d, J = 12.4 Hz, 2H), 1.81 (d, J = 14.3 Hz, 2H).522.21-(4-(4-(4-amino-7-methyl-5-(4-(pyrazin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.4 Hz, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 2.7, 1.4 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.31 - 7.23 (m, 2H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.47 (m, 2H), 4.14 (d, J = 13.5 Hz, 1H), 3.70 (s, 3H), 3.23 (t, J = 12.9 Hz, 1H), 2.84 (t, J = 12.8 Hz, 1H), 2.04 (s, 2H), 1.80 (d, J = 13.6 Hz, 2H).522.2N-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)cyclobutyl)-N-methylacrylamid e 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 7.75 (td, J = 7.7, 2.3 Hz, 1H), 7.50 (d, J = 12.4 Hz, 1H), 7.36 (dd, J = 8.7, 2.6 Hz, 2H), 7.18 - 7.14 (m, 2H), 7.04 - 7.00 (m, 1H), 6.82 (dd, J = 8.1, 3.2 Hz, 1H), 6.19 - 5.57 (m, 3H), 5.14 (d, J = 106.7 Hz, 1H), 4.90 (dt, J = 9.0, 4.8 Hz, 1H) 3.71 (d, J = 2.7 Hz, 3H), 3.16 - 2.91 (m, 3H), 2.90 - 2.54 (m, 6H), 2.35 (s, 3H).535.401-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1- 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.74 (t, J= 7.8 Hz, 1H), 7.67 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.85 (dd, J = 16.8, 10.6 Hz, 1H), 6.79 (d,J = 8.2 Hz, 1H), 6.12 (dd, J = 16.8, 2.4 Hz, 1H), 6.01 (s, 2H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 4.40 (s, 1H), 4.16 (d, J = 13.6 Hz, 1H), 3.58 (s, 3H), 3.20 (t, J = 12.2 Hz, 1H), 2.79 (s, 1H), 2.35 (s, 3H), 1.83 (s, 4H), 1.78 (s, 3H).549.25(E)-2-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)but-2-enenitrile 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.82 - 1.93 (m, 3H), 2.07 - 2.09 (m, 5H), 2.25 - 2.36 (m, 5 H), 2.80 - 3.08 (br, 1H), 3.70 (s, 3H), 3.82 - 4.70 (m, 3H), 5.50 - 6.10 (br, 1 H), 6.69 - 6.92 (m, 1H), 6.92 - 7.16 (m, 4H), 7.33 - 7.36 (m, 2H), 7.45 (s, 1H), 7.72 - 7.80 (m, 1H), 7.97 (s, 1H), 8.10 (s, 1H).574.401-(3-(4-(4-amino-7-methyl-5-(4-((6-Methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl) pyrrolidin-1-yl)but-2-yn-1-one 1< H NMR (400 MHz, DMSO-d6) δ 2.00 (d, J = 14.4 Hz, 3H), 2.36 (s, 5H), 3.31 (s, 1H), 3.49 (m, 1H), 3.62 - 3.80 (m, 5H), 3.88 - 4.05 (m, 1H), 5.04 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.11 - 7.19 (m, 2H), 7.30 - 7.39 (m, 2H), 7.48 (d, J = 2.8 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.99 (d, J = 9.6 Hz, 1H), 8.17 (d, J = 0.8 Hz, 1H).533.23(E)-1-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridn-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d] pyrimidin-6-yl)-1H-pyrazol-1-yl) pyrrolidin-1-yl)but -2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 3H), 2.36 (s, 5H), 3.51 (m, 1H), 3.70 (s, 4H), 3.80 - 4.05 (m, 1H), 4.95 - 5.11 (m, 1H), 6.25 (m, 1H), 6.64 - 6.73 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.11 - 7.18 (m, 2H), 7.34 (m, 2H), 7.48 (d, J = 4.4 Hz, 1H), 7.72 - 7.79 (m, 1H), 7.96 (d, J = 26.4 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H).535.2(E)-1-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-4-(dimethylamino)-2-methylbut-2-en-1-one 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 11.3 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.32 (m, 2H), 7.20 - 7.12 (m, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.92 (td, J = 6.5, 1.6 Hz, 2H), 5.27 (ddd, J = 13.4, 8.2, 5.2 Hz, 1H), 4.70 - 4.05 (m, 4H), 3.71 (s, 3H), 3.31 (s, 1H), 2.98 (d, J = 6.5 Hz, 2H), 2.36 (s, 3H), 2.14 (s, 6H), 1.75 (d, J = 1.4 Hz, 3H).578.45(E)-1-(3-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)but-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.82 - 1.84 (m, 4H), 2.36 (s, 1H), 3.71 (s, 1H), 4.12 - 4.19 (m, 1H), 4.31 - 4.58 (m, 2H), 4.61 - 4.69 (m, 1 H), 5.27 - 5.33 (m, 1H), 6.01 - 6.06 (m, 1 H), 6.66 - 6.68 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.0 Hz, 2H), 7.35 (dd, J = 2.0 Hz, 2H), 7.52 (s, 1H), 7.76 (t, J = 15.6 Hz, 1H), 8.13 (s, 1H), 8.17 (s, 1H).521.201-(4-(4-(4-amino-7-methyl-5-(4-(( 6-methylpyridin -2-yl)oxy)phenyl) -7H-pyrrolo[2,3-d ]pyrimidin-6-yl)-1H-pyrazol-1-yl) piperidin-1-yl)-2-(morpholinometh yl) prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.81 (s, 2H), 2.04 (d, J = 12.5 Hz, 2H), 2.35 (s, 4H), 2.37 (s, 3H), 2.85 (s, 1H), 3.10 (s, 1H), 3.22 (s, 1H), 3.54 (t, J = 4.8 Hz, 4H), 3.70 (s, 3H), 3.98 (s, 1H), 4.38 - 4.51 (m, 2H), 5.20 (s, 1H), 5.35 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 7.12 - 7.18 (m, 2H), 7.32 - 7.38 (m, 2H), 7.47 (d, J = 0.8 Hz, 1H), 7.75 (m, 1H), 7.94 (s, 1H), 8.16 (s, 1H).634.51-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)but-2-yn-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.73 (m, 1H), 1.86 (m, 1H), 2.03 (s, 4H), 2.10 (d, J = 13.2 Hz, 1H), 2.36 (s, 3H), 2.80 - 2.92 (m, 1H), 3.27 (d, J = 2.8 Hz, 1H), 3.70 (s, 3H), 4.34 (m, 2H), 4.41 - 4.52 (m, 1H), 6.21 (d, J = 273.6 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.10 - 7.21 (m, 2H), 7.31 - 7.40 (m, 2H), 7.44 (d, J = 0.7 Hz, 1H), 7.75 (dd, J = 7.3, 8.2 Hz, 1H), 7.97 (s, 1H), 8.16 (s, 1H).547.25(E)-1-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)but-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.75 (dd, J = 8.2, 7.4 Hz, 1H), 7.44 (d, J = 0.7 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.17 - 7.13 (m, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.75 - 6.64 (m, 1H), 6.54 (dd, J = 14.9, 1.7 Hz, 1H), 6.20 - 5.50 (m, 1H), 4.53 - 4.37 (m, 2H), 4.14 (s, 1H), 3.70 (s, 3H), 3.24 - 3.12 (m, 1H), 2.78 (s, 1H), 2.36 (s, 3H), 2.14 - 1.98 (m, 2H), 1.84 (dd, J = 6.7, 1.5 Hz, 3H), 1.77 (s, 2H).549.25(E)-1-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-morpholinobut-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.79 (d, J = 18.2=4 Hz, 2H), 2.06 (d, J = 16.0 Hz, 2H), 2.36 (s, 6H), 3.09 (d, J = 5.6 Hz, 4H), 3.58 (t, J = 4.8 Hz, 4H), 3.70 (s, 3H), 4.12 (d, J = 13.6 Hz, 1H), 4.46 (m, 2H), 5.84 (s, 1H), 6.53 - 6.72 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.24 - 7.40 (m, 2H), 7.44 (s, 1H), 7.95 (s, 1H), 8.15 (d,J = 4.4 Hz, 2H)634.3(E)-1-(4-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-(dimethylamino)-2-methylbut-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.97 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.37 - 7.31 (m, 2H), 7.19 - 7.13 (m, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.51 (td,J = 6.6, 1.7 Hz, 2H), 4.60 - 4.33 (m, 1H), 4.38 - 3.79 (m, 1H), 3.70 (s, 3H), 3.34 (s, 1H), 2.93 (d, J = 6.7 Hz, 4H), 2.35 (s, 3H), 2.13 (s, 6H), 2.04 (d, J = 12.7 Hz, 2H), 1.88 - 1.72 (m, 5H).606.451-(4-(4-(4-amino-7-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.49 - 7.38 (m, 3H), 7.36 - 7.28 (m, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.07 - 7.02 (m, 2H), 5.84 (s, 2H), 5.24 - 5.12 (m, 1H), 5.01 (t, J = 1.3 Hz, 1H), 4.51 - 4.34 (m, 2H), 3.91 (d, J = 28.7 Hz, 1H), 3.70 (s, 3H), 3.22 (s, 1H), 2.86 (s, 1H), 2.04 (d, J = 12.6 Hz, 2H), 1.88 (d, J = 1.4 Hz, 3H), 1.78 (tt, J = 12.2, 6.1 Hz, 2H).534.401-(4-(4-(4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.94 (s, 1H), 7.36 (s, 1H), 7.28 - 7.22 (m, 2H), 7.07 - 6.90 (m, 2H), 5.76 (s, 2H), 5.26 - 5.14 (m, 1H), 5.01 (t, J = 1.3 Hz, 1H), 4.44 (ddt, J = 11.1, 8.0, 4.0 Hz, 2H), 3.97 (s, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.03 (d, J = 139.1 Hz, 2H), 2.04 (d, J = 12.5 Hz, 2H), 1.88 (d, J = 1.4 Hz, 3H), 1.78 (qd, J = 12.1, 4.4 Hz, 2H).472.357-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(1-(1-(vinylsulfonyl)pi peridin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.97 - 7.94 (m, 1H), 7.75 (dd, J = 8.2, 7.3 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.20 - 7.12 (m, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.91 - 6.79 (m, 2H), 6.21 - 6.09 (m, 2H), 5.85 (s, 2H), 4.33 (dt, J = 7.2, 4.1 Hz, 0H), 3.70 (s, 3H), 3.60 (d, J = 12.4 Hz, 2H), 2.84 (td, J = 12.2, 2.7 Hz, 2H), 2.36 (s, 3H), 2.10 (d, J = 12.9 Hz, 2H), 1.95 (qd, J = 12.0, 4.2 Hz, 2H).571.151-(4-(4-(4-amino-5-(3-methoxy-4-((6-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.67 (dd, J = 8.2, 7.4 Hz, 1H), 7.49 (d, J = 0.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (dd, J = 16.8, 10.6 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.12 (dd, J = 16.8, 2.6 Hz, 1H), 5.93 (s, 2H), 5.69 (dd, J = 10.6, 2.4 Hz, 1H), 4.54 - 4.43 (m, 2H), 4.15 (d, J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.61 (s, 3H), 3.23 (t, J = 13.4 Hz, 1H), 2.83 (t,J = 12.4 Hz, 1H), 2.32 (s, 3H), 2.06 (d, J = 18.0 Hz, 2H), 1.87 - 1.71 (m, 2H).565.251-(4-(4-(4-amino-5-(3-methoxy-4-(m-tolyloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.79 (m, 2H), 2.03 (s, 2H), 2.29 (s, 3H), 2.83 (m, 1H), 3.23 (m, 1H), 3.67 (d, J = 20.4 Hz, 6H), 4.14 (d, J = 14.0 Hz, 1H), 4.40 - 4.54 (m, 2H), 5.69 (m, 1H), 6.12 (m, 1H), 6.66 (m, 1H), 6.76 - 6.91 (m, 4H), 7.02 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.95 (s, 1H), 8.16 (s, 1H).564.451-(4-(4-(4-amino-5-(3-methoxy-4-(pyridin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.11 (dd, J = 5.2, 2.0 Hz, 1H), 7.96 (s, 1H), 7.82 (ddd, J = 8.4, 7.2, 2.1 Hz, 1H), 7.52 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (ddd, J = 7.2, 4.9, 0.9 Hz, 1H), 7.03 - 6.92 (m, 3H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.95 (s, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.57 - 4.36 (m, 2H), 4.13 (t, J = 11.7 Hz, 1H), 3.69 (s, 3H), 3.60 (s, 3H), 3.29 - 3.14 (m, 1H), 2.84 (t, J = 12.7 Hz, 1H), 2.05 (s, 2H), 1.79 (t, J = 13.1 Hz, 2H).551.201-(4-(3-(4-amino-5-(3-methoxy-4-((6-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 2H), 5.86 (s, 1H), 5.68 (dd, J = 10.4, 2.5 Hz, 1H), 4.57 - 4.43 (m, 2H), 4.16 (d, J = 13.7 Hz, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 3.25 (d, J = 12.7 Hz, 1H), 2.86 (t, J = 12.0 Hz, 1H), 2.30 (d, J = 17.8 Hz, 6H), 1.90 (d, J = 22.3 Hz, 4H).579.451-(4-(4-(4-amino-5-(3-methoxy-4-((6-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.73 - 7.63 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.94 (d,J = 7.3 Hz, 1H), 6.90 - 6.78 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.12 (dd, J = 16.6, 2.4 Hz, 2H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.56 - 4.35 (m, 2H), 4.17 (d, J = 13.7 Hz, 1H), 3.60 (s, 3H), 3.47 (s, 3H), 3.20 (t, J = 13.1 Hz, 1H), 2.79 (s, 1H), 2.31 (s, 3H), 1.78 (s, 7H).579.451-(4-(4-(4-amino-5-(3-methoxy-4-(6-methylpyridin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-2-methylpiperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (d, J = 1.3 Hz, 1H), 8.04 (s, 1H), 7.71 - 7.62 (m, 1H), 7.53 (s, 1H), 7.13 (dd, J = 9.2, 8.0 Hz, 1H), 7.04 (dd, J = 6.3, 1.9 Hz, 1H), 6.97 - 6.88 (m, 2H), 6.88 - 6.70 (m, 1H), 6.66 (dd, J= 8.3, 4.5 Hz, 1H), 6.10 (dd, J = 16.6, 2.4 Hz, 1H), 5.95 (s, 1H), 5.72 - 5.62 (m, 1H), 4.46 (s, 1H), 4.06 (s, 1H), 3.69 (s, 3H), 3.62 (d, J = 3.7 Hz, 3H), 2.31 (d, J = 1.9 Hz, 3H), 2.28 - 2.18 (m, 1H), 2.07 (dd, J = 16.7, 8.8 Hz, 2H), 1.32 - 1.18 (m, 1H), 0.84 (d, J = 6.8 Hz, 2H).578.67 71-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d, J = 4.8 Hz, 2H), 8.17 (s, 1H), 7.30 - 7.22 (m, 2H), 7.10 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.80 (ddd, J = 28.0, 16.6, 10.4 Hz, 1H), 6.31 - 5.87 (m, 3H), 5.69 (t, J = 8.7 Hz, 1H), 4.20 (d, J i= 31.7 Hz, 2H), 3.66 (d, J = 5.4 Hz, 8H), 2.18 (s, 2H).484.251-(4-(4-amino-5-(4-((6-ethylpyridin-2-yl)oxy)-3-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J = 11.4, 7.8 Hz, 2H), 6.75 (dd, J = 38.1, 9.5 Hz, 2H), 6.38 - 5.84 (m, 3H), 5.69 (t, J = 9.3 Hz, 1H), 4.42 - 4.06 (m, 2H), 3.66 (d, J = 3.1 Hz, 8H), 2.57 (q, J = 7.5 Hz, 2H), 2.18 (s, 2H), 1.08 (t, J = 7.5 Hz, 3H).511.251-(4-(4-amino-5-(3-methoxy-4-((5-methylpyridin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.94 (s, 1H), 7.64 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.90 - 6.71 (m, 2H), 6.30 - 5.85 (m, 3H), 5.68 (d, J = 9.9 Hz, 1H), 4.20 (d, J = 32.5 Hz, 2H), 3.66 (d, J = 3.5 Hz, 8H), 2.24 (s, 3H), 2.17 (s, 2H).497.351-(4-(4-amino-5-(3-methoxy-4-((5-methylpyridin-3-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.18 - 8.07 (m, 3H), 7.18 - 7.08 (m, 3H), 6.96 (dd, J = 8.0, 1.9 Hz, 1H), 6.79 (ddd, J = 26.9, 16.6, 10.4 Hz, 1H), 6.17 - 6.07 (m, 2H), 5.96 (d, J = 18.9 Hz, 1H), 5.74 - 5.64 (m, 1H), 4.19 (d, J = 33.2 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 5H), 2.29 (s, 3H), 2.16 (s, 2H), 2.08 (s, 1H).497.201-(3-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrol-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (dd, J = 12.3, 4.7 Hz, 2H), 8.19 (d, J = 1.1 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.38 - 7.27 (m, 3H), 6.62 - 6.25 (m, 2H), 6.15 (dd, J = 16.8, 2.4 Hz, 1H), 5.89 (s, 2H), 5.69 (ddd, J = 14.8, 10.2, 2.4 Hz, 1H), 4.56 (dt, J = 4.8, 2.4 Hz, 1H), 4.35 - 4.22 (m, 2H), 4.05 (q, J = 2.4 Hz, 1H), 3.78 (d, J = 4.1 Hz, 3H).440.151-(3-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrol-1-yl)-2-methylprop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t, J = 4.6 Hz, 2H), 8.18 (s, 1H), 7.49 - 7.41 (m, 2H), 7.38 - 7.28 (m, 3H), 6.28 (dd, J = 39.5, 2.3 Hz, 1H), 5.86 (s, 2H), 5.32 - 4.93 (m, 2H), 4.50 - 4.28 (m, 2H), 4.06 (d, J = 10.4 Hz, 2H), 3.79 (d, J = 4.9 Hz, 3H), 1.90 - 1.72 (m, 3H).454.154-(6-(1-(1-acryloylpiperidin -4-yl)-1H-pyrazol-4-yl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-hydroxy-2-methylpropyl)be nzamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (t, J = 6.1 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.92 - 7.81 (m, 2H), 7.43 - 7.35 (m, 3H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.82 (s, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.55 (s, 1H), 4.51 - 4.43 (m, 1H), 4.13 (d, J = 13.6 Hz, 1H), 3.69 (s, 3H), 3.27 (d, J = 6.2 Hz, 2H), 2.82 (d, J = 12.1 Hz, 1H), 2.05 (d,J = 12.7 Hz, 2H), 1.79 (s, 2H), 1.12 (s, 6H).543.354-(6-(1-(1-acryloylpiperidin -4-yl)-1H-pyrazol-4-yl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(tetrahydrofuran-3-yl)benzamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J = 6.4 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 - 7.86 (m, 2H), 7.43 - 7.33 (m, 3H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.83-5.69 (dd, J= 10.4, 2.4 Hz, 2H), 4.52 - 4.41 (m, 3H), 4.14 (d, J = 13.6 Hz, 1H), 3.87 (dd, J = 8.8, 6.5 Hz, 2H), 3.73 (td, J = 8.1, 5.8 Hz, 1H), 3.68 (s, 3H), 3.59 (dd, J = 8.8, 4.3 Hz, 1H), 3.23 (t, J = 13.1 Hz, 1H), 2.83 (t, J = 12.9 Hz, 1H), 2.16 (dq, J= 12.4, 7.5 Hz, 1H), 2.05 (d, J= 12.4 Hz, 2H), 1.94 (tt, J = 12.4, 5.6 Hz, 1H), 1.78 (d, J = 13.0 Hz, 2H).541.251-(4-(4-(5-(4-(2-azabicyclo[2.1.1] hexane-2-carbonyl)phenyl) -4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.44 - 7.33 (m, 3H), 6.84 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.87 (s, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.13 (d, J = 13.8 Hz, 1H), 3.69 (s, 3H), 3.47 (s, 2H), 3.32 - 3.17 (m, 1H), 2.89 (s, 1H), 2.81 (d, J = 12.3 Hz, 1H), 2.10 - 1.95 (m, 5H), 1.77 (s, 2H), 1.49 (s, 1H), 1.36 (s, 1H).537.454-(6-(1-(1-acryloylpiperidin -4-yl)-1H-pyrazol-4-yl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)benza mide 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.39 (d, J = 14.2 Hz, 5H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.11 (dd,J = 16.7, 2.4 Hz, 1H), 5.89 (s, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.94 (s, 2H), 4.45 (s, 2H), 4.12 (d, J = 13.8 Hz, 1H), 3.69 (s, 3H), 3.17 (d, J = 33.9 Hz, 4H), 2.82 (t, J = 12.9 Hz, 1H), 2.37 (s, 3H), 2.05 (d, J = 26.0 Hz, 2H), 1.78 (d, J = 13.9 Hz, 2H).581.301-(4-(4-(4-amino-7-methyl-5-(4-((1-methyl-1H-pyrazol-3-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.46 - 7.38 (m, 2H), 7.26 (s, 1H), 7.20 - 7.16 (m, 2H), 6.87 - 6.80 (m, 1H), 6.11 (dd, J = 16.7, 2.4 Hz, 1H), 6.07 - 5.99 (m, 1H), 5.70 - 5.66 (m, 1H), 4.56 - 4.38 (m, 2H), 4.18 - 4.09 (m, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.21 (t, J = 12.7 Hz, 1H), 2.81 (t, J = 12.7 Hz, 1H), 2.02 (d, J= 12.5 Hz, 2H), 1.84 - 1.68 (m, 2H).524.354-(6-(1-(1-acryloylpiperidin -4-yl)-1H-pyrazol-4-yl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2-methoxy-2-methylpropyl)be nzamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 8.00 (s, 2H), 7.88 (d, J = 7.9 Hz, 2H), 7.43 - 7.35 (m, 3H), 6.84 (dd, J = 16.8, 10.7 Hz, 1H), 6.12 (d, J = 16.6 Hz, 1H), 5.69 (d, J = 10.8 Hz, 2H), 4.48 (d, J = 14.5 Hz, 2H),4.13(s, 1H) 3.68 (s, 3H), 3.40-3.23 (s, 3H), 3.16 (s, 3H), 2.83 (s, 1H), 2.04 (s, 2H), 1.79 (s, 2H), 1.13 (s, 6H).557.451-(4-{4-[4-amino-5-(2-chloro-4-phenoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.88 (s, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.28 - 7.14 (m, 4H), 7.00 (dd, J = 8.4, 2.6 Hz, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.13 (dd, J = 16.8, 2.4 Hz, 1H), 5.77 (s, 2H), 4.47 (tt, J = 11.4, 4.1 Hz, 2H), 4.14 (d, J = 13.7 Hz, 1H), 3.76 (s, 3H), 3.24 (t, J = 12.8 Hz, 1H), 2.85 (t, J = 12.7 Hz, 1H), 2.03 (s, 2H), 1.78 (t, J = 12.6 Hz, 2H).554.051-(4-{4-[4-amino-5-(3-methoxy-4-phenoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidin-1-yl)prop-2-en-1-one; formic acid 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.49 (s, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.10 - 7.00 (m, 3H), 7.00 - 6.79 (m, 4H), 6.13 (dd, J = 16.7, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 4.49 (tt, J = 11.6, 4.1 Hz, 2H), 4.14 (d, J = 13.8 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.24 (t, J = 12.9 Hz, 1H), 2.85 (t, J = 12.7 Hz, 1H), 2.03 (s, 2H), 1.80 (t, J = 12.6 Hz, 2H).595.661-(4-{4-[4-amino-5-(4-chloro-3-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.00 (d, J = 1.9 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.89 - 6.80 (m, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.92 (s, 2H), 5.70 (dd, J = 10.5, 2.4 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.14 (d, J = 14.0 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.23 (t, J = 13.2 Hz, 1H), 2.84 (t, J = 12.9 Hz, 1H), 2.04 (d, J = 12.8 Hz, 2H), 1.80 (s, 2H).491.981-(4-{4-[4-amino-5-(2-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.87 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.5, 2.4 Hz, 1H), 5.69 (dd, J = 10.3, 2.4 Hz, 1H), 5.57 (s, 2H), 4.42 (dt, J = 15.2, 5.3 Hz, 2H), 4.12 (d, J = 13.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 2.82 (t, J = 12.9 Hz, 3H), 2.02 (d, J = 12.5 Hz, 2H), 1.81 - 1.70 (m, 2H).457.53 81-(4-{4-[4-amino-5-(5-chloro-2H-1,3-benzodioxol-4-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.96 (s, 1H), 7.37 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 6.01 (d, J = 1.0 Hz, 1H), 5.96 (d, J = 1.0 Hz, 1H), 5.70 (dd, J = 10.5, 2.4 Hz, 1H), 4.53 - 4.43 (m, 2H), 4.13 (d, J = 13.8 Hz, 1H), 3.80 (s, 3H), 3.25 (d, J = 13.6 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.04 (d, J = 12.5 Hz, 2H), 1.79 (s, 2H).505.96 Example 9

[0357] N-(4-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-6-yl)phenyl)methacrylamide

[0358]

[0359] Step 1: A resealable reaction vial was charged with 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 2.34 mmol), 2-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-enamide (804 mg, 2.80 mmol), K3PO4 (1.48 g, 7.02 mmol), Pd(dppf)Cl 2 (171 mg, 234 µmol) and a stir bar before being evacuated and purged with nitrogen three times. DMF / H2O (10 mL) was added, and the mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by prep-TLC (eluting with dichloromethane / methanol; 15:1). Concentration in vacuo resulted in N-(4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide (280 mg, 34%) as an off-white amorphous solid.N-(4-{4-amino-5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2- enamide

[0360]

[0361] Step 2: A round bottomed flask was charged with N-(4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide (260 mg, 886 µmol), dimethylformamide (5 mL) was added, then NBS (313 mg, 1.77 mmol) was added at 0 °C, and the solution was stirred for 1 h at 0 °C. The reaction mixture was diluted with Na2SO3(a.q.) (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by prep-TLC (eluting with dichloromethane / methanol; 20:1). Concentration in vacuo resulted in N-(4- { 4-amino-5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide (350 mg, 87%) as an orange amorphous solid.N-(4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacrylamide

[0362]

[0363] Step 3: A resealable reaction vial was charged with N-(4- { 4-amino-5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide (300 mg, 665 µmol), tetrahydrofuran (6 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times. At -78 °C n-BuLi (0.8 mL, 2 mmol) was added, and the mixture was stirred at -78 °C for 5 min. The reaction mixture was diluted with water (5 mL), and the aqueous phase was extracted with dichloromethane (5 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by TLC (eluting with dichloromethane / methanol; 15:1). Concentration in vacuo resulted in N-(4-{4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide (100 mg, 40%) as an off-white amorphous solid.N-(4-(4-amino-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacrylamide

[0364]

[0365] Step 4: A resealable reaction vial was charged with N-(4- {4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-6-yl } phenyl)-2-methylprop-2-enamide (90.0 mg, 241 µmol), 2-methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine (82.4 mg, 265 µmol), K 3 PO 4 (153 mg, 722 µmol), Pd(dppf)Cl 2 (17.6 mg, 24.1 µmol), DMF / H 2 O (4 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC (Column: XBridge Prep OBD C18 Column, 30×150mm 5um; Mobile Phase A:undefined, Mobile Phase B:undefined; Flow rate:60 mL / min; Gradient:35 B to 50 B in 8 min; 220 nm; RT1:7.54; RT2:; Injection Volumn: ml; Number Of Runs:;). Lyophilization yielded N-[4-(4-amino-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl]-2-methylprop-2-enamide (7.62 mg, 6%) as an off-white amorphous solid.

[0366] Additional compounds prepared according to the methods of Example 9 are depicted in Table 8 below. Table 8. Additional Exemplary Compounds Compound Structure Proton NMR MS [M+1] N-(4-(4-amino-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyr rolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacr ylamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.41 - 7.34 (m, 2H), 7.23 - 7.13 (m, 4H), 7.05 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.50 (s, 1H), 2.38 (s, 3H), 1.94 (s, 3H).477.20N-(4-(4-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)p yrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacr ylamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.64 - 7.51 (m, 4H), 7.42 - 7.36 (m, 2H), 7.14 - 7.08 (m, 2H), 5.77 (d, J = 1.3 Hz, 1H), 5.50 (t, J = 1.5 Hz, 1H), 3.48 (dt, J = 13.3, 6.3 Hz, 4H), 2.01 - 1.71 (m, 7H).467.35N-(4-(4-amino-5-(4-(pyrrolidin-1-ylsulfonyl)phenyl) pyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacr ylamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.54 (dd, J = 8.4, 5.8 Hz, 4H), 7.01 (d, J = 8.6 Hz, 2H), 5.76 (s, 1H), 5.50 (s, 1H), 3.25 - 3.13 (m, 4H), 1.96 - 1.89 (m, 3H), 1.77 - 1.57 (m, 4H).503.35N-(4-(4-amino-5-(3-fluoro-4-((5-fluoropyrimidin-2-yl)oxy)phenyl)pyr rolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacr ylamide 1< H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.81 (s, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.62 - 7.56 (m, 2H), 7.49 (t, J = 8.3 Hz, 1H), 7.36 (dd, J = 11.2,2.0 Hz, 1H), 7.24 (dd, J = 8.3, 2.1 Hz, 1H), 7.21 - 7.10 (m, 2H), 5.79 (s, 1H), 5.54 - 5.45 (m, 1H), 1.95 (t, J = 1.3 Hz, 3H).500.301-(3-(4-amino-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyr rolo[2,1-fJ[1,2,4]triazin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one 1< H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 1.5 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.45 (dd, J = 8.6, 2.6 Hz, 2H), 7.29 - 7.19 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.55 (ddd, J = 16.8, 13.5, 10.3 Hz, 1H), 6.12 (dt, J = 16.9, 2.0 Hz, 1H), 5.65 (ddd, J = 9.8, 6.9, 2.4 Hz, 1H), 4.70 (d, J = 8.6 Hz, 1H), 3.91 - 3.59 (m, 2H), 3.59 - 3.42 (m, 1H), 3.37 (s, 1H), 3.28 - 3.14 (m, 2H), 2.37 (d, J = 3.0 Hz, 3H), 2.25 - 1.85 (m, 2H).441.30N-(4-(4-amino-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyr rolo[2,1-f][1,2,4]triazin-6-yl)phenyl)acrylam ide 1< H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.81 - 7.73 (m, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.44 - 7.32 (m, 2H), 7.24 - 7.13 (m, 4H), 7.05 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 6.42 (dd, J = 16.9, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.1 Hz, 1H), 2.38 (s, 3H).463.30N-(4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyr rolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacr ylamide 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.96 (s, 1H), 7.83 - 7.71 (m, 1H), 7.64 - 7.57 (m, 2H), 7.35 - 7.24 (m, 2H), 7.16 - 7.06 (m, 4H), 7.02 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.77 (t,J = 1.1 Hz, 1H), 5.60 - 5.39 (m, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 1.94 (d, J = 1.2 Hz, 3H).491.30 Example 10

[0367] 4-(4-amino-7-(hydroxymethyl)-6-(4-methacrylamidophenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0368] 4-(4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0369]

[0370] Step 1: A resealable reaction vial was charged with (4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)methanol (600 mg, 2.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (983 mg, 2.99 mmol), Pd(dtbpf)Cl2 (162 mg, 249 µmol), CsF ( 1.14 g, 7.47 mmol), DMF:water=16:1 (8 mL) and a stir bar before being evacuated and purged with nitrogen three times. The solution was stirred for 2h at 90 °C. The reaction mixture was quenched with water, extracted with DCM. The organic phase was separated and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude material was purified by prep-TLC. Concentration in vacuo resulted in 4-(4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (400 mg, 44%) as a yellow oil.4-(4-amino-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0371]

[0372] Step 2: A resealable reaction vial was charged with 4-(4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (380 mg, 1.04 mmol), Imidazole (283 mg, 4.16 mmol), DMF (5 mL) and a stir bar. TBSCl (314 mg, 2.08 mmol) was added, and the solution was stirred for 1h at room temperature. The resulted mixture was purified through C18 Column. Concentration in vacuo resulted in 4-(4-amino-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (420 mg, 84%) as a yellow amorphous solid.4-(4-amino-6-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0373]

[0374] Step 3: A round bottomed flask was charged with 4-(4-amino-7-(((tertbutyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (400 mg, 0.84 mmol), dimethylformamide (5 mL) and a stir bar. NBS (225 mg, 1.00 mmol) was added, and the solution was stirred for 1h at room temperature. The reaction mixture was quenched with water, extracted with DCM. The organic phase was separated and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography. Concentration in vacuo resulted in 4-(4-amino-6-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (450 mg, 94%) as a yellow amorphous solid.6-{5-[2-(tert-butyldimethylsilyl)ethynyl]-3-methylpyrazin-2-yl}-7-methyl-5-{4-[(4-methylpyrimidin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0375]

[0376] Step 4: A resealable reaction vial was charged with 4-(4-amino-6-bromo-7-(((tertbutyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (200 mg, 0.36 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (124 mg, 0.43 mmol), Pd(dtbpf)Cl2 (23.4 mg, 36 µmol), CsF (164 mg, 1.08 mmol), DMF: water=16:1 (4 mL) and a stir bar before being evacuated and purged with nitrogen three times. The solution was stirred for 2h at 90 °C under N 2 . The reaction mixture was quenched with water, extracted with DCM. The organic phase was collected and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude material was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250mm,5um; Mobile Phase A:Water(10MMOL / L NH 4 HCO 3 ), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:20 B to 50 B in 8 min; 220 nm; RT1:7.23;). Lyophilization yielded 4-(4-amino-7-(hydroxymethyl)-6-(4-methacrylamidophenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (30.4 mg, 16%) as an off-white amorphous solid.

[0377] Additional compounds prepared according to the methods of Example 10 are depicted in Table 9 below. Table 9....

Claims

1. A compound of formula X: or a pharmaceutically acceptable salt thereof, wherein: RW is R5B is hydrogen or RB, wherein R5B is substituted with n instances of R5D; each instance of R6 is independently RA or RB, wherein R6 is substituted by q instances of RC; or two instances of R6, or an instance of R6 and an instance of RL are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of RC; R7 is H or RB, wherein R7 is substituted with t instances of R7A; each of L5 and L6 is independently a covalent bond, or a C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-5 cycloalkylene, 3-5 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O )2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; each of RWA, RWB, and RWC is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or a group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or RWA and RWB, RWB and RWC, RWA and an instance of RL, or RWC and an instance of RL are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R5C, R5D, R7A, and RL is independently RA or RB, and is substituted by u instances of RC; each instance of RA is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O) R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; each instance of RB is independently C1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of RC is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, - N(R)S(O)2NR2, -N(R)S(O)2R, or a group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or a group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein L5 is -O-.

3. The compound of claim 1 or 2, wherein R5B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5B is substituted with n instances of R5D; and / or: wherein n is 1.

4. The compound of any one of claims 1-3, wherein R5D is C1-6 aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of any one of claims 1-4, wherein R5C is halogen, -CN, -OR, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, or -N(R)C(O)R.

6. The compound of any one of claims 1-5, wherein R7 is C1-6 aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of any one of claims 1-6, wherein RWA is hydrogen or C1-6 aliphatic.

8. The compound of any one of claims 1-7, wherein RW is 9. The compound of any one of claims 1-8, wherein L6 is -NH-.

10. The compound of any one of claims 1-9, wherein m is 1.

11. The compound of any one of claims 1-10, wherein p is 0.

12. The compound of any one of claims 1-11, wherein t is 0.

13. A compound selected from or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition, comprising a compound of any one of claims 1-13, and a pharmaceutically acceptable carrier.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14, for use in a method of inhibiting FGFR2 signaling activity in a subject, or for use in a method of treating an FGFR2-mediated disorder in a subject, or for use in a method of treating a disorder in a subject, said use comprising administering a therapeutically effective amount of said compound or composition to a subject in need thereof, wherein the disorder is bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, or urothelial cancer; optionally, wherein: (I) the disorder is bile duct cancer; optionally wherein the bile duct cancer is intrahepatic cholangiocarcinoma; or: (II) the disorder is liver cancer; optionally wherein the liver cancer is hepatocellular carcinoma; or: (III) the disorder is lung cancer; optionally wherein the lung cancer is lung squamous cell carcinoma or non-small cell lung cancer.