FGFR inhibitors and methods of use thereof

Abstract

The present application relates to FGFR inhibitors and methods of use thereof. The present disclosure relates to novel compounds and pharmaceutical compositions thereof and methods of inhibiting FGFR enzyme activity using the compounds and compositions of the invention. The disclosure further relates to, but is not limited to, methods of treating conditions associated with FGFR signaling using the compounds and compositions of the invention.

Description

[0001] This application is a divisional application of an application filed on May 12, 2020, with application number 202080035916.4 and invention name “FGFR inhibitors and methods of use thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 846,991, filed May 13, 2019; U.S. Provisional Application No. 62 / 993,957, filed March 24, 2020; and U.S. Provisional Application No. 63 / 011,469, filed April 17, 2020, each of which is incorporated herein by reference. Technical Field

[0004] This application relates to FGFR inhibitors and methods of use thereof. Background Art

[0005] 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. The binding of FGF ligands causes receptor dimerization and conformational changes in the intracellular domain, thereby causing intermolecular transphosphorylation of the kinase domain and the intracellular tail. The phosphorylated residues serve as docking sites for attached proteins, which promote downstream signal cascades, thereby producing cell behaviors, including proliferation, survival, differentiation, migration and angiogenesis. Dysregulated FGFR signaling can occur via the following: FGFR gene amplification or fusion, FGFR missense mutations, overexpression of receptors caused by abnormal regulation of epigenetic and / or transcriptional regulatory factors, or upregulation of FGF ligands in the tumor microenvironment. FGFR is expressed in many cell types; therefore, abnormal FGFR signaling has been implicated in neoplasia, tumor deterioration and resistance to treatment of many tumor types. (For review of FGFR signaling, see N. Turner and R. Grose, Nat. Rev. Cancer 2010, 10: 116-129; and references cited therein).

[0006] Pan-FGFR1-3 inhibitors have produced clinical responses to a variety of cancers with FGFR changes, however, on-target toxicity limits the administration of these inhibitors. One of the most common side effects of pan-FGFR inhibition is hyperphosphatemia. The regulation of phosphate reabsorption is mediated by FGFR3 and FGFR1. Therefore, there is a need for FGFR selective inhibitors that do not harm FGFR1. (J. Gattineni et al., Am. J. Physiol. Renal Physiol. 2014, 306: F351-F358; X. Han et al., PLoS One 2016, 11: e0147845.). Cancers containing FGFR2 gene fusions and cancers with FGFR2 amplification and / or FGFR2 activating mutations have shown responses to pan-FGFR inhibition, however, the low response rate and duration indicate that they are limited by toxicity. Therefore, there is a need for FGFR2 selective inhibitor compounds and methods of using these compounds to treat cancer and other conditions. (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 of the Invention

[0007] In some embodiments, the present disclosure provides compounds of formula I-1:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy 6 , L 6 、R 5 and R W Each of which is as defined in the Examples and various classes and subclasses herein.

[0010] In some embodiments, the present invention provides compounds of formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein Cy 6 , L 6 、R 5 、R 7 and R WEach of which is as defined in the Examples and various classes and subclasses herein.

[0013] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present disclosure, such as a compound of Formula I-1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0014] In some embodiments, the present invention provides a method for treating an FGFR-mediated disorder comprising administering to a patient in need thereof a compound of Formula I or a composition comprising said compound. In some embodiments, the present invention provides a method for treating an FGFR-mediated disorder comprising administering to a patient in need thereof a compound of the present disclosure, e.g., a compound of Formula I-1, or a composition comprising said compound.

[0015] In some embodiments, the present invention provides a method for providing a compound of Formula I or a synthetic intermediate thereof. In some embodiments, the present invention provides a method for providing a compound of the present disclosure (eg, a compound of Formula 1-1) or a synthetic intermediate thereof.

[0016] In some embodiments, the present invention provides a method for providing a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the present invention provides a method for providing a pharmaceutical composition comprising a compound of the present disclosure (eg, a compound of Formula 1-1). DETAILED DESCRIPTION

[0017] 1. General Description of Certain Embodiments of the Invention

[0018] The compounds of the present invention and their pharmaceutical compositions are suitable for use as FGFR2 inhibitors. In some embodiments, the present invention provides a compound of formula I-1:

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] Cy A for

[0022] in Indicates connection to R 5 The bond and Indicates connection to Cy 6 The bond

[0023] R 5 -R 5A -L5 -R 5B ;

[0024] R 5A R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Instance replacement;

[0025] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0026] Cy 6 is phenylene; a 3- to 14-membered saturated or partially unsaturated divalent carbocyclic ring; a 3- to 14-membered saturated or partially unsaturated divalent heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 14-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement;

[0027] R W Is halogen, -CN,

[0028] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0029] Two R's 6 Example, an R 6 Example and an R L Example, an R 6 Example and an R WA instance, or an R 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0030] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0031] R 8 is H, -NR2, halogen, -OH, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0032] R 9 is H, -NR2, halogen, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0033] R 10 is H or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0034] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent hydrocarbon chain, wherein one or two methylene units in the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; wherein said C 3-6 Each of the cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene groups is optionally substituted with one R A or C 1-6 Aliphatic instance replacement;

[0035] R WA 、R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0036] RWA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by w R C Instance replacement;

[0037] R WD is halogen or -OS(O)2R;

[0038] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement; or

[0039] Two R's 5C Example, an R 5C Example and an R 5D Instance, or two R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C Instance replacement;

[0040] R A Each example of is independently oxy, 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;

[0041] R B Each instance of is independently C 1-6aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0042] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0043] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0044] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0045] Each of m, n, p, q, r, t, u, v and w is independently 0, 1, 2, 3 or 4.

[0046] In some embodiments, the present invention provides a compound of formula I:

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein:

[0049] R 5 Yes-R5A -L 5 -R 5B ;

[0050] R 5A It is R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Instance replacement;

[0051] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0052] Cy 6 is a phenylene group or a 6-membered heteroarylene group having 1 to 3 nitrogen atoms, wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement;

[0053] R W Is halogen, -CN,

[0054] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0055] Two R's 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0056] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0057] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0058] R WA 、R WB and R WC Each of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0059] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0060] R WD is halogen or -OS(O)2R;

[0061] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement;

[0062] R AEach example of is independently oxy, 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;

[0063] R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0064] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0065] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0066] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0067] Each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0068] 2. Compounds and Definitions

[0069] The compounds of the present invention include those generally described herein and are further described according to the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version (Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Chemical name, common name, and chemical structure may be used interchangeably to describe the same structure. If a compound is referred to by both its chemical structure and its chemical name and there is a discrepancy between the structure and the name, the structure shall prevail.

[0070] As used herein, the term "aliphatic" or "aliphatic group" means a substituted or unsubstituted straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but 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, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but 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, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0071] As used herein, unless otherwise indicated, the term "alkyl" refers to a monovalent aliphatic hydrocarbon radical having a linear, branched, monocyclic or polycyclic moiety, or a combination thereof, wherein the radical is optionally substituted at one or more carbon atoms in the linear, branched, monocyclic or polycyclic moiety, or a combination thereof, with one or more substituents at each carbon atom, wherein the one or more substituents are independently C1-C 10 Alkyl. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0072] The term "lower alkyl" refers to C 1-4 Straight or branched chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0073] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl groups.

[0074] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (e.g., in N-substituted pyrrolidinyl)).

[0075] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0076] As used herein, the term "C 1-8 (or C 1-6 or C 1-4 ) saturated or unsaturated, straight or branched divalent hydrocarbon chain” refers to divalent alkylene, alkenylene and alkynylene chains as defined herein that are straight or branched.

[0077] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0078] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0079] The term "halogen" means F, Cl, Br or I.

[0080] The term "aryl," used alone or as part of a larger moiety (e.g., "aralkyl," "aralkoxy," or "aryloxyalkyl"), refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, and the like.

[0081] As used herein, unless otherwise defined, the term "heteroaryl" or "heteroaromatic" refers to a 5- to 6-membered monocyclic aromatic ring containing one or more heteroatoms (e.g., one to three heteroatoms such as nitrogen, oxygen, and sulfur), or an 8- to 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 the aromatic ring. A heteroaryl ring can be attached to the adjacent group through 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, and the like. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, for example:

[0082]

[0083] Unless otherwise defined, the term "heterocyclyl" or "heterocyclic group" refers 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. The heterocyclyl ring can be attached to the adjacent group through carbon or nitrogen.

[0084] Unless otherwise defined, the term "partially unsaturated" in the context of a ring refers to a monocyclic, or a constituent ring within a polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one degree of unsaturation in addition to the unsaturation 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, and the like. Where a partially unsaturated ring is part of a polycyclic ring system, the other constituent 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 the partially unsaturated constituent ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidinyl ring, for example:

[0085]

[0086] Unless otherwise defined, the term "saturated" in the context of a ring refers to a 3- to 10-membered monocyclic or 7- to 14-membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or a constituent ring that is the point of attachment of the polycyclic ring system does not contain additional unsaturation beyond that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like. Where a saturated ring is part of a polycyclic ring system, the other constituent 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 constituent 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 N-azetidinyl ring, for example:

[0087]

[0088] As used herein, the terms "alkylene," "arylene," "cycloalkylene," "heteroarylene," "heterocycloalkylene," and other similar terms having the prefix "alkylene" refer to the divalent bonded form of the group modified by the prefix. For example, "alkylene" is a divalent alkyl group that attaches the group to that to which it is attached.

[0089] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic ring system with at least one bridge bond, i.e., a carbocyclic ring or a heterocyclic ring. As defined by IUPAC, a "bridge bond" is a valence bond connecting two bridge heads or an unbranched chain of multiple atoms or an atom, wherein a "bridge head" is any backbone atom of a ring system bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted with one or more substituents as described for an aliphatic group. Alternatively or in addition, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0090]

[0091]

[0092] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether or not preceded by the term "optionally," 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 designated structure may be substituted with more than one substituent selected from a designated group, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not undergo substantial change when subjected to conditions that allow its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more purposes disclosed herein.

[0093] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°; -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°; -(CH2) which may be substituted by R° 0-4 Ph; -(CH2) which may be substituted by R° 0-4 O(CH2) 0-1Ph; -CH=CHPh which may be substituted by R°; -(CH2) which may be substituted by R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)(OR°)R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene) C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of R° taken together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which ring may be substituted as defined below.

[0094] Suitable monovalent substituents on R° (or two R° occurring alone together with their intervening atoms to form a ring) are independently halogen, -(CH2) 0-2 R ● 、-(halogen R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2;-O(halogen R ● )、-CN、-N3、-(CH2) 0-2 C(O)R ● 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● 、-(CH2) 0-2 SR ● 、-(CH2) 0- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR ● 3. -C(O)SR ● 、-(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR · , where each R · is unsubstituted or, when crowned with "halo", is substituted only with one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aromatic 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.

[0095] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, each of which appears alone * is selected from hydrogen, C which may be substituted as defined below 1-6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, each of which appears alone * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0096] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR ● 、-NR · 2 or -NO2, where each R · unsubstituted or, in the case of a "halo" prefix, substituted only with one or more halogens and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0097] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Among them are independently hydrogen, C 1-6aliphatic, unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or, regardless of the above definitions, two of the above Together with its intervening atoms, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0098] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR ● 、-NR · 2 or -NO2, where each R · is unsubstituted or, when prefixed with "halo", is substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0099] As used herein, the term "isomer" refers to compounds having the same chemical formula but different structures or optical configurations. As used herein, the term "stereoisomer" refers to and includes isomeric molecules having the same molecular formula but different positioning of atoms and / or functional groups in space. All stereoisomers of the compounds of the invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are encompassed within the scope of this disclosure. Therefore, unless otherwise indicated, single stereochemical isomers of the compounds of the invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers, are within the scope of this invention.

[0100] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It should be understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions caused by reorganization of some bonded electrons. Proton tautomers include interconversions that occur via proton migration, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the invention are within the scope of the invention.

[0101] As used herein, the term "isotope substitution" refers to the substitution of an atom with its isotope. As used herein, the term "isotope" refers to an atom having the same atomic number as the atom predominantly found in nature, but having a different mass number (neutron number) than the atom predominantly found in nature. It should be understood that a compound having isotope substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that may be substituted with their isotopes include, but are not limited to, hydrogen, carbon, and oxygen. Examples of hydrogen atom isotopes include 2 H (also expressed as D) and 3 H. Examples of carbon atom isotopes include 13 C and 14 C. Examples of oxygen isotopes include 18 O. Unless otherwise specified, all isotopic substitutions of the compounds of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, for example, the warhead portion R of the provided compounds is W Contains one or more deuterium atoms.

[0102] As used herein, the term "pharmaceutically acceptable salts" 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 excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio. Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, PL, Int. J. Pharmaceutics 1986, 33, 201-217; (each of which is incorporated herein by reference in its entirety).

[0103] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic 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, and the like.

[0104] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0105] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound to acid is 2:1, respectively. Exemplary hemi-salts are those derived from acids containing 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 derived from diprotic mineral acids, such as sulfuric acid. Preferred exemplary hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

[0106] As used herein, the term "about" is used herein to mean approximately, roughly, around, or in the neighborhood 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 ​​recited. Generally, the term "about" is used herein to modify a numerical value above and below the recited value by a deviation of 20% above or below (higher or lower).

[0107] As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is an amount of a compound sufficient to achieve a beneficial or desired result, including a clinical result. Thus, an effective amount can be sufficient, for example, to reduce or ameliorate the severity and / or duration of a disorder associated with FGFR2 signaling, or one or more symptoms thereof; prevent the progression of a condition or symptom associated with a disorder associated with FGFR2 signaling; or enhance or otherwise improve the prophylactic or therapeutic effect of another therapy. An effective amount also includes an amount of a compound that avoids or substantially reduces undesirable side effects.

[0108] As used herein and as is well understood in the art, "treatment" is a way to obtain beneficial or desired results (including clinical results). Beneficial or desired clinical results may include, but are not limited to, relief or improvement of one or more symptoms or conditions, alleviation of the degree of disease or pain, stabilization of the state of disease or pain (i.e., no worsening), prevention of disease or pain spread, delay or slowing of disease or pain progression, improvement or alleviation of disease or pain state, and relief (whether partially or completely), whether detectable or undetectable. "Treatment" may also mean that survival is prolonged compared to the expected survival without treatment. In some embodiments, therapy may be administered after one or more symptoms have appeared. In other embodiments, therapy may be administered in the absence of symptoms. For example, therapy may be administered to susceptible individuals (e.g., according to symptom history and / or according to genetic or other predisposing factors) before the onset of symptoms. Treatment may also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

[0109] The phrase "in need thereof" refers to a need for symptomatic or asymptomatic relief from a condition associated with FGFR2 signaling activity, or which may otherwise be alleviated by the compounds and / or compositions of the present disclosure.

[0110] 3. Description of Exemplary Embodiments

[0111] As described above, in some embodiments, the present invention provides a compound of formula I-1:

[0112]

[0113] or a pharmaceutically acceptable salt thereof, wherein:

[0114] Cy A for

[0115]

[0116] in Indicates connection to R 5 The bond and Indicates connection to Cy6 The bond

[0117] R 5 -R 5A -L 5 -R 5B ;

[0118] R 5A R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Instance replacement;

[0119] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0120] Cy 6 is phenylene; a 3- to 14-membered saturated or partially unsaturated divalent carbocyclic ring; a 3- to 14-membered saturated or partially unsaturated divalent heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 14-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement;

[0121] R W Is halogen, -CN,

[0122] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement: or

[0123] Two R's 6 Example, an R 6 Example and an R L Example, an R 6 Example and an R WA instance, or an R 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is terminated by r R C Instance replacement;

[0124] R7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0125] R 8 is H, -NR2, halogen, -OH, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0126] R 9 is H, -NR2, halogen, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0127] R 10 is H or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0128] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent hydrocarbon chain, wherein one or two methylene units in the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; wherein said C 3-6 Each of the cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene groups is optionally substituted with one R A or C 1-6 Aliphatic instance replacement;

[0129] R WA 、R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0130] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by w R C Instance replacement;

[0131] R WD is halogen or -OS(O)2R;

[0132] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement; or

[0133] Two R's 5C Example, an R 5C Example and an R 5D Instance, or two R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C Instance replacement;

[0134] R A Each example of is independently oxy, 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;

[0135] R B Each instance of is independently C 1-6aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0136] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0137] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0138] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0139] Each of m, n, p, q, r, t, u, v and w is independently 0, 1, 2, 3 or 4.

[0140] As generally defined above, Cy A for in Indicates connection to R 5 The bond and Indicates connection to Cy 6 In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for

[0141] In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A for In some embodiments, Cy A is a group selected from the compounds described in Table 1.

[0142] As generally defined above, Cy 6 is phenylene; a saturated or partially unsaturated 3- to 14-membered divalent carbocyclic ring; a saturated or partially unsaturated divalent 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 14-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0143] In some embodiments, Cy 6 is phenylene; a 3- to 7-membered saturated or partially unsaturated divalent monocyclic carbocyclic ring; an 8- to 14-membered saturated or partially unsaturated divalent bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated divalent monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 14-membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0144] In some embodiments, Cy 6 is a 3- to 14-membered saturated or partially unsaturated divalent carbon ring; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 3- to 7-membered saturated or partially unsaturated divalent monocyclic carbocyclic ring, or an 8- to 14-membered saturated or partially unsaturated divalent bicyclic carbocyclic ring; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 3- to 7-membered saturated or partially unsaturated divalent monocyclic carbon ring; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is an 8- to 14-membered saturated or partially unsaturated divalent bicyclic carbon ring; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0145] In some embodiments, Cy 6 is a 3- to 14-membered saturated or partially unsaturated divalent heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 3- to 7-membered saturated or partially unsaturated divalent monocyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 14-membered saturated or partially unsaturated divalent bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0146] In some embodiments, Cy 6 is a 3- to 7-membered saturated or partially unsaturated divalent monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6In some embodiments, Cy 6 is a 5- to 6-membered saturated or partially unsaturated divalent monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a divalent pyrrolidine or dihydropyrrolidine ring; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0147] In some embodiments, Cy 6 is a 5- to 14-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 5- to 6-membered monocyclic heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9- to 10-membered bicyclic heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0148] In some embodiments, Cy 6 is a 5- to 6-membered monocyclic heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 5- to 6-membered monocyclic heteroarylene group having 1 to 2 nitrogen atoms; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 5-membered monocyclic heteroarylene group having 1 to 2 nitrogen atoms; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0149] In some embodiments, Cy6 is a 9- to 10-membered bicyclic heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 9- to 10-membered bicyclic heteroarylene group having 1 to 3 nitrogen atoms; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement.

[0150] In some embodiments, Cy 6 is a group selected from the compounds described in Table 1.

[0151] In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0152]

[0153] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0154]

[0155] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0156]

[0157] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0158]

[0159] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein.

[0160] As generally defined above, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or two R 6 Example, an R 6 Example and an R L Example, an R 6 Example and an R WA instance, or an R 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement.

[0161] In some embodiments, two R 6 Example, an R 6 Example and an R L Example, an R 6 Example and an R WA instance, or an R 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement.

[0162] In some embodiments, an R 6 Example and an R WA Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C In some embodiments, an R 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement.

[0163] In some embodiments, an R6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C In some embodiments, an R 6 Example and an R 7a Examples together with their intervening atoms form a 4- to 8-membered partially unsaturated ring having one nitrogen atom; wherein the ring is optionally substituted with 1, 2 or 3 atoms independently selected from halogen, -CN, -O-(C 1-4 Alkyl) and -(C 1-4 alkyl) is substituted; wherein each C 1-4 Alkyl is optionally substituted with 1, 2, or 3 fluorine groups. 6 Example and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated ring. In some embodiments, one R 6 Example and an R 7a The examples, together with their intervening atoms, form a 4- to 8-membered partially unsaturated ring having one nitrogen atom.

[0164] In some embodiments, each R 6 is a group selected from the compounds described in Table 1.

[0165] As generally defined above, R 8 is H, -NR2, halogen, -OH, or C optionally substituted with 1 to 3 halogens 1-6 In some embodiments, R 8 is H. In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is C optionally substituted with 1 to 3 halogens 1-6 Fatty.

[0166] In some embodiments, R 8 is -NH2. In some embodiments, R 8 It is C 1-4 In some embodiments, R 8 In some embodiments, R 8 is -NH2 or methyl. In some embodiments, R 8 is a group selected from the compounds described in Table 1.

[0167] As generally defined above, R 9is H, -NR2, halogen, or C optionally substituted with 1 to 3 halogens 1-6 In some embodiments, R 9 is H. In some embodiments, R 9 In some embodiments, R 9 is -NH2. In some embodiments, R 9 In some embodiments, R 9 is C optionally substituted with 1 to 3 halogens 1-6 In some embodiments, R 9 It is C 1-4 In some embodiments, R 9 is a group selected from the compounds described in Table 1.

[0168] As generally defined above, R 10 is H or C optionally substituted with 1 to 3 halogens 1-6 In some embodiments, R 10 is H. In some embodiments, R 10 is C optionally substituted with 1 to 3 halogens 1-6 In some embodiments, R 10 It is C 1-4 In some embodiments, R 10 In some embodiments, R 10 is H or methyl. In some embodiments, R 10 is a group selected from the compounds described in Table 1.

[0169] As generally defined above, L 6 is a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 6-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; wherein said C 3-6Each of the cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene groups is optionally substituted with one R A or C 1-6 Aliphatic instance replacement.

[0170] In some embodiments, L 6 It is C 3-6 cycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heteroarylene, each of which is optionally substituted by one R A or C 1-6 In some embodiments, L 6 It is C 3-6 cycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heteroarylene.

[0171] In some embodiments, L 6 is a group selected from the compounds described in Table 1.

[0172] As generally defined above, R 5C and R 5D Each instance of is independently R A or R B , and after u R C Instance replacement; or two R 5C Example, an R 5C Example and an R 5D Instance, or two R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C Instance replacement.

[0173] In some embodiments, two R 5C Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C Instance replacement.

[0174] In some embodiments, an R 5C Example and an R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C In some embodiments, an R 5C Example and an R 5D The instance and its intervening atoms together form a R C Examples include substituted 3- to 7-membered saturated or partially unsaturated carbocyclic rings.

[0175] In some embodiments, two R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted by v R C In some embodiments, two R 5D The instance and its intervening atoms together form a R C Examples include substituted 3- to 7-membered saturated or partially unsaturated carbocyclic rings.

[0176] In some embodiments, R 5C and R 5D Each example of is a group depicted in the compounds selected from Table 1.

[0177] As generally defined 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, 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 ​​shown for the compounds in Table 1.

[0178] As generally defined 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, 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 ​​shown for the compounds in Table 1.

[0179] In some embodiments, the present invention provides compounds of Formula 1-1, wherein each variable is as defined below in the description of Formula I or Formula 1-2 and described individually and in combination in the Examples herein.

[0180] As described above, in some embodiments, the present invention provides compounds of formula I-2:

[0181]

[0182] or a pharmaceutically acceptable salt thereof, wherein:

[0183] R 5 Yes-R 5A -L 5 -R 5B ;

[0184] R 5A It is R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Instance replacement;

[0185] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0186] Cy 6 is a phenylene group or a 6-membered heteroarylene group having 1 to 3 nitrogen atoms, wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement;

[0187] R W Is halogen, -CN,

[0188] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0189] Two R's 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0190] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0191] L 5 and L 6Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0192] R WA 、R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0193] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0194] R WD is halogen or -OS(O)2R;

[0195] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement;

[0196] R A Each example of is independently oxy, 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;

[0197] R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0198] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0199] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0200] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0201] Each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0202] As generally defined above, R WA 、R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0203] In some embodiments, R WA 、R WB and R WC Each of is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, or -C(O)N(R)OR. In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen, deuterium or an optionally substituted C 1-6 In some embodiments, R WA 、R WB and R WC Each of which 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 fluorine groups. WA 、R WBand R WC Each of the is independently hydrogen, deuterium, or -C optionally substituted with 1, 2 or 3 fluorines 1-4 In some embodiments, R WA 、R WB and R WC Each of is independently hydrogen, deuterium or -C 1-4 In some embodiments, R WA 、R WB and R WC Each of R is independently hydrogen, deuterium or -CH3. In some embodiments, R WA 、R WB and R WC Each of R is independently hydrogen or deuterium. In some embodiments, R WA 、R WB and R WC Each of is deuterium.

[0204] In some embodiments, the present invention provides compounds of Formula 1-2, wherein each variable is as defined below in the description of Formula I and described individually and in combination in the Examples herein.

[0205] As described above, in some embodiments, the present invention provides compounds of formula I:

[0206]

[0207] or a pharmaceutically acceptable salt thereof, wherein:

[0208] R 5 Yes-R 5A -L 5 -R 5B ;

[0209] R 5A It is R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Instance replacement;

[0210] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0211] Cy 6 is a phenylene group or a 6-membered heteroarylene group having 1 to 3 nitrogen atoms, wherein except -L 6 -R W In addition, Cy 6 Also through p R 6Instance replacement;

[0212] R W Is halogen, -CN,

[0213] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0214] Two R's 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0215] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0216] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0217] R WA 、R WB and R WCEach of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0218] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0219] R WD is halogen or -OS(O)2R;

[0220] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement;

[0221] R A Each example of is independently oxy, 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;

[0222] R B Each instance of is independently C 1-6aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0223] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0224] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0225] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0226] Each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0227] As generally defined above, R 5A It is R B A divalent group, except -L 5 -R 5B In addition, R 5A Also m R 5C Example substitution; in some embodiments, R 5A For divalent C 1-6Aliphatic, except -L 5 -R 5B In addition, it also passes through m R 5C Example substitution. In some embodiments, R 5A is phenylene, except -L 5 -R 5B In addition, it also passes through m R 5C Example substitution. In some embodiments, R 5A is a 5- to 6-membered monocyclic heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, except -L 5 -R 5B In addition, the ring also passes through m R 5C Example substitution. In some embodiments, R 5A is an 8- to 10-membered bicyclic heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, except -L 5 -R 5B In addition, the ring also passes through m R 5C Example substitution. In some embodiments, R 5A is a 3- to 7-membered saturated or partially unsaturated divalent carbon ring, except -L 5 -R 5B In addition, the carbon ring is also connected by m R 5C Example substitution. In some embodiments, R 5A is a 3- to 7-membered saturated or partially unsaturated divalent monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, except -L 5 -R 5B In addition, the monocyclic heterocycle is further substituted by m R 5C Example substitution. In some embodiments, R 5A is a 7- to 12-membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, except -L 5 -R 5B In addition, the bicyclic heterocycle is further substituted by m R 5C Example substitution. In some embodiments, R 5A is a group selected from the compounds described in Table 1.

[0228] As generally defined above, L 5 is a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 5 In some embodiments, L 5 It is C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0229] In some embodiments, L 5 It is C 1-2 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 5It is C 1-2 A saturated or unsaturated, linear or branched divalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently substituted with —O—, —C(O)—, —C(O)NH— or —C(O)N(R L )-replacement.

[0230] In some embodiments, L 5 Is -O-, -C(O)-, -C(O)NH- or -C(O)N(R L )-. In some embodiments, L 5 In some embodiments, L 5 In some embodiments, L 5 is -C(O)NH-. In some embodiments, L 5 Yes-C(O)N(R L )-. In some embodiments, L 5 is a group selected from the compounds described in Table 1.

[0231] As generally defined above, R 5B is hydrogen or R B , where R 5B After n R 5D Example substitution. In some embodiments, R 5B In some embodiments, R 5B is through n R 5D Example replaced by R B In some embodiments, R 5B is through n R 5D Instance replaced by C 1-6 In some embodiments, R 5B is through n R 5D In some embodiments, R 5B is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n R 5D Example substitution. In some embodiments, R 5B is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is substituted by n R 5D Example substitution. In some embodiments, R 5B For n R 5D Examples of substituted 3- to 7-membered saturated or partially unsaturated carbocyclic rings. In some embodiments, R 5B is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic heterocyclic ring is substituted by n R 5D Example substitution. In some embodiments, R 5Bis a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the bicyclic heterocyclic ring is substituted by n R 5D Instance replacement.

[0232] In some embodiments, R 5B is a 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic heterocyclic ring is substituted by n R 5D Example substitution. In some embodiments, R 5B is a 5-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said monocyclic heteroaryl ring being substituted by n R 5D Example substitution. In some embodiments, R 5B is a 6-membered monocyclic heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, the monocyclic heteroaryl ring being substituted by n R 5D Example substitution. In some embodiments, R 5B A group selected from the group depicted in the compounds of Table 1.

[0233] As generally defined above, R 5C Each instance of is independently R A or R B , and after u R C Example substitution. In some embodiments, R 5C Each instance of R A In some embodiments, R 5C Each example of is independently selected from halogen, -CN, -OR, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, and -N(R)C(O)R. In some embodiments, R 5C Each example of is independently selected from halogen, -CN, -OR and -C(O)NR2. In some embodiments, R 5C Each example of 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, R 5C Each example of is independently selected from halogen, -CN, -O-(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0234] In some embodiments, R 5C Each instance of R B , where R 5C After u R CExample substitution. In some embodiments, R 5C Each instance of R B , where R 5C After an R C Example substitution. In some embodiments, R 5C Each instance of is independently selected from C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is optionally substituted by u R C Instance replacement.

[0235] In some embodiments, R 5C Each instance of is independently selected from C 1-6 aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is optionally substituted by u R C Example substitution. In some embodiments, R 5C Each example of is independently selected from: optionally through one R C Instance replaced by C 1-4 aliphatic; a 3- to 5-membered saturated carbocyclic ring; and a 3- to 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, R 5C Each example of is independently selected from: optionally via -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; a 3- to 5-membered saturated carbocycle; and a 3- to 5-membered saturated monocyclic heterocycle having 1 oxygen atom; each of which is optionally substituted with 1, 2 or 3 fluorine or chlorine.

[0236] In some embodiments, R 5C Each example of is independently selected from halogen, -CN, -OR, -C(O)NR2, and the following groups (each of which is optionally substituted by u R C Instance replacement): C 1-6 aliphatic; 3-7 membered saturated or partially unsaturated carbocyclic ring; and 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 5C Each example of 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(C1-4 alkyl) 2, optionally through one R C Instance replaced by C 1-4 aliphatic; 3-5 membered saturated carbocyclic ring; and 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 5C Each example of 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 fluorine or chlorine): optionally substituted with -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; 3 to 5 membered saturated carbocyclic ring; and 3 to 5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 5C is a group selected from the compounds described in Table 1.

[0237] As generally defined above, R 5D Each instance of is independently R A or R B , and after u R C Example substitution. In some embodiments, R 5D Each instance of R A In some embodiments, R 5D Each example of is independently selected from halogen, -CN, -OR, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, and -N(R)C(O)R. In some embodiments, R 5D Each example of is independently selected from halogen, -CN, -OR and -C(O)NR2. In some embodiments, R 5D Each example of 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, R 5D Each example of is independently selected from halogen, -CN, -O-(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0238] In some embodiments, R 5D Each instance of R B , where R 5D After u R C Example substitution. In some embodiments, R 5D Each instance of RB , where R 5D After an R C Example substitution. In some embodiments, R 5D Each instance of is independently selected from C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is optionally substituted by u R C Instance replacement.

[0239] In some embodiments, R 5D Each instance of is independently selected from C 1-6 aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is optionally substituted by u R C Example substitution. In some embodiments, R 5D Each example of is independently selected from: optionally through one R C Instance replaced by C 1-4 aliphatic; a 3- to 5-membered saturated carbocyclic ring; and a 3- to 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, R 5D Each example of is independently selected from: optionally via -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; a 3- to 5-membered saturated carbocycle; and a 3- to 5-membered saturated monocyclic heterocycle having 1 oxygen atom; each of which is optionally substituted with 1, 2 or 3 fluorine or chlorine.

[0240] In some embodiments, R 5D Each example of is independently selected from halogen, -CN, -OR, -C(O)NR2, and the following groups (each of which is optionally substituted by u R C Instance replacement): C 1-6 aliphatic; 3-7 membered saturated or partially unsaturated carbocyclic ring; and 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 5D Each example of 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, optionally through one R C Instance replaced by C1-4 aliphatic; 3-5 membered saturated carbocyclic ring; and 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 5D Each example of 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 fluorine or chlorine): optionally substituted with -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; 3 to 5 membered saturated carbocyclic ring; and 3 to 5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 5D is a group selected from the compounds described in Table 1.

[0241] As generally defined above, in some embodiments, the present invention provides compounds of Formula I, wherein R 5 Yes-R 5A -L 5 -R 5B In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0242]

[0243] Among them L 5 、R 5B 、R 5C Each of m and m is as defined in the Examples and classes and subclasses herein.

[0244] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0245]

[0246] where R 5B 、R 5C Each of and m is as defined in the Examples and various classes and subclasses herein.

[0247] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0248]

[0249] where R 5B 、R 5C Each of and m is as defined in the Examples and various classes and subclasses herein.

[0250] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0251]

[0252] where R 5B 、R 5C Each of and m is as defined in the Examples and various classes and subclasses herein.

[0253] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0254]

[0255] where R 5B 、R 5C Each of and m is as defined in the Examples and various classes and subclasses herein.

[0256] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0257]

[0258] where R 5B and R 5C Each of which is as defined in the Examples and various classes and subclasses herein.

[0259] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B Combined together) is:

[0260]

[0261] where R 5B and R 5C Each of which is as defined in the Examples and various classes and subclasses herein.

[0262] In some embodiments, R 5 (i.e., -R 5A -L 5 -R 5B taken together) are selected from the groups depicted in the compounds of Table 1.

[0263] Cy 6 is a phenylene group or a 6-membered heteroarylene group having 1 to 3 nitrogen atoms, wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is phenylene, except -L 6 -R W In addition, it also passes through p R 6 In some embodiments, Cy 6 is a 6-membered heteroarylene group having 1 to 3 nitrogen atoms; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 In some embodiments, Cy 6 is a 6-membered heteroarylene group having 1 to 2 nitrogen atoms, except -L 6 -R W In addition, it also passes through p R 6 In some embodiments, Cy 6 It is a 6-membered heteroarylene group with 1 nitrogen atom, except -L 6 -R W In addition, it also passes through p R 6 In some embodiments, Cy 6 It is a 6-membered heteroarylene group with 2 nitrogen atoms, except -L 6 -R W In addition, it also passes through p R 6 In some embodiments, Cy 6 is a 6-membered heteroarylene group having 2 nitrogen atoms, which is only 6 -R W In some embodiments, Cy 6 is a 6-membered heteroarylene group having 1 to 2 nitrogen atoms, except -L 6 -R W In addition, it also passes through p R 6 Example replacement, where L 6 is a covalent bond, and -R W Yes -CN or In some embodiments, Cy 6is a group selected from the compounds described in Table 1.

[0264] As generally defined above, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or two R 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Example substitution. In some embodiments, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement.

[0265] In some embodiments, two R 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C In some embodiments, two R 6 Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement.

[0266] In some embodiments, an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C In some embodiments, an R 6 Example and an R L Examples together with their intervening atoms form a 4- to 7-membered partially unsaturated ring having one nitrogen atom; wherein the ring is optionally substituted with 1, 2 or 3 atoms independently selected from halogen, -CN, -O-(C 1-4 Alkyl) and -(C 1-4 alkyl) is substituted; wherein each C 1-4 Alkyl is optionally substituted with 1, 2, or 3 fluorine groups. 6 Example and an R LThe examples, together with their intervening atoms, form a 4- to 7-membered partially unsaturated ring having one nitrogen atom.

[0267] In some embodiments, R 6 Each instance of R A In some embodiments, R 6 Each example of is independently selected from halogen, -CN, -OR, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, and -N(R)C(O)R. In some embodiments, R 6 Each example of is independently selected from halogen, -CN, -OR and -C(O)NR2. In some embodiments, R 6 Each example of 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, R 6 Each example of is independently selected from halogen, -CN, -O-(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0268] In some embodiments, R 6 Each instance of R B , where R 6 After q R C Example substitution. In some embodiments, R 6 Each instance of R B , where R 6 After an R C Example substitution. In some embodiments, R 6 Each instance of is independently selected from C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted by q R C Instance replacement.

[0269] In some embodiments, R 6 Each instance of is independently selected from C 1-6 aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is optionally substituted by q R C Example substitution. In some embodiments, R 6Each example of is independently selected from: optionally through one R C Instance replaced by C 1-4 aliphatic; a 3- to 5-membered saturated carbocyclic ring; and a 3- to 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, R 6 Each example of is independently selected from: optionally via -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; a 3- to 5-membered saturated carbocycle; and a 3- to 5-membered saturated monocyclic heterocycle having 1 oxygen atom; each of which is optionally substituted with 1, 2 or 3 fluorine or chlorine.

[0270] In some embodiments, R 6 Each example of is independently selected from halogen, -CN, -OR, -C(O)NR2, and the following groups (each of which is optionally substituted by q R C Instance replacement): C 1-6 aliphatic; 3-7 membered saturated or partially unsaturated carbocyclic ring; and 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 6 Each example of 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, optionally through one R C Instance replaced by C 1-4 aliphatic; 3-5 membered saturated carbocyclic ring; and 3-5 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 6 Each example of 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 fluorine or chlorine): optionally substituted with -OH, -O-(C 1-4 alkyl) or -N(C 1-4 An example of an alkyl)2 substituted C 1-4 alkyl; 3 to 5 membered saturated carbocyclic ring; and 3 to 5 membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 6 is a group selected from the compounds described in Table 1.

[0271] As generally defined above, L 6 is a covalent bond, or C 1-4A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(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 It is C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0272] In some embodiments, L 6 It is C 1-2 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -NH-, -N(R L )-、-NHC(O)-、-N(R L )C(O)-、-C(O)NH-、-C(O)N(RL )-、-NHS(O)2-、-N(R L )S(O)2-, -S(O)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 6 It is C 1-2 A saturated or unsaturated, linear or branched divalent hydrocarbon chain wherein one methylene unit of the chain is optionally substituted with -NH- or -N(R L )-replacement.

[0273] In some embodiments, L 6 is -NH- or -N(R L )-. In some embodiments, L 6 In some embodiments, L 6 Yes-N(R L )-. In some embodiments, L 6 is -NH- or -N(CH3)-. In some embodiments, L 6 is -N(CH3)-. In some embodiments, L 6 is a group selected from the compounds described in Table 1.

[0274] As generally defined above, R W Is halogen, -CN, In some embodiments, R W Is halogen, -CN,

[0275] In some embodiments, R W In some embodiments, R W In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes

[0276] In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes In some embodiments, R W yes

[0277] In some embodiments, R W Yes-CN, In some embodiments, R W yes In some embodiments, R W yes

[0278] In some embodiments, R W yes And R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0279] In some embodiments, R W yes And R WA and R WB or R WB and R WCTogether with their intervening atoms, they form a 4- to 7-membered partially unsaturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. W yes And R WA and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 1 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R W yes And R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R W is a group selected from the compounds described in Table 1.

[0280] 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 portion of protein kinases, such as Cys491 of FGFR2. W The invention relates to a protein kinase that is characterized in that it can covalently bind to a cysteine ​​residue, thereby irreversibly inhibiting a protein kinase. In some embodiments, the protein kinase is FGFR. In certain embodiments, the protein kinase is FGFR2. In certain embodiments, the protein kinase is FGFR2 and the cysteine ​​residue is Cys491.

[0281] As generally defined above, R WA 、R WB and R WC Each of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0282] In some embodiments, R WA 、RWB and R WC Each of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 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 R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0283] In some embodiments, R WA 、R WB and R WC Each of is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, or -C(O)N(R)OR. In some embodiments, R WA 、R WB and R WC Each of which is independently an optionally substituted group selected from the following: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0284] In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen or an optionally substituted C 1-6 In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen or an optionally substituted C 1-6 In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen, -C 1-4 Alkyl, -(C 1-4 alkyl)-O-(C 1-4 alkyl), or -(C 1-4alkyl)-N(C 1-4 Alkyl)2; wherein each C 1-4 Alkyl is optionally substituted with 1, 2, or 3 fluorine groups. WA 、R WB and R WC Each of the is independently hydrogen or -C optionally substituted with 1, 2 or 3 fluorine 1-4 In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen or -C 1-4 In some embodiments, R WA 、R WB and R WC Each of which is independently hydrogen or -CH3.

[0285] In some embodiments, R WA and R WB or R WB and R WC Together with their intervening atoms, they form a 4- to 7-membered partially unsaturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. WA and R WB or R WB and R WC Together with the intervening atoms, R forms a 4- to 7-membered partially unsaturated carbocyclic ring. WA and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 1 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WC and an R L Examples are taken together with their intervening atoms to form a 5- to 6-membered partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R WA 、R WB and R WC Each of is a group selected from the compounds depicted in Table 1.

[0286] As generally defined above, R WD is halogen or -OS(O)2R. In some embodiments, R WD In some embodiments, R WD In some embodiments, R WD In some embodiments, RWD In some embodiments, R WD is -OS(O)2-(optionally substituted C 1-3 In some embodiments, R WD is -OS(O)2CH3 or -OS(O)2CF3. In some embodiments, R WD is -OS(O)2-(optionally substituted phenyl). In some embodiments, R WD is a group selected from the compounds described in Table 1.

[0287] In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0288]

[0289] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0290]

[0291] Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0292]

[0293] Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0294]

[0295] Among them L 6 and R WEach of which is as defined in the Examples and various classes and subclasses herein.

[0296] In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and various classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein.

[0297] In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -RW Combined together they are: Among them L 6 and R W Each of which is as defined in the Examples and various classes and subclasses herein.

[0298] In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0299]

[0300] Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0301]

[0302] Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0303]

[0304] Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are:

[0305]

[0306] Among them L 6 and R W Each of which is as defined in the Examples and various classes and subclasses herein.

[0307] In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 、R W Each of and p is as defined in the Examples and classes and subclasses herein.

[0308] In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 、R 6 and R W Each of the following is as defined in the Examples and classes and subclasses herein. In some embodiments, -Cy 6 -L 6 -R W Combined together they are: Among them L 6 and R W Each of which is as defined in the Examples and various classes and subclasses herein.

[0309] In some embodiments, -Cy6 -L 6 -R W is a group selected from the compounds described in Table 1.

[0310] As generally defined above, R 7 Is H or R B , where R 7 After t R 7A Example substitution. In some embodiments, R 7 is H. In some embodiments, R 7 It is R B , where R 7 After t R 7A Example substitution. In some embodiments, R 7 It is C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by t R 7A Example substitution. In some embodiments, R 7 It is C 1-6 aliphatic; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is t R 7A Instance replacement.

[0311] In some embodiments, R 7 It is C 1-6 alkyl; a 3- to 7-membered saturated carbocyclic ring; or a 3- to 7-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; each of which is substituted by 0 to 1 R 7A Examples and 0 to 3 halogen substitutions. In some embodiments, R 7 Is 0 to 1 R 7A Examples and 0 to 3 halogen-substituted C 1-6 In some embodiments, R 7 Yes-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 fluorine groups. 7 is -C optionally substituted with 1, 2 or 3 fluorine groups 1-4In some embodiments, R 7 In some embodiments, R 7 Is 0 to 1 R B Examples and 0 to 3 halogen-substituted C 1-6 alkyl.

[0312] In some embodiments, R 7 Is 0 to 1 R 7A Examples and 0 to 3 halogen-substituted 3 to 7 membered saturated carbocyclic rings. In some embodiments, R 7 is a 3- to 7-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; which is 7A Examples and 0 to 3 halogen substitutions. In some embodiments, R 7 is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1 oxygen atom; 7A Examples and 0 to 3 halogen substitutions. In some embodiments, R 7 is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1 oxygen atom; which is substituted by 0 to 3 halogens and 0 to 1 selected from -C 1-4 Alkyl, -OH, -O-(C 1-4 alkyl) or N(C 1-4 alkyl)2 group substituted; wherein each C 1-4 Alkyl is optionally substituted with 1, 2, or 3 fluorine groups. 7 is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1 oxygen atom. In some embodiments, R 7 is a group selected from the compounds described in Table 1.

[0313] As generally defined 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, or 2. In some embodiments, m is 1, 2, or 3. 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 ​​shown for the compounds in Table 1.

[0314] As generally defined 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, or 2. In some embodiments, n is 1, 2, or 3. 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 selected from the values ​​shown for the compounds in Table 1.

[0315] As generally defined 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, 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 ​​shown for the compounds in Table 1.

[0316] As generally defined 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, or 2. In some embodiments, q is 1, 2, or 3. 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 ​​shown for the compounds in Table 1.

[0317] As generally defined 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, or 2. In some embodiments, r is 1, 2, or 3. 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 ​​shown for the compounds in Table 1.

[0318] As generally defined 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, 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 ​​shown for the compounds in Table 1.

[0319] As generally defined 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, or 2. In some embodiments, u is 1, 2, or 3. 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 ​​shown for the compounds in Table 1.

[0320] In some embodiments, the present invention provides a compound of formula I-1 comprising a pyrrolopyrimidine, pyrrolotriazine, pyrazolopyrazine, pyrrolopyridine, furanopyrimidine, thienopyrimidine, or pyrrolopyridazinone, thereby forming a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, or Ih:

[0321]

[0322] or a pharmaceutically acceptable salt thereof, wherein Cy6 , L 6 、R W 、R 5 、R 7 、R 8 、R 9 and R 10 Each of which is as defined in the Examples and various classes and subclasses herein.

[0323] In some embodiments, the present invention provides compounds of formula I-1, wherein R 5A is phenylene, pyridylene or cyclohexenylene, thereby forming a compound of formula II-1, III-1, IV-1 or V-1:

[0324]

[0325] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy 6 , L 5 , L 6 、R 5B 、R 5C 、R W Each of m and m is as defined in the Examples and various classes and subclasses herein.

[0326] In some embodiments, the present invention provides compounds of formula I-1, wherein Cy 6 is phenylene, pyridinylene or pyrimidinylene, thereby forming a compound of formula VI-1, VII-1, VIII-1 or IX-1:

[0327]

[0328] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 6 、R 5 、R W 、R 6 Each of and p is as defined in the Examples and various classes and subclasses herein.

[0329] In some embodiments, the present invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is phenylene, thereby forming a compound of formula X-1, XI-1, XII-1 or XIII-1, respectively:

[0330]

[0331] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 5 , L 6 、R 5B、R 5C 、R W 、R 6 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0332] For example, in some embodiments, the present invention provides compounds of formula X-1, XI-1, XII-1, or XIII-1:

[0333]

[0334] or a pharmaceutically acceptable salt thereof, wherein:

[0335] Cy A for

[0336] wherein Cy A in Indicates a bond to: And Cy A in Indicates connection to The bond of

[0337] R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0338] R W Is halogen, -CN,

[0339] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0340] Two R's 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0341] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0342] R 8 is H, -NR2, halogen, -OH, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0343] R 9 is H, -NR2, halogen, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0344] R 10 is H or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0345] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0346] R WA 、R WB and R WC Each of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0347] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or RWC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0348] R WD is halogen or -OS(O)2R;

[0349] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement;

[0350] R A Each example of is independently oxy, 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;

[0351] R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0352] R CEach example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0353] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0354] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0355] Each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0356] In some embodiments, the present invention provides compounds of formula X-1, XI-1, XII-1, or XIII-1:

[0357]

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

[0359] Cy A yes

[0360]

[0361] Among them, Cy A in Indicates a bond to: And Cy A in Indicates connection to The bond of

[0362] R 5B hydrogen or R B , where R 5B After n R 5D Instance replacement;

[0363] R W Is halogen, -CN,

[0364] R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or

[0365] Two R's 6 instance, or an R 6 Example and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with r R C Instance replacement;

[0366] R 7 Is H or R B , where R 7 After t R 7A Instance replacement;

[0367] R 8 is H, -NR2, halogen, -OH, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0368] R 9 is H, -NR2, halogen, or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0369] R 10 is H or C optionally substituted with 1 to 3 halogens 1-6 aliphatic;

[0370] L 5 and L 6 Each of is independently a covalent bond, or C 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -NH-, -N(RL )-、-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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0371] R WA 、R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0372] R WA and R WB 、R WB and R WC 、R WA and an R L Instance, or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0373] R WD is halogen or -OS(O)2R;

[0374] R 5C 、R 5D 、R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement;

[0375] R AEach example of is independently oxy, 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;

[0376] R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0377] R C Each example of is independently an oxy group, 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0378] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0379] Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0380] Each of m, n, p, q, r, t, and u is independently 0, 1, 2, 3, or 4.

[0381] In some embodiments, the present invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is a pyridylene group, thereby forming a compound of formula XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1 or XXI-1, respectively:

[0382]

[0383] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 5 , L 6 、R 5B 、R 5C 、R W 、R 6 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0384] In some embodiments, the present invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is a pyrimidinyl group, thereby forming a compound of formula XXII-1, XXIII-1, XXIV-1 or XXV-1, respectively:

[0385]

[0386] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 5 , L 6 、R 5B 、R 5C 、R W 、R 6 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0387] In some embodiments, the present invention provides compounds 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 for

[0388] in Indicates the R connected to 5 The bond and Indicates connection to Cy 6 The bond.

[0389] In some embodiments, the present invention provides compounds 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 yes in Indicates connection to R 5 The bond and Indicates connection to Cy 6 The bond.

[0390] In some embodiments, the present invention provides compounds 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-, -C(O)-, -C(O)NH- or -C(O)N(R LIn some embodiments, the present invention provides compounds 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 In some embodiments, the present invention provides compounds 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 In some embodiments, the present invention 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 In some embodiments, the present invention provides compounds 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 Yes-C(O)N(R L )-.

[0391] In some embodiments, the present invention 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 invention provides compounds 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 It is -NH-.

[0392] In some embodiments, the present invention 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 invention 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 invention 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.

[0393] In some embodiments, the present invention 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 invention provides compounds 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 invention 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.

[0394] In some embodiments, the present invention provides compounds 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 yes In some embodiments, the present invention provides compounds 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 yes In some embodiments, the present invention provides compounds 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 yes

[0395] In some embodiments, the present invention provides compounds of formula I, wherein R 5A is phenylene, pyridylene or cyclohexenylene, thereby forming a compound of Formula II, III, IV or V:

[0396]

[0397] or a pharmaceutically acceptable salt thereof, wherein Cy 6 , L 5 , L 6 、R 5B 、R 5C 、R W 、R 7 Each of m and m is as defined in the Examples and various classes and subclasses herein.

[0398] In some embodiments, the present invention provides compounds of formula I, wherein Cy 6 is phenylene, pyridinylene or pyrimidinylene, thereby forming a compound of Formula VI, VII, VIII or IX:

[0399]

[0400] or a pharmaceutically acceptable salt thereof, wherein L 6 、R 5 、R W 、R 6 、R 7Each of and p is as defined in the Examples and various classes and subclasses herein.

[0401] In some embodiments, the present invention provides compounds of Formula II, III, IV, or V, wherein Cy 6 is phenylene, thereby forming a compound of formula X, XI, XII or XIII, respectively:

[0402]

[0403] or a pharmaceutically acceptable salt thereof, wherein L 5 , L 6 、R 5B 、R 5C 、R W 、R 6 、R 7 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0404] In some embodiments, the present invention provides compounds of Formula II, III, IV, or V, wherein Cy 6 is pyridinylene, thereby forming a compound of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX or XXI, respectively:

[0405]

[0406] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 5 , L 6 、R 5B 、R 5C 、R W 、R 6 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0407] In some embodiments, the present invention provides compounds of Formula II, III, IV, or V, wherein Cy 6 is pyrimidinyl, thereby forming a compound of formula XXII, XXIII, XXIV or XXV, respectively:

[0408]

[0409] or a pharmaceutically acceptable salt thereof, wherein Cy A , L 5 , L 6 、R 5B 、R 5C 、R W 、R 6 Each of , m, and p is as defined in the embodiments and classes and subclasses herein.

[0410] In some embodiments, the present invention provides compounds 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 invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII, wherein L 5 In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5 In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5 In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein L 5 Yes-C(O)N(R L )-.

[0411] In some embodiments, the present invention provides compounds 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 invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII, wherein L 6 It is -NH-.

[0412] In some embodiments, the present invention 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 invention 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 invention provides a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein m is 1.

[0413] In some embodiments, the present invention 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 invention 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 invention provides a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein p is 1.

[0414] In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W yes In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W yes In some embodiments, the present invention provides compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, wherein R W yes

[0415] In some embodiments, the present invention provides compounds 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 invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, wherein L 5 In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, wherein L 5 In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, wherein L 5In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, wherein L 5 Yes-C(O)N(R L )-.

[0416] In some embodiments, the present invention provides compounds 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 invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, wherein L 6 It is -NH-.

[0417] In some embodiments, the present invention 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 invention 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 invention provides a compound of formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein m is 1.

[0418] In some embodiments, the present invention 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 invention provides a compound of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein p is 0. In some embodiments, the present invention provides a compound of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein p is 1.

[0419] In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W yes In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W yes In some embodiments, the present invention provides compounds of Formula XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, wherein R W yes

[0420]

[0421] Examples of compounds of the present invention include those listed in the Tables and Examples herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof. In some embodiments, the present invention comprises a compound selected from the compounds depicted in Table 1 below, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof. In some embodiments, the present invention provides the compounds shown in Table 1 below, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds shown in Table 1 below.

[0422] Table 1. Representative compounds of the present invention with biological activity data.

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722] In the chemical structures of Table 1 above, when a stereogenic center is depicted with a dashed line or a wedge-shaped bond and is labeled "abs" (or unlabeled), the compound is essentially a single isomer at that stereogenic center (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 stereogenic center is depicted with a dashed line or a wedge-shaped bond and is also labeled "or 1," the compound is a single isomer at that stereogenic center, but the absolute stereochemistry at that stereogenic center has not been determined. (See, for example, the structures of Examples 397 and 398.) When a stereogenic center is depicted with a dashed line or a wedge-shaped bond and is also labeled "and 1" or "and 1," the compound is a mixture of the following two isomers at that stereogenic center: the structure as depicted, and an isomer in which the stereocenter has the opposite configuration. (See, for example, the structure of Example 581.)

[0723] Certain compounds described in Table 1 above exist as non-interconverting isomers across the biaryl bond in solution at room temperature. When one atom in the biaryl bond is labeled "or 1," this indicates that the compound exists as a non-interconverting isomer in solution at room temperature and that the compound is essentially a single isomer (rather than an equimolar mixture). (See, for example, the structures of Examples 516 and 517).

[0724] In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a biochemical FGFR2 Caliper IC 50 In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a biochemical FGFR2 Caliper IC 50 In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a biochemical FGFR2 Caliper IC 50 It is represented by "A" or "B" or "C".

[0725] In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a cell SNU-16IC 50 In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a cell SNU-16IC50 In some embodiments, the present invention provides compounds in Table 1 above, wherein the compounds have a cell SNU-16IC 50 It is represented by "A" or "B" or "C".

[0726] 4. General Methods for Providing Compounds of the Invention

[0727] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semisynthetic methods known to those skilled in the art for similar compounds and by the methods described in detail in the Examples herein.

[0728] 5. Usage, formulation and application

[0729] Pharmaceutically acceptable compositions

[0730] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits FGFR2 protein kinase or its mutant in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits FGFR2 protein kinase or its mutant in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0731] As used herein, the terms "subject" and "patient" refer to an animal (i.e., a member of the kingdom Animalia), 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.

[0732] 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 formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0733] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof.

[0734] As used herein, the term "inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an FGFR2 protein kinase inhibitor or a mutant thereof.

[0735] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally, or intravenously.

[0736] The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in acceptable non-toxic parenteral diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0737] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) are suitable for the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (e.g., Tween, Span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0738] The pharmaceutically acceptable compositions of the present invention can be orally administered in any acceptable oral dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. When administered orally in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings, or coloring agents may also be added.

[0739] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories 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 will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0740] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the therapeutic target includes areas or organs readily accessible by topical administration, including diseases of the eye, skin, or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

[0741] Topical administration to the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Transdermal patches may also be used.

[0742] For topical administration, the pharmaceutically acceptable compositions provided can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated as a suitable lotion or cream containing the active ingredient 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.

[0743] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions, or preferably as solutions, in pH-adjusted isotonic sterile saline in the presence or absence of a preservative (e.g., benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as ointments, such as paraffin wax.

[0744] The pharmaceutically acceptable compositions of the present invention 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 using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0745] The pharmaceutically acceptable compositions of the present invention are preferably formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0746] The amount of carrier material that a compound of the invention can be combined with to produce a single dosage form of the composition will vary depending on the patient being treated, the particular mode of administration, and the type of patient being treated. The provided compositions should preferably be formulated so that a dosage of between 0.01 and 100 mg of the inhibitor per kilogram of body weight per day can be administered to a patient receiving these compositions.

[0747] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of elimination, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0748] The exact dosage used in the composition will also depend on the route of administration and should be determined according to the judgment of the practitioner and the individual circumstances. In certain embodiments of the present disclosure, dosage ranges suitable for oral administration of the compounds of the present invention are generally from about 1 mg per day to about 1000 mg per day. In some embodiments, the oral dosage is from about 1 mg per day to about 800 mg per day. In some embodiments, the oral dosage is from about 1 mg per day to about 500 mg per day. In some embodiments, the oral dosage is from about 1 mg per day to about 250 mg per day. In some embodiments, the oral dosage is from about 1 mg per day to about 100 mg per day. In some embodiments, the oral dosage is from about 5 mg per day to about 50 mg per day. In some embodiments, the oral dosage is about 5 mg per day. In some embodiments, the oral dosage is about 10 mg per day. In some embodiments, the oral dosage is about 20 mg per day. In some embodiments, the oral dosage is about 30 mg per day. In some embodiments, the oral dosage is about 40 mg per day. In some embodiments, the oral dosage is about 50 mg per day. In some embodiments, the oral dosage is about 60 mg per day. In some embodiments, the oral dosage is about 70 mg per day. In some embodiments, the oral dosage is about 100 mg per day. It will be recognized that any one of the dosages listed herein may constitute the upper or lower limit of a dosage range and may be combined with any other dosage to constitute a dosage range including the upper and lower limits.

[0749] In some embodiments, the pharmaceutically acceptable composition contains a provided compound and / or a pharmaceutically acceptable salt thereof at a concentration in the range of 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 capsule, and the like. Pharmaceutical compositions can be prepared as aqueous solutions and can contain other components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-adjusting ingredients, and the like.

[0750] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, 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.

[0751] Examples of pharmaceutically acceptable carriers include, for example, water or physiological saline solutions, polymers (e.g., polyethylene glycol), carbohydrates and their derivatives, 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. Pharmaceutical carriers may also be physiological saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, and colorants may also be used. Other examples of suitable pharmaceutical carriers are described, for example, in 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.); and Pharmaceutical Excipients, 7th ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.). E. ed., Pharmaceutical Press (2012) (each of which is herein incorporated by reference in its entirety).

[0752] Pharmaceutically acceptable carriers used herein can be selected from various organic or inorganic substances, which are used as materials for pharmaceutical formulations and are incorporated as analgesics, buffers, adhesives, disintegrants, diluents, emulsifiers, excipients, extenders, slip agents, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity increasing agents. Pharmaceutical additives such as antioxidants, aromatics, colorants, flavor improvers, preservatives and sweeteners can also be added. The example of acceptable pharmaceutical carriers includes carboxymethyl cellulose, crystalline cellulose, glycerol, gum arabic, lactose, magnesium stearate, methylcellulose, powders, normal saline, sodium alginate, sucrose, starch, talc and water and other. In certain embodiments, the term "pharmaceutically acceptable" means approved by the regulatory agencies of the federal government or state governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias as being applicable to animals and more particularly to humans.

[0753] Surfactants such as detergents are also suitable for use in the formulation. Specific examples of surfactants include polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives such as methacrylates and others; anionic surfactants such as alkaline stearates, in particular sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids, in particular those derived from coconut oil; cationic surfactants such as those having the formula N + R'R"R"'R""Y - A water-soluble quaternary ammonium salt of wherein the R groups are the same or different, are optionally hydroxylated hydrocarbon groups, and Y - It is an anion of a strong acid, such as a halide, sulfate, and sulfonate anion; Cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, which has the formula N + Amine salts of R'R"R"', wherein the R groups are the same or different, optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride is one of the cationic surfactants that can be used; nonionic surfactants, such as optionally polyoxyethylated sorbitan esters, in particular polysorbate 80 or polyoxyethylated alkyl ethers; polyethylene glycol stearates, polyoxyethylated castor oil derivatives, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide; amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0754] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. If necessary, the compositions of the present invention may also contain small amounts of wetting agents or emulsifiers, or pH buffering agents.

[0755] Tablet and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is known in the art. Examples of such include carbohydrates (e.g., lactose or sucrose), anhydrous calcium hydrogen phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearate, silicon dioxide, talc, sodium starch glycolate, gum arabic, flavorings, preservatives, buffers, disintegrants, and coloring agents. Compositions for oral administration may contain one or more optional agents, such as sweeteners, e.g., fructose, aspartame, or saccharin; flavorings, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically palatable formulation.

[0756] Uses of compounds and pharmaceutically acceptable compositions

[0757] The compounds and compositions described herein are generally useful for inhibiting kinases or mutants 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.

[0758] The compounds or compositions of the present disclosure may be suitable for use in applications that benefit from inhibition of FGFR2 phosphatases.For example, the FGFR2 inhibitors of the present invention are generally useful in the treatment of proliferative diseases.

[0759] Activating FGFR2 gene fusions have been detected in many cancers, including intrahepatic bile duct carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell lung cancer, thyroid cancer, gastric cancer, and ovarian cancer (IS Babina and N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332; YM Wu et al., Cancer Discov. 3:636-647, and references cited therein).

[0760] FGFR2 amplification has been described in gastric cancer, breast cancer, triple-negative breast cancer, and colorectal cancer (IS 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).

[0761] Activating FGFR2 mutations have been detected in endometrial cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, breast cancer, and urothelial carcinoma. 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). FGFR2 inhibitors can also target resistance mutations present in FGFR2 treated with pan-FGFR1-3 inhibitors. These mutations include V564F, E565A, N549K / H / T, and L617V. (IS 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).

[0762] Inhibition of FGFR2 also has anti-tumor activity against tumors in which expression of FGFR2 ligands is enhanced ( Figures 1-4 , 7 , 8 , 10 , 21 - 23 ) ( N. Turner and R. Grose, Nat. Rev. Cancer 2010, 10: 116-129 and references cited therein).

[0763] Inhibition of FGFR2 also has anti-tumor activity against tumors in which the FGFR adaptor protein FRS2 is amplified or overexpressed (IS Babina and N.C. Turner, Nat. Rev. Cancer, 2017, 17:318-332; and references cited therein).

[0764] Selective inhibition of FGFR2 is generally effective for 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.

[0765] Activating mutations in FGFR2 have also been detected in craniosynostosis syndromes, including Crouzon, Apert, Pfeiffer, Antley-Bixler, Beare-Stevenson gyrus, Jackson-Weiss, camptoskeletal dysplasia, and Seathre-Chotzen-like syndromes, which cause premature fusion of cranial sutures. (SC Azoury et al., Int. J. Biol. Sci. 2017, 13:1479-1488; and references cited therein). Inhibition of FGFR2 is also effective in these craniosynostosis syndromes.

[0766] The activity of the compound used in the present invention as an inhibitor of FGFR kinase (such as FGFR2) or its mutant can be analyzed in vitro, in vivo or in a cell line. In vitro analysis includes an analysis of the inhibition of phosphorylation activity and / or subsequent functional results or activation of FGFR2 or its mutant ATPase activity. Alternative in vitro analysis quantifies the ability of the inhibitor to be bound to FGFR2. Inhibitor binding can be measured by radiolabeling the inhibitor, separating the inhibitor / FGFR2 complex and measuring the radiolabeled binding amount before binding. Alternatively, inhibitor binding can be measured by running a competition experiment, wherein the new inhibitor is cultivated together with the FGFR2 bound to a known radioligand. Representative in vitro and in vivo analyses suitable for analyzing FGFR2 inhibitors include those described and disclosed in the patents and scientific publications described herein. The detailed conditions for analyzing the compound used as the inhibitor of FGFR2 or its mutant in the present invention are described in the following examples.

[0767] Treatment of symptoms

[0768] The compounds provided are FGFR2 inhibitors and are therefore useful for treating one or more conditions associated with the activity of FGFR2 or its mutants. Thus, in certain embodiments, the present invention provides a method for treating an FGFR2-mediated condition in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In certain embodiments, the present invention provides a method for treating an FGFR2-mediated condition in an individual, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0769] As used herein, the term "FGFR2-mediated" disorders, diseases, and / or conditions refers to any disease or other deleterious condition in which FGFR2 or a mutant thereof is known to play a role. Thus, another embodiment of the present invention 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 craniosynostosis syndrome.

[0770] In some embodiments, the present invention provides a method for treating one or more conditions, wherein the condition is selected from a proliferative condition and craniosynostosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In some embodiments, the present invention provides a method for treating one or more conditions, wherein the condition is selected from a proliferative condition and craniosynostosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0771] In some embodiments, the present invention provides a method of treating a condition in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, wherein the condition 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 condition is intrahepatic bile duct cancer. In some embodiments, the condition is hepatocellular carcinoma. In some embodiments, the condition is squamous cell carcinoma of the lung or non-small cell lung cancer.

[0772] In some embodiments, the condition is bile duct cancer. In some embodiments, the bile duct cancer is intrahepatic bile duct cancer. In some embodiments, the condition is liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the condition is lung cancer. In some embodiments, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

[0773] In some embodiments, the present invention provides a method of treating intrahepatic bile duct cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing. In some embodiments, the present invention provides a method of treating hepatocellular carcinoma in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing. In some embodiments, the present invention provides a method of treating squamous cell carcinoma of the lung or non-small cell lung cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

[0774] In some embodiments, the disease is associated with FGFR2 signaling. It is known that FGFR2 and other receptor tyrosine kinases (RTKs) have multiple upstream and downstream signaling pathways (see Turner and Grose, << Nature Review Cancer (Nat. Rev. Cancer) > (2010) 10, 116), and inhibition of FGFR2 can be used to treat diseases associated with abnormal signaling within those pathways. In some embodiments, the disease is associated with FGF signaling, JAK-STAT signaling, PI3K-Akt signaling, PLC-γ signaling, or MAPK signaling.

[0775] In some embodiments, the methods of treatment comprise 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 the provided compound in a therapeutically effective amount to treat, suppress and / or prevent a disease state or condition in a subject in need of such treatment.

[0776] In some embodiments, the methods of treatment comprise 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 the composition in a therapeutically effective amount to treat, suppress and / or prevent a disease state or condition in a subject in need of such treatment.

[0777] Another aspect of the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for use in treating a condition described herein. Another aspect of the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for use in treating a condition described herein. Similarly, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for the preparation of a medicament for treating a condition described herein.

[0778] Proliferative disorders

[0779] 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.

[0780] In some embodiments, the proliferative disorder is intrahepatic bile duct carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell carcinoma of the lung, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, or urothelial carcinoma. In some embodiments, the proliferative disorder is intrahepatic bile duct carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell carcinoma of the lung, 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 cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, breast cancer, or urothelial carcinoma.

[0781] 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 in one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in FGFR2 is a mutation in the intracellular kinase domain. In some embodiments, the activating mutation in FGFR2 is a mutation in 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.

[0782] 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.

[0783] Administration route and dosage form

[0784] The compounds and compositions can be administered according to the methods of the present invention using any amount and any route of administration that is effective for treating or alleviating the severity of a condition (e.g., a proliferative condition or craniosynostosis syndrome). The exact amount required will vary from individual to individual, depending on the species, age, and general condition of the individual, the severity of the infection, the specific agent, its mode of administration, and similar factors. The compounds of the present invention are preferably formulated into unit dosage forms for ease of administration and uniform dosing. As used herein, the expression "unit dosage form" refers to a physical, discrete unit of a dosage suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and the rate of excretion of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and factors well known in the medical art.

[0785] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., via powders, ointments, or drops), buccally, as an oral or nasal spray, or the like. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg to about 50 mg, and preferably about 1 mg to about 25 mg, per kilogram of body weight per day, one or more times a day to achieve the desired therapeutic effect.

[0786] 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 compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatics.

[0787] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in acceptable non-toxic parenteral diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, conventional sterile fixed oils are used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, injectables are prepared using fatty acids (such as oleic acid).

[0788] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0789] To prolong the effects of the compounds of the invention, it is often necessary to slow the absorption of the compound following subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the properties of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0790] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention 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.

[0791] 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 pharmaceutically acceptable inert excipient or carrier (e.g., 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) disintegrating agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite; 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.

[0792] In the soft filling and hard filling gelatin capsules using the excipients such as lactose or milk sugar and high molecular weight polyethylene glycol and the like, it is also possible to use a similar solid composition of type as a filler. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings known in enteric coatings and the pharmaceutical formulation technology. It can optionally contain an emulsifier and can also have a composition that only or preferentially releases an active ingredient in a certain part of the intestinal tract or optionally releases the active ingredient in a delayed manner. The example of spendable embedding composition comprises polymeric substances and wax. In the soft filling and hard filling gelatin capsules using the excipients such as lactose or milk sugar and high molecular weight polyethylene glycol and the like, it is also possible to use a similar solid composition of type as a filler.

[0793] The active ingredient can be in microencapsulated form together with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well known in pharmaceutical formulation technology. In such solid dosage forms, the active compound can be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As is common practice, such dosage forms can also contain other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can include a buffer. It can optionally contain an emulsifier and can also have a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0794] The dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. If necessary, the active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms may be prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers may also be used to enhance the flow of the compound across the skin. The rate may be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0795] Dosage and therapy

[0796] According to the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure is administered to a subject, for example, to reduce or ameliorate the symptoms of a condition in the subject. This amount is readily determined by one skilled in the art based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0797] In some embodiments, the methods comprise administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments, the therapeutically effective dose 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 2 ...5 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 25 mg / kg body weight, at least about 25 mg / kg body weight, at least about 25 mg / kg body weight, at least about 25 mg / kg body weight, at least about

[0014] In some embodiments, the dosage form of the present invention may be at least about 150 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 one of the dosages listed herein may constitute the upper or lower limit of a dosage range and may be combined with any other dosage to constitute a dosage range including the upper and lower limits.

[0798] In some embodiments, the therapeutically effective dose ranges from about 0.1 mg to about 10 mg per kg body weight, about 0.1 mg to about 6 mg per kg body weight, about 0.1 mg to about 4 mg per kg body weight, or about 0.1 mg to about 2 mg per kg body weight.

[0799] In some embodiments, the therapeutically effective dose ranges from 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.

[0800] In some embodiments, the method comprises a single dose or administration (e.g., a single injection or deposition). Alternatively, in some embodiments, the method comprises administering to a subject in need once daily, twice daily, three times daily, or four times daily for about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days, or longer. In some embodiments, the method comprises chronic administration. In yet other embodiments, the method comprises administering over a period of weeks, months, years, or decades. In yet other embodiments, the method comprises administering over a period of weeks. In yet other embodiments, the method comprises administering over a period of months. In yet other embodiments, the method comprises administering over a period of years. In yet other embodiments, the method comprises administering over a period of decades.

[0801] The dosage of the drug may vary depending on known factors, such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; the time of administration of the active ingredient; the age, sex, health condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment, the frequency of treatment and the desired effect; and the rate of excretion. These factors are readily determined and can be used by those skilled in the art to adjust or titrate the dosage and / or dosing regimen.

[0802] Inhibition of protein kinases

[0803] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0804] According to another embodiment, the present invention relates to a method for inhibiting the activity of FGFR2 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method for reversibly inhibiting the activity of FGFR2 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of FGFR2 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0805] In some embodiments, the present invention relates to a method for irreversibly inhibiting FGFR2 or a mutant thereof, wherein the compound of the present invention forms a covalent bond with FGFR2 or a mutant thereof. In some embodiments, the present invention relates to a method for irreversibly inhibiting FGFR2 or a mutant thereof, wherein the compound of the present invention forms a covalent bond with FGFR2 or a mutant thereof. W In some embodiments, the present invention relates to a method for irreversibly inhibiting FGFR2 or its mutants, wherein the compound of the present invention forms a covalent bond with the cysteine ​​of FGFR2 or its mutant. W Forms a covalent bond with Cys491 of FGFR2 or its mutants.

[0806] According to another embodiment, the present invention relates to FGFR2 or a mutant thereof that is irreversibly inhibited by a compound of the present invention. In some embodiments, the present invention relates to FGFR2 or a mutant thereof that is covalently bound to a compound of the present invention. In some embodiments, the present invention relates to FGFR2 or a mutant thereof that is covalently bound to a compound of the present invention, wherein the covalent bond is between R W In some embodiments, the present invention relates to FGFR2 or a mutant thereof covalently bonded to a compound of the invention, wherein the covalent bond is between R W Between Cys491 of FGFR2 or its mutants.

[0807] In another embodiment, the present invention provides a method for selectively inhibiting FGFR2 relative to one or more of FGFR1, FGFR3 and FGFR4. In some embodiments, the compounds of the present invention have a selectivity greater than 5 times relative to FGFR1, FGFR3 and FGFR4. In some embodiments, the compounds of the present invention have a selectivity greater than 10 times relative to FGFR1, FGFR3 and FGFR4. In some embodiments, the compounds of the present invention have a selectivity greater than 50 times relative to FGFR1, FGFR3 and FGFR4. In some embodiments, the compounds of the present invention have a selectivity greater than 100 times relative to FGFR1, FGFR3 and FGFR4. In some embodiments, the compounds of the present invention have a selectivity greater than 200 times relative to FGFR1, FGFR3 and FGFR4.

[0808] As used herein, the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0809] Inhibiting FGFR2 (or its mutant) activity in a biological sample is applicable to a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological analysis.

[0810] Another embodiment of the present invention is directed to a method of inhibiting protein kinase activity in a patient comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

[0811] According to another embodiment, the present invention relates to a method of inhibiting the activity of FGFR2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting the activity of one or more of FGFR2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. According to another embodiment, the present invention relates to a method of reversibly inhibiting the activity of one or more of FGFR2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of irreversibly inhibiting the activity of one or more of FGFR2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

[0812] In some embodiments, the present invention relates to a method for irreversibly inhibiting the activity of one or more of FGFR2 or its mutants in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound, wherein the compound forms a covalent bond with FGFR2 or its mutants. In some embodiments, the present invention relates to a method for irreversibly inhibiting the activity of one or more of FGFR2 or its mutants in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound, wherein the compound forms a covalent bond with FGFR2 or its mutants. W In some embodiments, the present invention relates to a method for irreversibly inhibiting the activity of one or more of FGFR2 or its mutants in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound, wherein the compound is at the R W Forms a covalent bond with Cys491 of FGFR2 or its mutants.

[0813] According to another embodiment, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein. In some embodiments, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits FGFR2 or a mutant thereof.

[0814] In some embodiments, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound irreversibly inhibits FGFR2 or a mutant thereof. In some embodiments, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound forms a covalent bond with FGFR2 or a mutant thereof. In some embodiments, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound is in the R WIn some embodiments, the present invention provides a method for treating a condition mediated by FGFR2 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound is at the R W Forms a covalent bond with Cys491 of FGFR2 or its mutants.

[0815] According to another embodiment, the present invention provides a method of inhibiting the signaling activity of FGFR2 or a mutant thereof in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method of inhibiting the signaling activity of FGFR2 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0816] In some embodiments, the present invention 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 the patient a compound of the present invention or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits FGFR2 or a mutant thereof.

[0817] Compounds described herein can also inhibit FGFR2 function by being incorporated into an agent that catalyzes the destruction of FGFR2. For example, compounds can be incorporated into a chimera (PROTAC) targeting proteolysis. PROTAC is a bifunctional molecule, one of which is capable of engaging an E3 ubiquitin ligase and the other is capable of binding to a target protein that is desired to be degraded by a cellular protein quality control mechanism. The target protein is recruited to a specific E3 ligase so that it is marked for destruction (i.e., ubiquitination) and subsequently degraded by the proteasome. Any E3 ligase can be used. The portion in PROTAC that is engaged with the E3 ligase is connected to the portion in PROTAC that is engaged with the target protein via a linking group, and the linking group is composed of a variable atom chain. FGFR2 is recruited to the E3 ligase and will therefore destroy FGFR2 protein. The variable atom chain may include, for example, rings, heteroatoms and / or repeating polymer units. It may be rigid or flexible. It can be connected to the above-mentioned two parts using standard techniques in organic synthesis technology.

[0818] Combination therapy

[0819] Depending on 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 the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are referred to as "appropriate for the disease or condition being treated."

[0820] Thus, in certain embodiments, the methods of treatment comprise administering a compound or composition of the invention in combination with one or more other therapeutic agents. In certain other embodiments, the methods of treatment comprise administering a compound or composition of the invention as a sole therapeutic agent.

[0821] In some embodiments, the one or more additional therapeutic agents are selected from an antibody, an antibody-drug conjugate, a kinase inhibitor, an immunomodulator, and a histone deacetylase inhibitor. In some embodiments, the one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts 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, such as ulixertinib, MK-8353, and LY-3214996; VEGF receptor inhibitors, such as bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, and sorafenib; tyrosine kinase inhibitors, such as erlotinib, linifanib, sunitinib, and pazopanib; Epidermal growth factor receptor (EGFR) inhibitors: gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors, such as trastuzumab, neratinib, lapatinib, and lapatinib; MET inhibitors, such as crizotinib and cabozantinib; CD20 antibodies, such as rituximab, tositumomab, and ofivantumab ofatumumab; DNA synthesis inhibitors: for example, capecitabine, gemcitabine, nelarabine, hydroxycarbamide; anti-neoplastic agents: for example, oxaliplatin, cisplatin; HER dimerization inhibitors: for example, pertuzumab; human granulocyte colony-stimulating factor (G-CSF) regulators: for example, filgrastim; immunomodulators: for example, afutuzumab, lenalidomide, domide), thalidomide, pomalidomide; CD40 inhibitors: such as dacetuzumab; pro-apoptotic receptor agonists (PARA): such as dulanermin; heat shock protein (HSP) inhibitors: such as tanespimycin (17-allylamino-17-desmethoxygeldanamycin); Hedgehog antagonists: such as vismodegib; proteasome inhibitors: bortezomib;PI3K inhibitors: such as pictilisib, dactolisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; phospholipase A2 inhibitors: such as anagrelide; BCL-2 inhibitors: such as venetoclax; aromatase inhibitors: exemestane, letrozole, anastrozole, faslodex, Tamoxifen; topoisomerase I inhibitors such as irinotecan and topotecan; topoisomerase II inhibitors such as etoposide and teniposide; mTOR inhibitors such as temsirolimus, ridaforolimus, everolimus, and sirolimus; osteoclastic bone resorption inhibitors such as zoledronic acid; CD33 antibody-drug conjugates such as gemtuzumab ozogamicin. ozogamicin); CD22 antibody-drug conjugates, such as inotuzumab ozogamicin; CD20 antibody-drug conjugates, such as ibritumomab tiuxetan; somatostatin analogs, such as octreotide; interleukin-11 (IL-11), such as oprelvekin; synthetic erythropoietin, such as darbepoetin alfa. alfa); receptor activator of nuclear factor κB (RANK) inhibitors: such as denosumab; thrombopoietin mimetic peptides: such as romiplostim; cell growth stimulants: such as palifermin; anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: such as figitumumab; anti-CS1 antibodies: such as elotuzumab; CD52 antibodies: such as alemtuzumab; CTLA-4 inhibitors: such as tremelimumab and ipilimumab;PD1 inhibitors: e.g. nivolumab, pembrolizumab; immunoadhesins: e.g. pidilizumab, AMP-224; PDL1 inhibitors: e.g. MSB0010718C, YW243.55.S70, MPDL3280A, MEDI-4736, MSB 0010718C or MDX-1105; LAG-3 inhibitors such as BMS-986016; GITR agonists; GITR fusion proteins and anti-GITR antibodies; histone deacetylase inhibitors (HDIs) such as voninostat; anti-CTLA4 antibodies such as tremelimumab and ipilimumab; alkylating agents such as temozolomide, dactinomycin, melphalan, and altretamine. carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, mustine and mechloroethamine, streptozocin, thiotepa; biological response modifiers (e.g., bacillus Calmette-Guérin, denileukin-1), diftitox; antitumor antibiotics: for example, doxorubicin, bleomycin, daunorubicin, liposomal daunorubicin, mitoxantrone, epirubicin, idarubicin, and mitomycin C; antimicrotubule agents: for example, estramustine; cathepsin K inhibitors: for example, odanacatib; epothilone analogs: for example, ixabepilone;TpoR agonists, such as eltrombopag; antimitotic agents, such as docetaxel; adrenal steroid inhibitors, such as aminoglutethimide; antiandrogens, such as nilutamide; androgen receptor inhibitors, such as enzalutamide and abiraterone acetate. acetate), orteronel, galeterone, seviteronel, bicalutamide, flutamide; androgens such as fluoxymesterone; CDK1 inhibitors such as alvidib, palbociclib, ribociclib, trilaciclib, and abemaciclib; gonadotropin-releasing hormone (GnRH) receptor agonists such as leuprolide or leuprolide acetate; taxane antineoplastic agents such as cabazitaxel and larotaxel; 5-HT1a receptor agonists such as xaliproden; HPV vaccines such as those sold by GlaxoSmithKline; Sold by Merck Iron chelators: e.g., deferasirox; antimetabolites: e.g., claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, liposomal cytarabine, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin; bisphosphonates: e.g., pamidronate; demethylating agents: e.g., 5-azacitidine, decitabine; antitumor plant alkaloids: e.g., protein-bound paclitaxel protein-bound; vinblastine, vincristine, vinorelbine, paclitaxel; retinoids: for example, alitretinoin, tretinoin, isotretinoin, bexarotene; glucocorticoids: for example, hydrocortisone, dexamethasone, prednisolone, prednisone, methylprednisolone; cytokines: for example, interleukin-2, interleukin-11 (oprevelkin), interferon alpha (IFN-α); estrogen receptor downregulators: fulvestrant; antiestrogens: such as tamoxifen and toremifene; selective estrogen receptor modulators (SERMs): such as raloxifene; luteinizing hormone-releasing hormone (LHRH) agonists: such as goserelin; progestins: such as megestrol; cytotoxic agents: arsenic trioxide, asparaginase (also known as L-asparaginase, Erwinia L-asparaginase); anti-nausea drugs: such as NK-1 receptor antagonists (such as casopitant); cytoprotective agents: such as amifostine and leucovorin; and immune checkpoint inhibitors. The term "immune checkpoint" 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 that can act as immune checkpoint inhibitors suitable for use 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 TGFRβ.

[0822] In some embodiments, the one or more other therapeutic agents are selected from the following agents: anti-FGFR antibodies; cytotoxic agents; targeted estrogen receptor 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; YK Chae et al., Oncotarget 2017, 8: 16052-16074; L. Formisano et al., Nat. Comm. 2019, 10: 1373-1386; and references cited therein).

[0823] The structures of active compounds identified by code numbers, generic groups or trade names can be taken from the official standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0824] The compounds of the invention may also be used in combination with known treatments, such as administration of hormones or radiation. In certain embodiments, provided compounds are useful as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0825] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may be in the form of fixed combinations of the compounds of the present invention and one or more other therapeutic compounds, or staggered or independent administration of the fixed combination with one or more other therapeutic compounds. Alternatively or additionally, the compounds of the present invention may be combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor therapy. As described above, in the context of other treatment strategies, long-term therapy is also possible, as is adjuvant therapy. Other possible therapies are therapies that maintain the patient's status after tumor regression, or even chemopreventive therapy, for example, for patients at risk.

[0826] Those other agents may be administered separately from the composition containing the compounds of the invention as part of a multiple-dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention into a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (generally within five hours of each other).

[0827] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0828] The amount of the compound of the invention and the other therapeutic agent (in those compositions comprising another therapeutic agent as described above) that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that the compound of the invention can be administered at a dose between 0.01 and 100 mg per kilogram of body weight per day.

[0829] In those compositions that include another therapeutic agent, the other therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the other therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, the other therapeutic agent may be administered at a dosage of between 0.01 and 1,000 μg per kilogram of body weight per day.

[0830] The amount of the other therapeutic agent present in the compositions of the present invention will not exceed the amount normally administered in a composition comprising that therapeutic agent as the only active agent. The amount of another therapeutic agent in the compositions disclosed herein is preferably in the range of about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0831] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices (e.g., prostheses, artificial valves, vascular grafts, intravascular stents, and catheters). Intravascular stents, for example, have been used to overcome restenosis (restenosis of the blood vessel wall after injury). However, patients using intravascular stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the present invention.

[0832] Any of the compounds and / or compositions of the present disclosure may be provided in a kit comprising the compound and / or composition. Thus, in some embodiments, the compounds and / or compositions of the present disclosure are provided in a kit.

[0833] The present disclosure is further described by the following non-limiting examples.

[0834] Examples

[0835] Examples are provided herein to facilitate a more thorough understanding of the present disclosure. The following examples are used to illustrate exemplary methods for preparing and implementing the objectives of the present disclosure. However, the scope of the present disclosure should not be construed as being limited to the specific embodiments disclosed in these examples, which are merely illustrative.

[0836] As depicted in the Examples below, in certain exemplary embodiments, compounds were prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to other classes, subclasses, and species of each of these compounds as described herein. Other compounds of the present invention were prepared by methods substantially similar to those described herein in the Examples and methods known to those of ordinary skill in the art.

[0837] In the description of the following synthetic methods, unless otherwise stated, it will be understood that all reaction conditions (e.g., reaction solvents, atmospheres, temperatures, durations, and workup procedures) are selected from standard reaction conditions unless otherwise indicated. In the general schemes, it will be understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule should be compatible with the reagents and reactions proposed. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods (e.g., the use of protecting groups or alternative reactions) will therefore be specified. The starting materials in the examples are commercially available or readily prepared from known materials by standard methods.

[0838] At least some of the compounds identified herein as "intermediates" are encompassed as compounds of the present disclosure.

[0839] In some embodiments, compounds of Formula I are prepared according to the general procedure depicted in Scheme 1 below.

[0840] Process 1

[0841]

[0842] In some embodiments, step 1 comprises reacting Int-1 with a 7 Compounds are condensed to form compounds of formula Int-2, wherein R 7 is defined in the Examples herein and X is a leaving group.

[0843] In some embodiments, step 2 comprises iodination of the compound of formula Int-2. In some embodiments, the reagent used is N-iodosuccinimide.

[0844] In some embodiments, step 3 comprises reacting a compound of formula Int-3 with a suitable reactive group functionalized with a Cy 6 -L 6 -R W In some embodiments, the suitable reactive group is a borate ester. In some embodiments, the suitable reactive group is a pinacol borate ester.

[0845] In some embodiments, step 4 comprises reacting a compound of formula Int-4 with a suitable reactive group functionalized R 5 The synthetic building blocks of the present invention are coupled to form a compound of Formula I. In some embodiments, the suitable reactive group is a boronic acid or a boronic ester.

[0846] Example 1

[0847] N-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0848]

[0849] 5-Bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0850]

[0851] Step 1: 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3 g, 14.0 mmol), Cs2CO3 (9.10 g, 28.0 mmol), DMF (50 mL) and a stirring bar were added. The mixture was cooled to 0 ° C and iodomethane (1.98 g, 14.0 mmol) was added and the solution was stirred at 0 ° C for 3 hours. The reaction mixture was diluted with H2O (300 mL) and the aqueous phase was extracted three times with EA (300 mL). 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 (eluting with MeOH / DCM=1 / 80). Concentration in vacuo gave 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.20 g, 70%) as a yellow crystalline solid.

[0852] 5-Bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0853]

[0854] Step 2: A round-bottom 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 stirring bar. 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 at room temperature for 2 hours. The reaction mixture was diluted with saturated Na2SO3 solution (100 mL). The pH of the solution was adjusted to 7-8 with a saturated NaHCO3 solution. The solid was filtered and washed with H2O, then washed with a small amount of DCM to produce 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.70 g, 80%) as a white amorphous solid.

[0855] N-(4-(4-Amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0856]

[0857] Step 3: A resealable reaction bottle 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(PPh3)4 (1.21 g, 1.05 mmol), K3PO4 (6.68 g, 31.53 mmol), DMF (50 mL), H2O (3 mL) and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated in vacuo. The crude material was purified by silica gel chromatography (eluting with MeOH / DCM = 1 / 100 to 1 / 20). Concentration in vacuo gave 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.

[0858] N-(4-(4-amino-5-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0859]

[0860] 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 (20.1 mg, 0.031 mmol), CsF (240 mg, 0.930 mmol), DMF (4 mL), H2O (0.5), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90°C for 2 h. The reaction mixture was concentrated in vacuo. The crude material was purified by TLC (eluting with MeOH / DCM = 1 / 15). Concentration in vacuo gave 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.

[0861] Example 2

[0862] Alternative pathway to N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0863]

[0864] 6-(4-Aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0865]

[0866] Step 1: A round-bottom 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 stir bar. TFA (60 mL) was added. The solution was stirred at room temperature for 4 hours. The reaction mixture was basified with saturated aqueous Na2CO3 (40 mL), and the solid was filtered off 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 an off-white amorphous solid.

[0867] N-(4-(4-Amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0868]

[0869] 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 stirring bar, then evacuated and purged with nitrogen three times. The solution was cooled to 0°C. Methacryloyl chloride (4.0 g, 37.7 mmol) was then dissolved in DMF (10 mL) and added to the above solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (200 mL), and the aqueous phase was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was recrystallized from MeCN. Concentration in vacuo gave 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.

[0870] Example 3

[0871] 4-(4-amino-6-(4-methylacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(oxetan-2-ylmethyl)benzamide

[0872]

[0873] Methyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate

[0874]

[0875] 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)Cl2 (4.74 g, 7.29 mmol), CsF (33.1 g, 218 mmol), DMF (200 mL), H2O (25 mL) and a stirring bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90 °C for 1 hour. The reaction mixture was diluted with H2O (500 mL) and the aqueous phase was extracted three times with DCM (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. MeCN (10 mL) was added to the reaction mixture and the mixture was evaporated to room temperature via HPLC. The mixture was filtered through a pad of Celite® and 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.

[0876] Methyl 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate

[0877]

[0878] Step 2: A round-bottom 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 stirring bar. The mixture was cooled to 0 ° C, NIS (9.53 g, 42.4 mmol) was added, and the solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with Na2SO3 solution, and the aqueous phase was extracted three times with DCM (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. DCM (20 mL) was added and the mixture was stirred through The reaction mixture was filtered through a pad of Celite®, washing the pad with a small amount of 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 solid.

[0879] Methyl 4-(4-amino-6-(4-methacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate

[0880]

[0881] 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 (2.12 g, 2.91 mmol), KPO (18.5 g, 87.3 mmol), DMF (100 mL), H0 (12.5 mL), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90° C. for 1 hour. The reaction mixture was diluted with H0 (500 mL), and the aqueous phase was extracted three times with DCM (300 mL). 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 (eluting with MeOH / DCM = 1 / 40). Concentration in vacuo yielded 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.

[0882] 4-(4-Amino-6-(4-methylacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoic acid

[0883]

[0884] Step 4: A round-bottom 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 (2N, 40 mL) and a stirring bar. The solution was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to 6-7 with HCl (2 M). The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a pad of Celite® and 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), which was obtained as an off-white amorphous solid.

[0885] 4-(4-amino-6-(4-methylacrylamidophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(oxetan-2-ylmethyl)benzamide

[0886]

[0887] Step 5: A round-bottom 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 stir bar. Dimethylformamide (3 mL) was added, and the solution was stirred at 25° C. for 2 h. The crude material was purified by HPLC (column: XBridgePrep Phenyl OBD column, 19×150 mm, 5 μm, 13 nm). Lyophilization gave 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 an off-white amorphous solid.

[0888] Additional compounds prepared according to the methods of Examples 1-3 are depicted in Table 2 below.

[0889] Table 2. Other exemplary indole compounds

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032] Process 2

[1033]

[1034] Example 4

[1035] 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

[1036]

[1037] tert-Butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1038]

[1039] Step 1: A round-bottom 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 stir bar. The solution was stirred at 90°C for 2 hours. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted three times with dichloromethane (20 mL). 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; eluted with heptane / ethyl acetate 3:1). Concentration in vacuo yielded 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.

[1040] N-(4-(4-amino-7-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[1041]

[1042] Step 2: A round-bottom 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 TFA, 0.8 mL DCM, and a stir bar. The solution was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The resulting crude material was purified by HPLC (acetonitrile / water / 0.1% formic acid). Lyophilization gave 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 (16.8 mg, 71%) as a white amorphous solid.

[1043] 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

[1044]

[1045] Step 3: A round-bottom 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 1 hour. The reaction mixture was diluted with water (30 mL) and the aqueous phase was extracted three times with dichloromethane (20 mL). 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 gave 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.

[1046] Additional compounds prepared according to the method of Example 4 are depicted in Table 3 below.

[1047] Table 3. Other exemplary compounds

[1048]

[1049] Process 3

[1050]

[1051] Example 5

[1052] N-(4-(4-amino-7-methyl-5-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[1053]

[1054] tert-Butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1055]

[1056] Step 1: A round-bottom 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), K3PO4 (6.91 g, 32.6 mmol), and a stir bar. DMF (45 mL) and H2O (3 mL) were added, and the solution was stirred at 90°C for 3 h. 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 using DCM:MeOH=25:1 to give 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 a brown oil.

[1057] tert-Butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[1058]

[1059] Step 2: A round-bottom 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 stir bar. MeOH (50 mL) was added, and the solution was stirred at 50° C. under H 2 for 48 hours. The mixture was filtered and washed with MeOH five times, and the filtrate was concentrated to obtain tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidine-1-carboxylate (900 mg, 53%) as a brown oil.

[1060] tert-Butyl 4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[1061]

[1062] Step 3: A round-bottom 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 stirring bar. ACN (20 mL) was added and the solution was stirred at 25 ° C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain 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 a brown solid. The crude product was used in the next step without further purification.

[1063] 6-Bromo-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1064]

[1065] Step 4: A round-bottom 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 stirring bar. TFA (0.5 mL) was added and the solution was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure and diluted with DCM (30 mL), washed with saturated aqueous NaHCO 3 (3*15 mL), and the organic phase was concentrated to obtain the product 6-bromo-7-methyl-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (310 mg, 83%) as a brown oil.

[1066] (4-(4-Amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)(pyrrolidin-1-yl)methanone

[1067]

[1068] Step 5: A round-bottom 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 stir bar. Triphosgene (106 mg, 360 μmol) was added and the solution was stirred at room temperature for 1 hour, followed by the addition of pyrrolidine (512 mg, 7.21 mmol) and stirring at room temperature for 1 hour. The solvent was removed and the crude product was purified by C18 Flash to give 6-bromo-7-methyl-5-[1-(pyrrolidine-1-carbonyl)piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160 mg, 21%) as an off-white solid.

[1069] N-(4-(4-amino-7-methyl-5-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[1070]

[1071] 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, 0.34 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (112 mg, 0.41 mmol), Pd(dppf)Cl (25.1 mg, 34.3 μmol), KPO (216 mg, 1.02 mmol), and a stir bar, then evacuated and purged with nitrogen three times. DMF (1 mL) and H0 (0.1 mL) were added, and the mixture was stirred at 90°C for 3 h. The resulting mixture was purified via a C18 column. The crude material was purified by HPLC. Lyophilization gave 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.

[1072] Additional compounds prepared according to the method of Example 5 are depicted in Table 4 below.

[1073] Table 4. Exemplary compounds

[1074]

[1075] Process 4

[1076]

[1077] N-(4-(4-amino-7-methyl-5-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[1078]

[1079] tert-Butyl 4-(6-(4-acrylamidophenyl)-4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[1080]

[1081] Step 1: A round-bottom 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)Cl (124 mg, 0.17 mmol), KPO (1.08 g, 5.1 mmol), and a stir bar. DMF (10 mL) and H0 (1 mL) were added, and the solution was stirred at 90° C. for 3 h. The mixture was diluted with EtOAc (100 mL) and washed with water (3*100 mL), and the organic phase was concentrated and the crude product was purified by silica gel column using DCM:MeOH=25:1 to give 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 a yellow solid.

[1082] tert-Butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[1083]

[1084] Step 2: A round-bottom 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 stirring bar. TFA (0.5 mL) was added and the solution was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure and diluted with DCM (30 mL), washed with saturated aqueous NaHCO 3 (3*15 mL), and the organic phase was concentrated to obtain the product tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (240 mg, 89%) as a brown oil.

[1085] N-(4-(4-amino-7-methyl-5-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[1086]

[1087] Step 3: A round-bottom flask was charged with tert-butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (120 mg, 0.32 mmol), NaBH(OAc) (81 mg, 0.38 mmol), (CHO) (20 mg, 0.64 mmol), and a stir bar. DCM (5 mL) and AcOH (0.5 mL) were added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted three times with DCM (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by HPLC. Lyophilization gave 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 as a white amorphous solid (8 mg, 6%).

[1088] Additional compounds prepared according to the method of Example 6 are depicted in Table 5 below.

[1089] Table 5. Exemplary compounds

[1090]

[1091] Process 5

[1092]

[1093] Example 7

[1094] N-(4-(4-amino-7-methyl-5-(1-((methylcarbamoyl)glycinyl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide

[1095]

[1096] 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 stir bar. Dimethylformamide (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted three times with dichloromethane (15 mL). 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 gave 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 as a white amorphous solid (6.00 mg, 5%).

[1097] Additional compounds prepared according to the method of Example 7 are depicted in Table 6 below.

[1098] Table 6. Other exemplary compounds

[1099]

[1100] Example 8

[1101] Process 6

[1102]

[1103] 5-(4-Methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1104]

[1105] 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)Cl2 (4.74 g, 7.29 mmol), CsF (33.1 g, 218 mmol), DMF (200 mL), H2O (25 mL) and a stirring bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90 °C for 1 hour. The reaction mixture was diluted with H2O (500 mL) and the aqueous phase was extracted three times with DCM (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. MeCN (10 mL) was added to the reaction mixture and the mixture was evaporated to room temperature via HPLC. The mixture was filtered through a pad of Celite®, and 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%), which was obtained as a yellow amorphous solid.

[1106] 6-iodo-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1107]

[1108] Step 2: A round-bottom 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 stirring bar. The mixture was cooled to 0 ° C, NIS (9.53 g, 42.4 mmol) was added, and the solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with Na2SO3 solution, and the aqueous phase was extracted three times with DCM (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. DCM (20 mL) was added and the mixture was stirred through The reaction mixture was filtered through a pad of Celite®, washing the pad with a small amount of 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%), which was obtained as an off-white amorphous solid.

[1109] 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

[1110]

[1111] 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 (190 mg, 0.26 mmol), KPO (1.5 g, 6.9 mmol), DMF (20 mL), H0 (2 mL), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90° C. for 1 hour. The reaction mixture was diluted with H0 (100 mL), and the aqueous phase was extracted three times with DCM (100 mL). 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 (eluting with MeOH / DCM = 1 / 40). Concentrated in vacuo to yield 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.

[1112] 5-(4-Methoxyphenyl)-7-methyl-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate

[1113]

[1114]

[0266] Step 4: A round-bottom 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 at room temperature for 1 hour. The solvent was removed in vacuo to yield 5-(4-methoxyphenyl)-7-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate (795 mg, 100%) as a dark oil.

[1115] 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

[1116]

[1117] Step 5: A round-bottom 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 (120 mg, 0.24 mmol), Et3N (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 at -30°C for 0.5 h. The reaction mixture was quenched with MeOH and concentrated in vacuo. The crude material was purified by preparative HPLC. Lyophilized to give 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.

[1118] Additional compounds prepared according to the method of Example 8 are depicted in Table 7 below.

[1119] Table 7. Other exemplary compounds

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136] Example 9

[1137] Process 7

[1138]

[1139] N-(4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacrylamide

[1140]

[1141] 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), KPO (1.48 g, 7.02 mmol), Pd(dppf)Cl (171 mg, 234 μmol), and a stir bar, then evacuated and purged with nitrogen three times. DMF / H2O (10 mL) was added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (eluting with dichloromethane / methanol 15:1) and concentrated in vacuo to yield 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.

[1142] N-(4-{4-amino-5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-6-yl}phenyl)-2-methylprop-2-enamide

[1143]

[1144] Step 2: A round-bottom 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, followed by NBS (313 mg, 1.77 mmol) at 0°C, and the solution was stirred at 0°C for 1 hour. The reaction mixture was diluted with Na2SO3(aq) (10 mL), and the aqueous phase was extracted three times with dichloromethane (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (eluting with dichloromethane / methanol 20:1). Concentration in vacuo gave 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.

[1145] N-(4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacrylamide

[1146]

[1147] 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) and a stirring bar were added, followed by evacuation and purging with nitrogen three times. n-BuLi (0.8 mL, 2 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 5 minutes. The reaction mixture was diluted with water (5 mL), and the aqueous phase was extracted three times with dichloromethane (5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by TLC (eluting with dichloromethane / methanol 15:1). Concentration in vacuo gave 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.

[1148] N-(4-(4-amino-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)phenyl)methacrylamide

[1149]

[1150] 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) and a stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 90° C. for 1 hour. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted three times with dichloromethane (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by HPLC (column: XBridge Preparative OBD C18 column, 30×150 mm 5 μm; mobile phase A: undefined, mobile phase B: undefined; flow rate: 60 mL / min; gradient: 35B to 50B over 8 minutes; 220 nm; RT1: 7.54; RT2: ; injection volume: ml; number of operations: ). 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.

[1151] Additional compounds prepared according to the method of Example 9 are depicted in Table 8 below.

[1152] Table 8. Other exemplary compounds

[1153]

[1154]

[1155] Example 10

[1156] Process 8.

[1157]

[1158] 4-(4-amino-7-(hydroxymethyl)-6-(4-methylacrylamidophenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[1159]

[1160] 4-(4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[1161]

[1162] 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, then evacuated and purged with nitrogen three times. The solution was stirred at 90°C for 2 hours. The reaction mixture was quenched with water and extracted with DCM. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative TLC. Concentration in vacuo gave 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.

[1163] 4-(4-amino-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

[1164]

[1165]

[0146] 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 at room temperature for 1 hour. The resulting mixture was purified via a C18 column. Concentration in vacuo gave 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.

[1166] 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

[1167]

[1168] Step 3: A round-bottom flask was charged with 4-(4-amino-7-(((tert-butyldimethylsilyl)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 at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The organic phase was separated and dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography. Concentration in vacuo gave 4-(4-amino-6-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolo[2,l-f][l,2,4]triazin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide (450 mg, 94%) as a yellow amorphous solid.

[1169] 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

[1170]

[1171] Step 4: A resealable reaction vial was charged with 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 (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)Cl (23.4 mg, 36 μmol), CsF (164 mg, 1.08 mmol), DMF:water = 16:1 (4 mL), and a stir bar, then evacuated and purged with nitrogen three times. The solution was stirred at 90° C. under N for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was collected and dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: XBridge Preparative OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20B to 50B over 8 minutes; 220 nm; RT1: 7.23). Lyophilization yielded 4-(4-amino-7-(hydroxymethyl)-6-(4-methylacrylamidophenyl)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.

[1172] Additional compounds prepared according to the method of Example 10 are depicted in Table 9 below.

[1173] Table 9. Other exemplary compounds

[1174]

[1175]

[1176] Example 11

[1177] Process 9

[1178]

[1179] Methyl 4-(4-amino-6-(4-methacrylamidophenyl)-7H-cyclopenta[d]pyrimidin-5-yl)benzoate

[1180]

[1181] Step 1: A round-bottom flask was charged with N-(4-{4-amino-5-bromo-7H-cyclopenta[d]pyrimidin-6-yl}phenyl)-2-methylprop-2-enamide (800 mg, 2.15 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (731 mg, 2.79 mmol), Pd(dtbpf)Cl2 (139 mg, 215 μmol), CsF (980 mg, 6.45 mmol), DMF:H2O=16:1 (8 mL), and a stir bar. The solution was stirred at 90°C under N2 for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted three times with EtOAc (50 mL). 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. Concentration in vacuo gave methyl 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]-7H-cyclopenta[d]pyrimidin-5-yl}benzoate (600 mg, 56%) as an off-white amorphous solid.

[1182] 4-(4-Amino-6-(4-methylacrylamidophenyl)-7H-cyclopenta[d]pyrimidin-5-yl)benzoic acid

[1183]

[1184] Step 2: A round-bottom flask was charged with methyl 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]-7H-cyclopenta[d]pyrimidin-5-yl}benzoate (580 mg, 1.35 mmol), THF:LiOH (2M) = 1:1 (6 mL) and a stir bar. The solution was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 6-7 with aqueous HCl. The product was precipitated by adding HCl and dried. This produced 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]-7H-cyclopenta[d]pyrimidin-5-yl}benzoic acid (350 mg, 63%) as an off-white amorphous solid.

[1185] 4-(4-amino-6-(4-methylacrylamidophenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-(2-hydroxy-2-methylpropyl)benzamide

[1186]

[1187] Step 3: A resealable reaction vial was charged with 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]-7aH-cyclopenta[d]pyrimidin-5-yl}benzoic acid (60 mg, 145 μmol), 1-amino-2-methylpropan-2-ol (15.5 mg, 174 μmol), HATU (55.2 mg, 145 μmol), DIEA (37.4 mg, 290 μmol), dimethylformamide (10 mL), and a stir bar. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and purified by HPLC (column: XBridge Preparative C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15B to 50B over 7 minutes; 254 / 220 nm; RT1: 7.58). Lyophilization gave 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-N-(2-hydroxy-2-methylpropyl)benzamide (40.2 mg, 56.4%) as a white amorphous solid.

[1188] Additional compounds prepared according to the method of Example 11 are depicted in Table 10 below.

[1189] Table 10. Other exemplary compounds

[1190]

[1191]

[1192]

[1193] Example 12

[1194] Process 10

[1195]

[1196] N-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[1197]

[1198] Step 1: A round-bottom flask was charged with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10 g, 42.8 mmol), prop-2-enoyl chloride (3.87 g, 42.8 mmol), pyridine (10.1 g, 128 mmol), dichloromethane (150 mL) and a stirring bar. The solution was stirred at 0 ° C for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The organic phase was dried over Na2SO4, filtered and evaporated in vacuo. The resulting crude material was purified by silica gel chromatography. Concentration in vacuo gave N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (12 g, 98%) as a yellow oil.

[1199] N-(4-(4-Amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide

[1200]

[1201] Step 2: A round-bottom flask was charged with N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-enamide (1 g, 3.48 mmol), 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.22 g, 3.48 mmol), Pd(dppf)Cl (254 mg, 348 μmol), KPO (2.20 g, 10.4 mmol), DMF / H0 (16:1) (15 mL), and a stir bar. The solution was stirred at 50°C for 2 hours. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed three times with brine, dried over NaSO, filtered, and evaporated in vacuo. The crude material was purified by silica gel chromatography. Concentration in vacuo gave N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide (440 mg, 33%) as an off-white amorphous solid.

[1202] (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide

[1203]

[1204] Step 3: A resealable reaction vial was charged with N-(4-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3-methylphenyl)prop-2-enamide (200 mg, 517 μmol), 1-[(1R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonyl]pyrrolidine (156 mg, 517 μmol), Pd(pddf)Cl (37.8 mg, 517 μmol), NaCO (164 mg, 1.55 mmol), DMF (10 mL), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90° C. for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed three times with brine, dried over NaSO, filtered, and evaporated in vacuo. The crude material was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 40B to 62B over 8 minutes; 220 nm; RT1: 6.83). Lyophilization yielded (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide (40 mg, 16%) as an off-white amorphous solid.

[1205] (S)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide

[1206]

[1207] 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}-3-methylphenyl)prop-2-enamide (240 mg, 621 μmol), Pd(dppf)Cl (45.4 mg, 62.1 μmol), NaCO (197 mg, 1.86 mmol), 1-[(1S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonyl]pyrrolidine (189240 mg, 621 μmol), dimethylformamide / HO (8 mL), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 90° C. for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed three times with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude material was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 40B to 60B over 8 minutes; 220 nm; RT1: 7.67; RT2:; injection volume: ml; number of operations:;). Lyophilization yielded (S)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)acrylamide (39 mg, 14%) as an off-white amorphous solid.

[1208] Additional compounds prepared according to the method of Example 12 are depicted in Table 11 below.

[1209] Table 11. Other exemplary compounds

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250]

[1251]

[1252]

[1253] Example 13

[1254] Process 11

[1255]

[1256] N-(2-(4-bromophenyl)propan-2-yl)acrylamide

[1257]

[1258] Step 1: Under a nitrogen atmosphere, acryloyl chloride (0.63 g, 7.006 mmol) was added portionwise dropwise to a stirred solution / mixture of 2-(4-bromophenyl)propan-2-amine (1.50 g, 7.006 mmol) and TEA (2.13 g, 21.018 mmol) in DCM (30 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. The resulting mixture was extracted with CHCl. ​​The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give N-(2-(4-bromophenyl)propan-2-yl)acrylamide (500 mg, 27%) as a yellow solid.

[1259] N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)acrylamide

[1260]

[1261] Step 2: A solution / mixture of N-[2-(4-bromophenyl)prop-2-yl]prop-2-enamide (470.00 mg, 1.753 mmol), bis(pinacolato)diboron (667.63 mg, 2.629 mmol), AcOK (516.05 mg, 5.258 mmol), and Pd(dppf)Cl (128.25 mg, 0.175 mmol) in DMF (10 mL) was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc=4 / 1 to give N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)acrylamide (400 mg, 72%) as an off-white solid.

[1262] N-(2-(4-(4-amino-7-methyl-5-(4-(4-methylpyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)propan-2-yl)acrylamide

[1263]

[1264] Step 3: A solution / mixture of 6-iodo-7-methyl-5-[4-[(4-methylpyrimidin-2-yl)oxy]phenyl]pyrrolo[2,3-d]pyrimidin-4-amine (200.00 mg, 0.44 mmol), N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-yl]prop-2-enamide (165.1 mg, 0.52 mmol), K 3 PO 4 (277.9 mg, 1.31 mmol) and Pd(dppf)Cl 2 (31.9 mg, 0.04 mmol) in DMF (4 mL) and H 2 O (1 mL) was stirred at 90° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (column: XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25B to 43B over 7 minutes; 220 / 254 nm; RT1: 6.25; RT2:; injection volume: ml; number of operations:). Lyophilization gave N-(2-(4-(4-amino-7-methyl-5-(4-(4-methylpyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)propan-2-yl)acrylamide (51 mg, 22.3%) as an off-white amorphous solid.

[1265] Additional compounds prepared according to the method of Example 13 are depicted in Table 12 below.

[1266] Table 12. Other exemplary compounds

[1267]

[1268]

[1269]

[1270]

[1271]

[1272]

[1273]

[1274]

[1275]

[1276]

[1277]

[1278]

[1279]

[1280]

[1281]

[1282]

[1283]

[1284]

[1285]

[1286]

[1287] Example 14

[1288] Process 12

[1289]

[1290] tert-Butyl 3-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate

[1291]

[1292] Step 1: A resealable reaction vial was charged with tert-butyl 3-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2,5-dihydro-1H-pyrrole-1-carboxylate (1.2 g, 3.07 mmol), Pd—C (120 mg, 1.2 mol) and a stirring bar, then evacuated and purged with hydrogen three times. MeOH (20 mL) was added and the mixture was stirred at 50° C. overnight. The reaction mixture was stirred overnight. Filter through a pad of Celite®, which was washed with water, and the filtrate was concentrated in vacuo to give tert-butyl 3-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidine-1-carboxylate (0.9 g, 91.8%) as an off-white solid.

[1293] tert-Butyl 3-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate

[1294]

[1295] Step 2: A round-bottom flask was charged with tert-butyl 3-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidine-1-carboxylate (300 mg, 945 μmol), NBS (168 mg, 945 μmol) and a stir bar. Dichloromethane (5 mL) was added and the solution was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with dichloromethane (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield tert-butyl 3-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-pyrrolidine-1-carboxylate (230 mg, 61.4%) as a light yellow solid.

[1296] tert-Butyl 3-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate

[1297]

[1298] Step 3: A resealable reaction vial was charged with tert-butyl 3-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidine-1-carboxylate (200 mg, 504 μmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrimidine (165 mg, 554 μmol), Pd(dtbpf)Cl (32.8 mg, 50.4 μmol), KPO (320 mg, 1.51 mmol), and a stir bar, then evacuated and purged with nitrogen three times. DMF / water (2 mL) was added, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted three times with dichloromethane (10 mL). 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 (5 g column; eluting with dichloromethane / methanol / 0.1% triethylamine; ratio). Concentration in vacuo yielded tert-butyl 3-{4-amino-7-methyl-5-[4-(pyrimidin-2-yloxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidine-1-carboxylate (100 mg, 40.7%) as a light brown solid.

[1299] 7-Methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-6-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1300]

[1301] Step 4: A round-bottom flask was charged with tert-butyl 3-{4-amino-7-methyl-5-[4-(pyrimidin-2-yloxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidine-1-carboxylate (200 mg, 410 μmol) and a stirring bar. TFA / DCM (1 / 4 mL) was added and the solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo. It was then dissolved in saturated NaHCO and extracted three times with DCM. The combined organic layers were dried over anhydrous NaSO. Filtered and evaporated to give 7-methyl-5-[4-(pyrimidin-2-yloxy)phenyl]-6-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 94.4%) as an off-white solid.

[1302] 1-(3-(4-amino-7-methyl-5-(4-(pyrimidin-2-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one

[1303]

[1304] Step 5: A round-bottom flask was charged with 7-methyl-5-[4-(pyrimidin-2-yloxy)phenyl]-6-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 129 μmol), TEA (39.0 mg, 387 μmol), dichloromethane (4 mL) and a stirring bar. Prop-2-enoyl chloride (10.4 mg, 116 μmol) was added at -30°C and the solution was stirred at -30°C for 30 minutes. The reaction mixture was stirred by The mixture was filtered through a pad of 4-nitro-2-nitropropane-5-nitropropane-6-nitropropane-1-one (5.92 mg, 11.6%). The crude product was purified by HPLC (acetonitrile / water / 0.1% formic acid). Lyophilization gave 1-(3-{4-amino-7-methyl-5-[4-(pyrimidin-2-yloxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}pyrrolidin-1-yl)prop-2-en-1-one as a white amorphous solid (5.92 mg, 11.6%).

[1305] Additional compounds prepared according to the method of Example 14 are depicted in Table 13 below.

[1306] Table 13. Other exemplary compounds

[1307]

[1308]

[1309]

[1310]

[1311]

[1312]

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347]

[1348]

[1349]

[1350]

[1351]

[1352]

[1353]

[1354] Example 15

[1355]

[1356] (2S)-tert-Butyl 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate

[1357]

[1358] Step 1: A round-bottom flask was charged with 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 10.18 mmol), THF (30 mL), and a stir bar. LDA (7.63 mL, 15.26 mmol, 2 M) was added dropwise to the above solution at -78°C. After stirring at the same temperature for 1 hour, (S)-tert-butyl 2-methyl-4-oxopyrrolidine-1-carboxylate (4.05 g, 20.35 mmol) in THF (10 mL) was added at -78°C, and the mixture was allowed to warm to room temperature for 1 hour. The mixture was quenched with saturated NH4Cl (10 mL) and extracted three times with EtOAc (40 mL). The combined organic phases were washed with brine, dried over Na2SO4, and combined under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluted with PE / EtOAc=2:1) ​​to give tert-butyl (2S)-4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (550 mg, 1.50 mmol, 15%) as an off-white solid.

[1359] (2S)-tert-Butyl 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate

[1360]

[1361] Step 2: A 50 mL unsealed test tube was charged with tert-butyl (2S)-4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (550 mg, 1.50 mmol), NH3 / H2O (10 mL, 25%-30%) and 1,4-dioxane (10 mL). The test tube was sealed and the mixture solution was stirred at 100°C for 12 hours. The test tube was cooled to room temperature and the mixture was decanted. The solvent was concentrated and the crude product was washed three times with DCM (100 mL) and concentrated to give tert-butyl (2S)-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (400 mg, 77%) as an off-white solid.

[1362] (S)-7-Methyl-6-(5-methyl-2,5-dihydro-1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1363]

[1364] Step 3: A round-bottom flask was charged with tert-butyl (2S)-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (380 mg, 1.09 mmol), HCl (5 mL) and a stirring bar. The mixture was stirred at 100 ° C for 2 hours. After cooling to room temperature, the resulting mixture was concentrated and diluted with water (10 mL), the pH was adjusted to 7-8, and extracted three times with DCM (20 mL). The organic phases were combined and concentrated under reduced pressure to give the crude product (S)-7-methyl-6-(5-methyl-2,5-dihydro-1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (330 mg) as a brown solid.

[1365] 7-Methyl-6-((5S)-5-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1366]

[1367] Step 4: A resealable reaction vial was charged with (S)-7-methyl-6-(5-methyl-2,5-dihydro-1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (330 mg, crude), Pd / C (30 mg), MeOH (10 mL), and a stir bar. The mixture was evacuated and purged with nitrogen three times, then evacuated and purged with hydrogen five times. The mixture was stirred at 50° C. overnight. The mixture was then filtered, the filter cake was washed five times with MeOH, and the organic phase was concentrated to give 7-methyl-6-((5S)-5-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (220 mg, 63% (two steps)) as a brown solid.

[1368] tert-Butyl (2S)-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate

[1369]

[1370] Step 5: A round-bottom flask was charged with 7-methyl-6-((5S)-5-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (220 mg, 0.95 mmol), TEA (288 mg, 2.85 mmol), MeOH (5 mL), and a stir bar. BoC2O (308 mg, 1.42 mmol) was added, and the solution was stirred at room temperature for 12 hours. The mixture was diluted with water (10 mL) and extracted three times with DCM (50 mL). The organic phases were combined and washed with brine, dried over Na2SO4, concentrated in vacuo, and the crude product was purified by preparative TLC using DCM / MeOH (20:1) to give tert-butyl (2S)-4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate (190 mg, 60%) as a brown solid.

[1371] tert-Butyl (2S)-4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate

[1372]

[1373] Step 6: A round-bottom flask was charged with (2S)-tert-butyl 4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2-methylpyrrolidine-1-carboxylate (180 mg, 543 μmol), dimethylformamide (15 mL) and a stir bar. NBS (101 mg, 570 μmol μmol) was added and the solution was stirred at 0°C for 1 hour. The mixture was diluted with DCM (50 mL), washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by preparative TLC using DCM:MeOH (12:1) to give (2S)-tert-butyl 4-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2-methylpyrrolidine-1-carboxylate (200 mg, 85%) as a brown solid.

[1374] tert-Butyl (2S)-4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate

[1375]

[1376] Step 7: A resealable reaction vial was charged with tert-butyl (2S)-4-{4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2-methylpyrrolidine-1-carboxylate (200 mg, 487 μmol), 2-methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine (181 mg, 584 μmol), K 3 PO 4 (309 mg, 1.46 mmol), Pd(DtBPF)Cl 2 (47.5 mg, 73.0 μmol), and a stir bar, then evacuated and flushed with nitrogen three times. DMF:water (16:1) (10 mL) was added, and the solution was stirred at 90° C. for 1 hour. The mixture was diluted with EtOAc (50 mL) and washed three times with water and brine. The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by C18 flash chromatography to give tert-butyl (2S)-4-(4-amino-7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate (140 mg, 56%) as a light brown oil.

[1377] 7-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-((5S)-5-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1378]

[1379] Step 8: A round-bottom flask was charged with tert-butyl (2S)-4-(4-amino-7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidine-1-carboxylate (140 mg, 272 μmol), TFA / DCM (1:4 V / V, 15 mL) and a stir bar. The solution was stirred at room temperature for 3 hours. The solvent was removed and the crude product was diluted with DCM and adjusted to pH 7 with aqueous Na2CO3. The organic phase was concentrated to give 7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-6-[(5S)-5-methylpyrrolidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90.0 mg, 100%), which was used in the next step without purification.

[1380] 1-((2S)-4-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidin-1-yl)prop-2-en-1-one

[1381]

[1382] Step 9: A round-bottom flask was charged with TEA (65.7 mg, 651 μmol), prop-2-enoyl chloride (15.6 mg, 173 μmol), 7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-6-[(5S)-5-methylpyrrolidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90.0 mg, 217 μmol), and a stir bar. Dichloromethane (5 mL) was added, and the solution was stirred at -65 °C for 0.5 h. The mixture was quenched with MeOH and concentrated. The crude product was purified by preparative HPLC (column: XBridgeShield RP18 OBD column, 30*150 mm, 5 um; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25B to 50B, over 8 minutes; 220 nm; RT1: 7.23) to give 1-[(2S)-4-(4-amino-7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylpyrrolidin-1-yl]prop-2-en-1-one (38.3 mg, 38%) as a white solid.

[1383] Additional compounds prepared according to the method of Example 15 are depicted in Table 14 below.

[1384] Table 14. Other exemplary compounds

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391] Example 16

[1392] Process 13

[1393]

[1394] tert-Butyl 3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoropyrrolidine-1-carboxylate

[1395]

[1396] Step 1: A round-bottom flask was charged with tert-butyl 3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-hydroxypyrrolidine-1-carboxylate (200 mg, 0.39 mmol), DCM (10 mL), and a stir bar. DAST (74.8 mg, 0.46 mmol) was added, and the solution was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, extracted with DCM, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography. Concentration in vacuo gave tert-butyl 3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoropyrrolidine-1-carboxylate (127 mg, 63%) as a yellow solid.

[1397] 6-(4-fluoropyrrolidin-3-yl)-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1398]

[1399] Step 2: A resealable reaction vial was charged with tert-butyl 3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoropyrrolidine-1-carboxylate (127 mg, 0.24 mmol), DCM (5 mL), and a stir bar. TFA (2 mL) was added, and the solution was stirred at 25 °C for 1 hour. The reaction mixture was concentrated, diluted with water, and the pH was adjusted to 7 with saturated Na2CO3, extracted with DCM, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by preparative TLC. Concentration in vacuo gave 6-(4-fluoropyrrolidin-3-yl)-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (77 mg, 77%) as a brown solid.

[1400] 1-(3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoropyrrolidin-1-yl)prop-2-en-1-one

[1401]

[1402] Step 3: A round-bottom flask was charged with 6-(4-fluoropyrrolidin-3-yl)-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (77 mg, 180 μmol), TEA (55.8 mg, 0.55 mmol), DCM (5 mL) and a stir bar. Acryloyl chloride (13.2 mg, 147 μmol) was added and the solution was stirred at -35 °C for 0.5 h. The reaction mixture was quenched with MeOH, the resulting mixture was concentrated, and the crude material was purified by preparative HPLC. Lyophilization afforded 1-(3-(4-amino-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoropyrrolidin-1-yl)prop-2-en-1-one (5.2 mg, 6%) as a white amorphous solid.

[1403] Additional compounds prepared according to the method of Example 16 are depicted in Table 15 below.

[1404] Table 15. Other exemplary compounds

[1405]

[1406] Example 17

[1407] Process 14

[1408]

[1409] tert-Butyl 3-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-hydroxypyrrolidine-1-carboxylate

[1410]

[1411] Step 1: A resealable reaction vial was charged with 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (5 g, 29.9 mmol), tetrahydrofuran (200 mL), and a stirring bar, then evacuated and purged with nitrogen three times. LDA (30 mL, 59.9 mmol) was added dropwise at -78°C, and the mixture was stirred at -78°C for 30 minutes. 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (17 g, 89.8 mmol) in 100 mL of THF was added dropwise, and the mixture was stirred at -78°C for 1 hour. The mixture was allowed to warm to room temperature, and the reaction mixture was diluted with H2O (300 mL), and the aqueous phase was extracted three times with EA (300 mL). 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 (eluting with PE / EA = 10 / 1). Concentration in vacuo gave tert-butyl 3-(4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-hydroxypyrrolidine-1-carboxylate (2.20 g, 20.9%) as a light yellow solid.

[1412] tert-Butyl 3-(4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-hydroxypyrrolidine-1-carboxylate

[1413]

[1414] Step 2: A round-bottom flask was charged with tert-butyl 3-{4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3-hydroxypyrrolidine-1-carboxylate (976 mg, 2.76 mmol), NIS (621 mg, 2.76 mmol), TFA (943 mg, 8.28 mmol), and a stir bar. DCM (20 mL) was added, and the solution was stirred at room temperature under nitrogen for 3 h. The mixture was quenched with saturated aqueous Na2S2O3 solution (10 mL) and extracted with DCM (3*40 mL). The organic phases were combined and dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by C18 Flash to give tert-butyl 3-{4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3-hydroxypyrrolidine-1-carboxylate (980 mg, 73.9%) as a white solid.

[1415] tert-Butyl 3-(4-chloro-7-methyl-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-hydroxypyrrolidine-1-carboxylate

[1416]

[1417] Step 3: A resealable reaction vial was charged with tert-butyl 3-{4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3-hydroxypyrrolidine-1-carboxylate (800 mg, 1.67 mmol), 2-methyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine (519 mg, 1.67 mmol), Pd(PPh3)2Cl2 (175 mg, 250 μmol), K3PO4 (1.06 g, 5.01 mmol), and a stir bar. DMF / H2O (25 mL) was added, and the solution was stirred at 50°C for 1 hour. The mixture was diluted with EtOAc (100 mL) and washed with water (3*50 mL), the organic phase was concentrated and the crude product was purified by C18 flash and further purified by preparative TLC using EA:PE=2:1 to give tert-butyl 3-(4-chloro-7-methyl-5-{4-[(6-methylpyridin-2-yl)oxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-hydroxypyrrolidine-1-carboxyla...

Claims

1. A compound of formula I-1, or a pharmaceutically acceptable salt thereof, wherein: Cy A yes in Indicates connection to R 5 The key and Indicates connection to Cy 6 Keys; R 5 Yes-R 5A -L 5 -R 5B ; R 5A YesR B A divalent group, except -L 5 -R 5B In addition, R 5A Also through m R 5C Instance replacement; R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement; Cy 6 is phenylene; a 3- to 14-membered saturated or partially unsaturated divalent carbocyclic ring; a 3- to 14-membered saturated or partially unsaturated divalent heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5- to 14-membered heteroarylene ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein except -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement; R W Is halogen, -CN, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or Two R's 6 Example, an R 6 Examples and an R L Example, an R 6 Examples and an R WA Example or an R 6 Examples and an R 7a Examples are taken together with their intervening atoms to form a 4- to 8-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is terminated by r R C Instance replacement; R 7 Is H or R B , where R 7 After t R 7A Instance replacement; R 8 is H, -NR2, halogen, -OH or C optionally substituted with 1 to 3 halogens 1-6 Fat; R 9 is H, -NR2, halogen or C optionally substituted with 1 to 3 halogens 1-6 Fat; R 10 is H or C optionally substituted by 1 to 3 halogens 1-6 Fat; L 5 and L 6 Each of 1-4 A saturated or unsaturated, linear or branched divalent hydrocarbon chain, wherein one or two methylene units in the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; wherein the C 3-6 Each of the cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is optionally substituted by one R A or C 1-6 Aliphatic instance substitution; R WA , R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R WA and R WB , R WB and R WC , R WA and an R L Example or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is terminated by w R C Instance replacement; R WD is halogen or -OS(O)2R; R 5C , R 5D , R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement; or Two R's 5C Example, an R 5C Examples and an R 5D Example or two R 5D Examples are taken together with their intervening atoms to form a 3- to 7-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is terminated by v R C Instance replacement; R A Each example of is independently a pendant oxy, 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; R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R C Each example of 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 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- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms 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.

2. The compound according to claim 1, wherein Cy A yes 3. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: R 5 Yes-R 5A -L 5 -R 5B ; R 5A YesR B A divalent group, except -L 5 -R 5B In addition, R 5A Also through m R 5C Instance replacement; R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement; Cy 6 is a phenylene group or a 6-membered heteroarylene group having 1 to 3 nitrogen atoms, wherein except for -L 6 -R W In addition, Cy 6 Also through p R 6 Instance replacement; R W Is halogen, -CN, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or Two R's 6 Example or an R 6 Examples and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is terminated by r R C Instance replacement; R 7 Is H or R B , where R 7 After t R 7A Instance replacement; L 5 and L 6 Each of 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; R WA , R WB and R WC Each of the following is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R WA and R WB , R WB and R WC , R WA and an R L Example or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R WD is halogen or -OS(O)2R; R 5C , R 5D , R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement; R A Each example of is independently a pendant oxy, 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; R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R C Each example of 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 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- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms 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.

4. The compound according to any one of claims 1 to 3, wherein -Cy 6 -L 6 -R W Combined together they are:

5. The compound according to any one of claims 1 to 4, wherein R 5 yes:

6. The compound according to any one of claims 1 to 4, wherein R 5 yes:

7. A compound of formula X-1, XI-1, XII-1 or XIII-1, or a pharmaceutically acceptable salt thereof, wherein: Cy A yes Among them, Cy A of Indicates a bond to: And Cy A of Indicates connection to Key; R 5B is hydrogen or R B , where R 5B After n R 5D Instance replacement; R W Is halogen, -CN, R 6 Each instance of is independently R A or R B , where R 6 After q R C Instance replacement; or Two R's 6 Example or an R 6 Examples and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is terminated by r R C Instance replacement; R 7 Is H or R B , where R 7 After t R 7A Instance replacement; R 8 is H, -NR2, halogen, -OH or C optionally substituted with 1 to 3 halogens 1-6 Fat; R 9 is H, -NR2, halogen or C optionally substituted with 1 to 3 halogens 1-6 Fat; R 10 is H or C optionally substituted by 1 to 3 halogens 1-6 Fat; L 5 and L 6 Each of 1-4 A saturated or unsaturated, linear or branched divalent 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- to 5-membered heterocycloalkylene, 5- to 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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; R WA , R WB and R WC Each of the following is independently hydrogen, deuterium, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R WA and R WB , R WB and R WC , R WA and an R L Example or R WC and an R L Examples are taken together with their intervening atoms to form a 4- to 7-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R WD is halogen or -OS(O)2R; R 5C , R 5D , R 7A and R L Each instance of is independently R A or R B , and after u R C Instance replacement; R A each example of is independently oxy, 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; R B Each instance of is independently C 1-6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R C Each example of 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 an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 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- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0 to 3 heteroatoms 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.

8. The compound according to any one of claims 1 to 7, wherein R W yes 9. The compound according to any one of claims 1 to 7, wherein R W yes 10. The compound according to any one of claims 1 to 9, wherein L 6 It is -NH-.

11. The compound according to any one of claims 1 to 10, wherein the compound is selected from those compounds shown in Table 1 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. A method of inhibiting FGFR2 signaling activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12.

14. A method for treating a FGFR2-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12.

15. A method of treating a disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12, 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.

16. The method of claim 15, wherein the disorder is bile duct cancer.

17. The method of claim 16, wherein the bile duct cancer is intrahepatic bile duct cancer.

18. The method of claim 15, wherein the disorder is liver cancer. The method of claim 18 , wherein the liver cancer is hepatocellular carcinoma.

20. The method of claim 15, wherein the disorder is lung cancer.

21. The method of claim 20, wherein the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

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