Compounds and methods for modulating HER2

Abstract

Disclosed herein are compounds of Formula (I): # imgabs0 # or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein R1, R2, A, E1, E2, and G are as described in any embodiment described in the disclosure; compositions thereof; and uses thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 373,172, filed on August 22, 2022, U.S. Provisional Patent Application No. 63 / 507,357, filed on June 9, 2023, and U.S. Provisional Patent Application No. 63 / 399,989, filed on August 22, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compounds, compositions thereof, and uses thereof that can be used to modulate Her2. Background Art

[0004] Her2 (also referred to herein as HER2) belongs to the epidermal growth factor receptor (EGFR) family. This family consists of four HER receptors: human epidermal growth factor receptor 1 (Her1) (also known as EGFR), Her2, human epidermal growth factor receptor 3 (Her3), and human epidermal growth factor receptor 4 (Her4). The Her2 receptor is an 185 kDa transmembrane protein encoded by the Her2 (also known as erb-b2 receptor tyrosine kinase 2 [ERBB2]) gene. Her2 is normally expressed at low levels on the cell membranes of epithelial cells in several organs such as the lung, breast, and skin, as well as in the gastrointestinal, reproductive, and urinary tracts. In Her2-positive cancer cells, the Her2 gene copy (gene amplification) and the number of Her2 receptors increase, with protein overexpression increasing up to 40-fold to 100-fold. The increase in the amount of cell surface Her2 receptors associated with Her2 overexpression leads to an increase in receptor-receptor interactions, triggering continuous tyrosine phosphorylation of the kinase domain and thus constantly activating the signaling pathway.

[0005] Tumors driven by Her2 mutations or Her2 wild-type overexpression can benefit from tyrosine kinase inhibitors targeting Her2. HER2+ mutations in NSCLC mainly affect the tyrosine kinase domain of Her2 and cluster in exon 20 of the ERBB2 gene. It is estimated that approximately 4% of lung cancer patients carry activating mutations in Her2 exon 20. Clinically approved ERBB-targeted tyrosine kinase inhibitors are ineffective in these patients because they are limited by EGFR wild-type-mediated dose-limiting toxicity. Afatinib and other pan-ERBB blockers have shown limited efficacy in NSCLC patients with HER2 exon 20 mutations, mainly due to limitations in achieving effective doses. In particular, EGFR wild-type-mediated toxicity limits the effective dose. Pan-ERBB inhibitors of mutant Her2 exon 20 include allitinib, ibrutinib, neratinib, poziotinib, and pyrotinib, all of which are limited by EGFR wild-type-mediated toxicity.

[0006] Irreversible Her2 tyrosine kinase inhibitors currently in clinical development include poziotinib and pyrotinib, both of which lack selectivity for Her2-mutated tumors compared to EGFR and have an adverse event profile consistent with EGFR-related toxicity. Specifically, patients receiving poziotinib experienced grade 3 rash, as well as other grade 3 adverse events that were difficult to tolerate, resulting in significant dose reduction. In addition, patients receiving pyrotinib also experienced various grade 3 adverse events, including an increase in bowel movements to 7 or more times per day, often requiring hospitalization.

[0007] In addition, Her2 YVMA insertion mutations account for approximately 65% of insertion mutations in NSCLC. To date, no tyrosine kinase has been approved for the treatment of non-small cell lung cancer with Her2 mutations.

[0008] Therefore, the medical need for novel compounds targeting Her2 has not been met, and the urgency for novel Her2 inhibitors that are more potent against wild-type Her2 and / or YVMA Her2 exon 20 insertion mutations than EGFR wild-type to overcome EGFR wild-type-mediated dose-limiting toxicity is even higher. Summary of the Invention

[0009] The present disclosure provides novel compounds that modulate wild-type and / or mutant Her2, such as the YVMA Her2 exon 20 insertion mutation. In another embodiment, the present disclosure provides novel compounds that inhibit wild-type and / or Her2 by irreversibly binding to the tyrosine kinase domain. In another embodiment, the compounds of the present disclosure selectively inhibit wild-type Her2 and / or mutant Her2 rather than wild-type EGFR, and thus have a lower EGFR-related toxicity burden. In another embodiment, the compounds of the present disclosure selectively inhibit the YVMA Her2 exon 20 insertion mutation rather than wild-type EGFR, and thus have a lower EGFR-related toxicity burden.

[0010] One embodiment of the present disclosure relates to a novel compound as described in any embodiment herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein these novel compounds can modulate Her2 (which is the same as HER2 for the purposes of the present disclosure). Another embodiment of the present disclosure relates to a novel compound as described in any embodiment herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein these novel compounds can modulate Her2 with a mutation such as the YVMA Her2 exon 20 insertion mutation (also referred to herein as the Her2 YVMA insertion mutation). Another embodiment of the present disclosure relates to a novel compound as described in any embodiment herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein these novel compounds can selectively inhibit wild-type Her2 and / or mutant Her2 (such as the Her2 YVMA insertion mutation) rather than wild-type EGFR.

[0011] Another embodiment of the present disclosure relates to a compound of formula (I):

[0012]

[0013] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein R 1 、R 2 、A、E 1 、E 2 and G are as described in any embodiment of the present disclosure (including any sub-embodiments thereof).

[0014] Other embodiments and sub-embodiments of formula (I) are further described in the present disclosure.

[0015] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to formula (I) or any embodiment and sub - embodiment of formula (I) described herein in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of these compounds, and a pharmaceutically acceptable carrier or excipient.

[0016] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to formula (I) or any embodiment of formula (I) described herein in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of these compounds, and another therapeutic agent.

[0017] Another embodiment of the present disclosure relates to a method for treating a subject suffering from a disease or condition that is at least partially mediated by Her2 (e.g., Her2 wild - type tumors, Her2 - mutated tumors, including Her2 with YVMA insertion mutation), the method comprising administering to the subject an effective amount of a compound according to formula (I) or any embodiment of formula (I) described herein in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of these compounds, or a pharmaceutical composition of any compound as described in the present disclosure.

[0018] Also provided herein is the use of a compound according to formula (I) or any embodiment of formula (I) described herein in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of these compounds, or a pharmaceutical composition of any compound as described in the present disclosure for treating a disease or condition mediated by Her2.

[0019] Additional embodiments are further described in the detailed description of the present disclosure. Detailed Description

[0020] I. Definitions

[0021] Unless otherwise clearly stated, the following definitions apply as used herein:

[0022] It is noted here that unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" as used herein and in the appended claims include plural references.

[0023] Unless otherwise indicated at the point of attachment, the chemical moieties listed in the variable definitions of formula (I) of the present disclosure and all of its embodiments should be read from left to right, where the right side is directly attached to the defined parent structure. However, if the point of attachment (e.g., a dash "-") is shown on a chemical moiety (e.g., -C1 - C6 alkyl - N(R 6) If on the left side of (2), the left side of this chemical part is directly attached to the defined parent part.

[0024] Assume that when considering the general description of the compounds described herein for the purpose of constructing compounds, such construction results in the creation of stable structures. That is, one of ordinary skill in the art will recognize that, in theory, some constructs generally would not be regarded as stable compounds (i.e., physically and / or synthetically viable in space).

[0025] "Alkyl", by itself or as part of another substituent, unless otherwise specified, means a straight-chain or branched-chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 means one to six carbons). Representative alkyl groups include straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Further representative alkyl groups include straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. For each definition herein (e.g., alkyl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, etc.), when not including a prefix to indicate the number of carbon atoms in the alkyl portion, the alkyl portion or a part thereof will have 12 or fewer backbone carbon atoms or 8 or fewer backbone carbon atoms or 6 or fewer backbone carbon atoms. For example, C 1- C6 alkyl refers to a straight-chain or branched-chain hydrocarbon having 1, 2, 3, 4, 5, or 6 carbon atoms, and includes, but is not limited to, -CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1- C2 alkyl, C2 alkyl, C3 alkyl, C 1- C3 alkyl, C 1- C4 alkyl, C 1- C5 alkyl, C 1- C6 alkyl, C 2- C3 alkyl, C 2- C4 alkyl, C 2- C5 alkyl, C 2- C6 alkyl, C 3- C4 alkyl, C 3- C5 alkyl, C 3- C6 alkyl, C 4- C5 alkyl, C 4- C6 alkyl, C 5- C6 alkyl and C6 alkyl. It is understood that substitutions are attached at any available atom to produce a stable compound.

[0026] "Alkylene", by itself or as part of another substituent, means a straight or branched chain saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., C 1- C6 means from one to six carbons; C 1- C6 alkylene is intended to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, etc.). C 1- C4 alkylene includes methylene -CH2-, ethylene -CH2CH2-, propylene -CH2CH2CH2- and isopropylidene -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2-(CH2)2CH2-, -CH2-CH(CH3)CH2-, -CH2-C(CH3)2-CH2-CH2CH(CH3)-. Generally, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with these groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. When not including a prefix to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or a portion thereof will have 12 or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms, or 3 or fewer main chain carbon atoms, or 2 or fewer main chain carbon atoms, or 1 carbon atom.

[0027] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group, where alkyl is as defined herein. By way of example, "C1-C6 alkoxy" refers to an -O-C1-C6 alkyl group, where alkyl is as defined herein. Although it will be understood that substitution on the alkoxy attaches to any available atom to produce a stable compound, substitution of the alkoxy is such that O, S or N (except when N is a heteroaryl ring atom) is not bonded to the alkyl carbon bonded to the alkoxy O. Further, when an alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bonded to a carbon atom of O, S, N (except when N is a heteroaryl ring atom) bonded to the other moiety, or to an olefinic or acetylenic carbon of the other moiety.

[0028] "Amino" or "amine" denotes the group NH2.

[0029] "Aryl", either by itself or as part of another substituent, unless otherwise specified, refers to a monocyclic, bicyclic, or polycyclic polyunsaturated aromatic hydrocarbon group containing 6 to 14 ring carbon atoms, which may be fused together or covalently linked monocyclic or polycyclic (up to three rings). However, aryl does not include heteroaryl as defined below or overlap with heteroaryl in any way. If one or more aryl rings are fused to a heteroaryl ring, the resulting ring system is heteroaryl. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term "arylene" refers to a divalent aryl, where aryl is as defined herein.

[0030] "Cycloalkyl" or "carbocyclic" or "carbocyclic-" either by itself or as part of another substituent, unless otherwise specified, refers to a saturated or partially unsaturated non-aromatic monocyclic, bridged, spiro, fused (e.g., bicyclic or tricyclic carbocyclic system), or cubane, having the number of carbon atoms indicated in the prefix, or if not specified, each ring having 3-6, 4-6, and 5-6 ring members, such as cyclopropyl, cyclopentyl, cyclohexyl, where one or two ring carbon atoms may optionally be replaced by a carbonyl group. Additionally, the term cycloalkyl is intended to include ring systems fused to an aromatic ring (e.g., of an aryl or heteroaryl), regardless of the point of attachment to the rest of the molecule. Cycloalkyl refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3- Both C6 cycloalkyl and 3-6 membered cycloalkyl are meant to have three to six ring carbon atoms). The term "cycloalkenyl" refers to a cycloalkyl having at least one unsaturated unit. Substituents of cycloalkyl or cycloalkenyl may be located at the point of attachment of the cycloalkyl or cycloalkenyl group to form a quaternary center.

[0031] "Halogen" or "halo" refers to all halogens, i.e., chlorine (Cl), fluorine (F), bromine (Br), or iodine (I).

[0032] "Heteroatom" is intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0033] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring group containing 5 to 9 ring atoms (also referred to in the present disclosure as a 5- to 9-membered heteroaryl, including a monocyclic aromatic ring group containing 5 or 6 ring atoms (also referred to in the present disclosure as a 5- to 6-membered heteroaryl), containing one or more, 14, 13 or 12 heteroatoms independently selected from O, S and N. Any aromatic ring or ring system containing at least one heteroatom is a heteroaryl regardless of the point of attachment (i.e., through any of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxides of tri-cyclic nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, phthalazinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzothienyl, quinolinyl, isoquinolinyl, indazolyl, pteridinyl, thiadiazolyl, triazolopyridinyl, imidazotriazinyl and pyrrolotriazinyl. "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one ring heteroatom is N.

[0034] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, where both terms are as defined herein.

[0035] The terms "heterocycle" or "heterocyclic ring" are interchangeable and include heterocycloalkyl rings, heterocycloalkenyl rings and heteroaryl rings as defined herein. A heterocycle can be a saturated ring, an unsaturated ring or an aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, P and S atoms. Heterocycles include 3- to 10-membered monocycles, 6- to 12-membered bicycles, 5- to 12-membered spirobicycles and 5- to 12-membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated bicyclic, unsaturated bicyclic and aromatic bicyclic.

[0036] The term "spirocycle" or "spiro group" refers to a group having two or more rings, where two rings are joined together by a single atom. Spiro groups can include carbocycles and heterocycles. In some embodiments, a spiro group can include 6 to 12 members between 2 or more rings. In some embodiments, a spiro group can include 6-12 atoms (i.e., C 6-12Spirocyclic cycloalkyl and 6-12 membered spiroheterocycloalkyl) In some embodiments, the spirocyclic group can include 7-11 atoms (i.e., 7-11 membered spirocycloalkyl or 7-11 membered spiroheterocycloalkyl) In some embodiments, the spirocyclic group can be bicyclic or tricyclic. Non-limiting examples of spirocyclic groups include: spiro[2,2]pentyl, spiro[3,2]hexyl, spiro[3,3]heptyl, spiro[4,3]octyl, spiro[4,2]heptyl, spiro[5,5]undecyl, spiro[6,3]decyl, spiro[6,5]dodecyl, azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, diazaspiro[3.3]heptyl, diazaspiro[3.4]octane, azaspiro[3.5]nonyl, oxaspiro[3.5]nonyl, thiaspiro[3.5]nonyl, azaspiro[4.5]decyl, and diazaspiro[5.5]undecyl. The term "spirocyclic group" can also be used herein to describe a cyclic substituent that is attached to another cyclic substituent such that a spiro ring is formed.

[0037] The term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group that contains one to five heteroatoms selected from N, O, S (including S(O) and S(O)2) or P (including phosphine oxides), where the nitrogen, sulfur, and phosphorus atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized, and the remaining ring atoms are C, where one or two C atoms can optionally be present as a carbonyl group. The heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring does not become aromatic due to their presence. Additionally, the term heterocycloalkyl is intended to include any ring or ring system that contains at least one heteroatom and is not a heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those having a ring with formally charge-separated aromatic resonance structures, e.g., N-methylpyridone groups. Heterocycloalkyl can be substituted with one or two oxo groups and can include sulfone and sulfoxide derivatives. Heterocycloalkyl can be a monocyclic, bridged ring system, fused bicyclic, or fused polycyclic system of 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, where one to five ring atoms are heteroatoms selected from –N=, -N-, -O-, -S-, -S(O)-, or –S(O)2-, and further where one or two ring atoms are optionally substituted with a -C(O)- group. By way of example, a 4-9 membered heterocycloalkyl is a heterocycloalkyl having 4 to 9 ring members with at least one heteroatom. Heterocycloalkyl can also be a heterocycloalkyl ring fused to a cycloalkyl. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, piperidine, morpholine, pyridone, pyrrolidine, azepane, 1,4-diazepane, azetidine, 8-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octene, and 3,9-diazabicyclo[4.2.1]nonane, etc. The heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon or heteroatom. "Heterocycloalkenyl" refers to a heterocycloalkyl having at least one unsaturated unit. Substituents of the heterocycloalkyl or heterocycloalkenyl can be located at the point of attachment of the heterocycloalkyl or heterocycloalkenyl group to form a quaternary center.

[0038] The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group. Examples include, but are not limited to, azetidinylmethyl, morpholinomethyl, etc.

[0039] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl as defined herein that is substituted with one or more halogen atoms.

[0040] The term "-C1-C4 alkylene-NR a R b " refers to a -C1-C4 alkylene that is attached to the parent moiety and is substituted with NR a R b .

[0041] The term "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group substituted with one or more hydroxyl groups as defined herein.

[0042] The term "-C0-C4 alkylene-C3-C7 cycloalkyl" refers to a -C0-C4 alkylene- attached to a parent moiety and substituted with a C3-C7 cycloalkyl group as defined herein.

[0043] The term "oxo" refers to C(=O) or (O). In some embodiments, two possible attachment points on a carbon form an oxo group.

[0044] "Hydroxyl" or "hydroxy" refers to the group OH. The terms "hydroxyalkyl" or "hydroxyalkylene" refer to an alkyl group or an alkylene group substituted with 1-5 hydroxyl groups as defined herein, respectively.

[0045] The term "substituent" is an atom or a group of atoms that substitutes for a hydrogen atom at a hydrogen atom of a parent molecule. Non-limiting examples of substituents in the present disclosure include J 4 , which may include monovalent or divalent substituents. A monovalent substituent is bonded to a parent moiety by substituting a single hydrogen atom of the parent moiety by a single bond. The hydrogen atom substituted by the monovalent substituent may be an available hydrogen atom of a carbon or nitrogen atom of the parent moiety. A divalent substituent is bonded to a parent moiety by substituting two available hydrogen atoms of the parent moiety by a double bond. It is understood that the substituents described in the present disclosure cannot be attached to the parent moiety in a manner that results in an unstable molecule.

[0046] As used throughout the present disclosure, the term "optional substituent" or "optionally substituted" means that substitution on a compound may or may not occur, and the description includes both the case where substitution occurs and the case where substitution does not occur. For example, the phrase "optionally substituted with 1-3 J 1 groups" means that J 1 groups may or may not be present. It is assumed in the present disclosure that optional substitution on a compound occurs in a manner that results in a stable compound.

[0047] As used herein in connection with the compounds of the present disclosure, the terms "synthesis" and similar terms mean chemical synthesis from one or more precursor materials.

[0048] As used herein, the term "composition" refers to a preparation suitable for administration to a desired animal subject for therapeutic purposes, which contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0049] The term "pharmaceutically acceptable" indicates that, taking into account the disease or condition to be treated and the corresponding route of administration, the indicated material does not have properties that would cause a reasonable and prudent medical practitioner to avoid administering the material to a patient. For example, such materials are typically required to be substantially sterile, e.g., for injectables.

[0050] "Pharmaceutically acceptable salts" refer to salts that are acceptable for administration to a patient (such as a mammal), e.g., salts having acceptable mammalian safety for a given dosage regimen. Pharmaceutically acceptable salt forms considered include, but are not limited to, mono-salts, di-salts, tri-salts, tetra-salts, etc. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without preventing it from exerting its physiological action. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug. Such salts can be derived from pharmaceutically acceptable inorganic bases or organic bases and from pharmaceutically acceptable inorganic acids or organic acids, depending on the specific substituents found on the compounds described herein.

[0051] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous solution or an aqueous-alcoholic solution containing a suitable acid, and then the salt can be isolated by evaporation of the solution. In another example, the salt can be prepared by reacting the free base and the acid in an organic solvent.

[0052] When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (i.e., primary, secondary, tertiary, quaternary amines or cyclic amines; alkali metal hydroxides; alkaline earth metal hydroxides, etc.), either in pure form or in a suitable inert solvent. The desired acids can be, for example, pyranosidic acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. In some embodiments, the salts can be derived from pharmaceutically acceptable acids, such as acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, aminosulfonic acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, pamoic acid, ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylaminosulfonic acid, quinic acid, alginic acid, hydroxybutyric acid, galactaric acid and galacturonic acid, etc.

[0053] Also included are salts of amino acids, such as arginine salts, etc., and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, for example, Berge, S.M. et al., “Pharmaceutical Salts,” J. Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, allowing the compounds to be converted into base addition salts or acid addition salts.

[0054] The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and separating the parent compound in a conventional manner. The parent form of the compound differs in certain physical properties from the various salt forms, such as solubility in polar solvents, but for the purposes of the present disclosure, the salt and the parent form of the compound are equivalent in other respects.

[0055] Pharmaceutically acceptable salts of different compounds can exist in the form of complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, for example, dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.

[0056] As used herein, either alone or as part of a group, the term "deuterated" means a substituted deuterium atom. As used herein, either alone or as part of a group, the term "deuterated analogue" refers to a substituted deuterium atom that replaces hydrogen. The deuterated analogues of the present disclosure can be fully or partially deuterium-substituted derivatives. In some embodiments, the deuterium-substituted derivatives of the present disclosure contain fully or partially deuterium-substituted alkyl, aryl, or heteroaryl groups.

[0057] The present disclosure also includes isotopically labeled compounds of the present disclosure, which are identical to the compounds described herein, but with one or more atoms replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen with its natural abundance isotopic composition or its isotopes, such as deuterium (D) or tritium ( 3 H). Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with 3 H and 14 C) can be used for compound and / or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) and fluorine-18 ( 18 F) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2H) Substitution can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements) and can thus be preferred in some cases. The isotopically labeled compounds of the present disclosure can generally be prepared by substituting a non-isotopically labeled reagent with an isotopically labeled reagent by procedures similar to those described in the schemes and examples below.

[0058] "Prodrug" means any compound that, when administered to a subject, releases the active parent drug according to formula (I) in vivo. Prodrugs of the compounds of formula (I) are prepared by modifying the functional groups present in the compounds of formula (I) in a conventional manner or in vivo in such a way that the modification can be cleaved in vivo to release the parent compound. A prodrug can be converted from the prodrug form to the active form in a single step or can have one or more intermediate forms that can themselves be active or inactive. Some prodrugs are enzymatically activated to produce the active compound or compounds that are active in a further chemical reaction. Prodrugs include compounds of formula (I) in which a hydroxyl, amino, carboxyl, or thiol group in the compound of formula (I) is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, or thiol group. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc. of the hydroxyl functional group in the compound of formula (I). Other examples of prodrugs include, but are not limited to, carbonates, acylureas, solvates, or hydrates of the active compound. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," volume 14 of the A.C.S. Symposium Series; "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0059] As discussed in The Practice of Medicinal Chemistry, Chapters 31-32 (edited by Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can conceptually be divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, contain one or more protective groups, and are converted to the active form by metabolism or solvolysis. The active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of the active drug compound involves a metabolic process or reaction of one of the following types:

[0060] (1) Oxidation reactions: Examples of oxidation reactions are not limited to the oxidation of functional groups such as alcohols, carbonyls, and acids, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O-dealkylation, and S-dealkylation, oxidative deamination reactions, and other oxidation reactions.

[0061] (2) Reduction reactions: Examples of reduction reactions are not limited to the reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

[0062] (3) Reactions that do not change the oxidation state: Examples of reactions that do not change the oxidation state are not limited to hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, formation of new atomic bonds by dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecules, and other such reactions.

[0063] A prodrug is a pharmaceutical compound that contains a transport moiety, such as one that improves uptake and / or local delivery to the site of action. For such prodrugs, it is desirable that the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the pharmaceutical compound, and the prodrug and any released transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, generally the release of the transport moiety should be rapid. In other cases, it is desirable to utilize moieties that provide slow release, such as certain polymers or other moieties, such as cyclodextrins. (See, e.g., Cheng et al., U.S. Patent Publication No. 2004 / 0077595, incorporated herein by reference.) Such prodrugs are generally advantageous for oral administration of pharmaceuticals. Prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological action, increased site specificity, reduced toxicity and adverse reactions, and / or improvement of pharmaceutical formulations (e.g., stability, water solubility, suppression of undesirable sensory or physicochemical properties). For example, lipophilicity can be increased by esterification of a hydroxyl group with a lipophilic carboxylic acid, or esterification of a carboxylic acid group with an alcohol (e.g., a fatty alcohol).

[0064] The term "carrier" is also intended to include microspheres, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, such as exosomes), etc. It is well known that exosomes can be efficient pharmaceutical carriers, and drugs can be loaded into exosomes in a variety of ways, including those described in J Control Release. December 10, 2015; 219:396–405, the content of which is incorporated herein by reference in its entirety.

[0065] Metabolites, such as active metabolites, overlap with prodrugs, such as bioprecursor prodrugs, as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in an object's body. Among them, active metabolites are derivative compounds with pharmacological activity. For prodrugs, the prodrug compound is generally inactive or less active than the metabolite. For active metabolites, the parent compound can be an active compound or can be an inactive prodrug.

[0066] Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, e.g., Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230.

[0067] "Tautomer" means a compound produced by the phenomenon of proton transfer of an atom of a molecule to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 14th Edition, John Wiley & Sons, pages 69 - 74 (1992). A tautomer is also one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. Examples include keto - enol tautomers such as acetone / prop - 2 - en - 1 - ol, imine - enamine tautomers, etc., ring - chain tautomers such as glucose / 2,3,4,5,6 - pentahydroxyhexanal, and tautomeric forms of heteroaryl groups containing the - N = C(H)-NH - ring atom arrangement such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Tautomeric isomerism ("tautomerism") can occur when a compound contains, for example, a keto or oxime group or an aromatic moiety. The compounds described herein can have one or more tautomers and thus include various isomers. Those of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in this disclosure.

[0068] "Isomer" means a compound having the same molecular formula but different in the nature or sequence of its atomic bonding or the arrangement of its atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms, e.g., if they have one or more asymmetric centers or have asymmetrically substituted double bonds, they can thus be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, e.g., an atom such as carbon is bonded to four different groups, a pair of enantiomers may be formed. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R-sequencing rules and S-sequencing rules of Cahn and Prelog, or can be characterized by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+)-isomers or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". As another example, stereoisomers include geometric isomers, such as the cis or trans orientation of substituents on adjacent carbons of a double bond. Unless otherwise specified, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 6th Edition, J. March, John Wiley and Sons, New York, 2007), and differ in terms of the chirality at one or more stereocenters.

[0069] In the context of using, testing, or screening a compound that is or can be a modulator, the term "contact" means bringing the compound into sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other particular material such that a potential binding interaction and / or chemical reaction can occur between the compound and the other particular material.

[0070] "Assay" means creating experimental conditions and collecting data regarding a specific outcome upon exposure to the specific experimental conditions. For example, an enzyme can be assayed based on its ability to act on a detectable substrate. A compound can be assayed based on its ability to bind to a specific target molecule or molecules.

[0071] As used herein, the terms "ligand" and "modulator" are used interchangeably to refer to a compound that alters (i.e., increases or decreases) the activity of a target biomolecule, e.g., an enzyme, such as those described herein. In general, a ligand or modulator will be a small molecule, where "small molecule" refers to a compound having a molecular weight of 1500 daltons or less, 1000 daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an "improved ligand" is a ligand having better pharmacological and / or pharmacokinetic properties than a reference compound, where "better" can be defined by one of ordinary skill in the art for a particular biological system or therapeutic use.

[0072] The term "binding" relates to the interaction between a target and a potential binding compound, indicating that the potential binding compound associates with the target to a statistically significant extent compared to association with a protein in general (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that has a statistically significant association with a target molecule. In some embodiments, the binding compound interacts with a specific target with a dissociation constant (K D ) of 10 mM or less, 1,000 μM or less, 5000 nM or less, 3000 nM or less, 1500 nM or less, 1,000 nM or less, 500 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, or 25 nM or less.

[0073] The term "selective" indicates that a compound binds more tightly than a reference compound, or binds more tightly than the same compound under reference conditions, i.e., has a lower dissociation constant. Certain compounds of the present disclosure selectively inhibit wild-type Her2 and / or mutant Her rather than wild-type EGFR, thereby reducing EGFR dose-limiting toxicity.

[0074] In some embodiments, the greater affinity of one or more of the compounds in Table 1 is at least 1.5, 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity. Certain compounds of the present disclosure selectively inhibit wild-type Her2 and / or mutant Her rather than wild-type EGFR, thereby reducing EGFR dose-limiting toxicity.

[0075] The terms "modulate", "modulation", etc. refer to the ability of a compound to increase or decrease a target function and / or expression, such as the interaction between Her2 (including its mutant forms), where such functions can include transcriptional regulatory activity and / or binding. Modulation can occur in vitro or in vivo. As described herein, modulation includes directly or indirectly inhibiting, antagonizing, partially antagonizing, activating, agonizing or partially agonizing a function or characteristic associated with Her2, and / or directly or indirectly upregulating or downregulating the expression of Her2. In another embodiment, the modulation is direct. An inhibitor or antagonist is, for example, a compound that binds to, partially or completely blocks, stimulates, reduces, prevents, inhibits, delays activation, inactivates, desensitizes or downregulates signal transduction. An activator or agonist is, for example, a compound that binds to, stimulates, increases, opens, activates, promotes, enhances activation, activates, sensitizes or upregulates signal transduction. In another example, a compound that modulates Her2 can inhibit Her2 by irreversibly or covalently binding to the Her2 tyrosine kinase. In another example, a compound that modulates Her2 can inhibit Her2 by reversibly or non-covalently binding to the Her2 tyrosine kinase.

[0076] As used herein, the terms "treat", "treating", "therapy", "therapies" and like terms refer to administering a material in an amount effective to inhibit Her2 (including wild-type Her2 and mutant Her2, such as Her2 with a YVMA insertion mutation), for example, any one or more of the compounds described herein. In other embodiments of the present disclosure, these terms apply to administering the compounds of the present disclosure to a subject having a disease state associated with Her2 overexpression and / or HER2 amplification. In other embodiments, the terms "treat", "treating", "therapy", "therapies" and like terms refer to administering a material in an amount effective to prevent, alleviate or improve one or more symptoms of a disease or condition (i.e., an indication) and / or extend the survival period of the treated subject, for example, any one or more of the compounds described herein. In other embodiments of the present disclosure, these terms apply to administering the compounds of the present disclosure to a subject having a disease state associated with Her2 overexpression and / or HER2 amplification.

[0077] As used herein, the terms "prevent", "preventing", "prevention" and their grammatical variants refer to methods of partially or completely delaying or precluding the onset or recurrence of a disease, disorder or condition and / or one or more of its attendant symptoms, or of preventing a subject from acquiring or reacquiring a disorder or condition, or of reducing the risk that a subject will acquire or require a disorder or condition or one or more of its attendant symptoms.

[0078] As used herein, the terms "subject", "animal subject", etc. refer to a living organism, including but not limited to humans and non-human vertebrates, e.g., any mammal such as a human, other primates, sports animals and animals of commercial interest such as cows, horses, sheep or pigs, rodents or pets such as dogs and cats.

[0079] A "unit dosage form" is a composition designed for single administration to a subject suffering from a disease or medical condition. Each unit dosage form generally contains each active ingredient of the present disclosure plus a pharmaceutically acceptable excipient. Examples of unit dosage forms are single tablets, single capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions or suspensions. Treating a disease or condition may require regular administration of unit dosage forms, e.g., one unit dosage form two or more times a day, once per meal, once every four hours or other intervals, or only once a day. The expression "oral unit dosage form" denotes a unit dosage form designed for oral administration.

[0080] The term "administer" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a slow release device, e.g., a mini osmotic pump, into a subject. Administration is by any route, including parenterally and transmucosally (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery modes include but are not limited to use of liposomal formulations, intravenous infusions, transdermal patches, etc.

[0081] In the present context, the term "therapeutically effective" or "effective amount" indicates that the compound or material or amount of the compound or material is sufficient or effective, when administered, to prevent, alleviate or ameliorate one or more symptoms of the disease, disorder or medical condition being treated, and / or to prolong the survival of the subject being treated. A therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity, and the age, weight, etc. of the mammal to be treated. Generally speaking, a satisfactory outcome in a subject is indicated as being obtained at a daily dose of from about 0.1 to about 10 g / kg of the subject's body weight. In some embodiments, the daily dose ranges from about 0.10 to 10.0 mg / kg of body weight, from about 1.0 to 3.0 mg / kg of body weight, from about 3 to 10 mg / kg of body weight, from about 3 to 150 mg / kg of body weight, from about 3 to 100 mg / kg of body weight, from about 10 to 100 mg / kg of body weight, from about 10 to 150 mg / kg of body weight or from about 150 to 1000 mg / kg of body weight. The dose can be administered conveniently, for example, in sub-doses up to four times a day or in a sustained release form.

[0082] As used herein, the term "Her2-mediated disease or condition" (which is also intended to mean "disease or condition mediated by Her2" and "disease or condition mediated by wild-type Her2 and / or mutant Her2") refers to a disease or condition in which the biological function of Her2 affects the development and / or course of the disease or condition, and / or a disease or condition in which the regulation of Her2 interactions alters the development, course and / or symptoms. Her2-mediated diseases or conditions include those diseases or conditions in which interrupting Her2 interactions (e.g., by suppressing Her2 with a YVMA insertion mutation) provides a therapeutic benefit, e.g., in which treatment with a Her2 inhibitor (including the compounds described herein) provides a therapeutic benefit to a subject having or at risk of having the disease or condition. Her2-mediated diseases or conditions are intended to include cancers or tumors harboring loss-of-function mutations in Her2, or cancers in which Her2 is activated. In other embodiments of the present disclosure, Her2-mediated diseases or conditions are associated with Her2 overexpression and / or Her2 amplification. Her2-mediated diseases or conditions are also intended to include various human carcinomas, including lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma, and any associated comorbidities, such as pulmonary disorders, hypertension, hypercholesterolemia, cardiovascular disease, renal function disorders, thyroid disorders, obesity, depression anxiety, osteoporosis, liver disorders, autoimmune diseases, dementia, Alzheimer's disease.

[0083] Also in the context of a compound binding to a biomolecular target, the term "greater specificity" indicates that a compound binds to a specific target to a greater extent than one or more other biomolecules that can be present under relevant binding conditions, where binding to such other biomolecules results in a different biological activity than binding to the specific target. Typically, the specificity is with respect to a limited set of other biomolecules, e.g., in the case of Her2 or Her2+ mutations. In certain embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 20, 50, 100, 200, 400, 500, or 1000-fold greater specificity.

[0084] As used herein in connection with a binding compound or ligand, the term "specific for Her2" (which is intended to include wild-type Her2, mutant Her2, or both wild-type Her2 and mutant Her2) and terms of similar import mean that a particular compound binds to Her2 to a statistically greater extent than to other targets, such as wild-type EGFR, that may be present in a particular sample. Further, in instances where a biological activity other than binding is indicated, the term "specific for Her2" indicates that the biological effect associated with binding to Her2 that a particular compound has is greater than the biological effect with other enzymes, e.g., enzyme activity inhibition.

[0085] The term "first-line cancer therapy" refers to a therapy administered to a subject as an initial regimen for reducing the number of cancer cells. First-line therapy is also referred to as induction therapy, initial therapy, and primary treatment. First-line therapy can be administered in combination with one or more agents. A summary of the currently accepted methods of first-line treatment for certain diseases can be found in the NCI guidelines for such diseases.

[0086] The term "second-line cancer therapy" refers to cancer treatment administered to a subject who is non-responsive to first-line therapy, i.e., who typically has received first-line therapy or in whom cancer has recurred after remission. In certain embodiments, second-line therapies that can be administered include repeating an initially successful cancer therapy, which can be any of the treatments described under "first-line cancer therapy". A summary of the currently accepted methods of second-line treatment for certain diseases is described in the NCI guidelines for such diseases.

[0087] The term "refractory" means that a subject fails to respond to or otherwise is resistant to a cancer therapy or treatment. The cancer therapy can be first-line, second-line, or any subsequent treatment administered. In certain embodiments, refractory means that a subject fails to achieve a complete remission after two induction attempts. A subject can be refractory due to intrinsic resistance of the cancer cells to a particular therapy, or a subject can be refractory due to acquired resistance that develops during a particular therapy.

[0088] In addition, the abbreviations used herein have the following respective meanings:

[0089]

[0090]

[0091] II. Compound

[0092] Embodiment 1 of the present disclosure relates to a compound having the formula (I):

[0093]

[0094] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0095] A is N or CH;

[0096] E 1 is N or C(CN);

[0097] E 2 is C(R 4 ) or N;

[0098] R 1 is alkyl, haloalkyl or halogen;

[0099] R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -O-heteroaryl-alkylene-aryl, -NH-alkyl, -NH-aryl or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl moieties is optionally substituted with 1-4 J 1 groups;

[0100] or R 1 and R 2 together with the carbon atom to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted with 1-4 J 1 groups;

[0101] G is -L 1 -R 3 , L 1a -R 3a or -W-X-Y;

[0102] L 1 is a bond, -C(O)-, -S(O)2-, -N(R c ), alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein each of the alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is optionally substituted with 1-4 J 2 groups, provided that when L 1When it is CH2, L 1 is a carbon or nitrogen not attached to a saturated ring;

[0103] L 1a is -C0-C6 alkylene-C(O)N(H)-, -C0-C6 alkylene-S(O)2N(H)-;

[0104] R 3 is a 4-9 membered heterocycle containing at least one nitrogen ring atom, where R 3 is optionally substituted by 1-4 J 3 groups, and where one nitrogen atom of R 3 is substituted by -L 2 -R;

[0105] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, where the 7-11 membered spiro group containing at least one nitrogen ring atom is optionally substituted by 1-4 J 3 groups, and where one nitrogen atom of the 7-11 membered spiro group is substituted by -L 2 -R;

[0106] R 3a is optionally substituted by 1-4 J 2 groups and is C1-C6 alkylene-NR a R b ;

[0107] W is a bond, -C(O)- or -S(O)2-;

[0108] X is aryl, heteroaryl, heterocycloalkyl or cycloalkyl, each of which is optionally substituted by 1-4 J 2 groups;

[0109] Y is -C0-C4 alkylene-N(R d ))-L 2 -R, -C(O)-4-7 membered heterocycloalkyl containing at least one nitrogen atom and substituted by 1-2 oxo groups, -4-7 membered heterocycloalkyl-L 2R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4 ethenyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the C0-C4 alkylene moiety is optionally substituted by 1-4 groups independently selected from halogen, cycloalkyl, alkoxyalkoxyalkyl or hydroxy;

[0110] R 4 is H, halo, alkyl or -O-alkyl;

[0111] L 2 is -SO2- or -C(O)-;

[0112] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q, C1-C4 alkylene-NR a R b 、-CH2-CN or a haloalkyl in which one halogen of the haloalkyl is on the carbon atom adjacent to L 2 ;

[0113] Each Q is independently selected from halogen, haloalkyl, alkyl, -C1-C6 alkylene-NR a R b 、cyano, hydroxyalkyl, -C0-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-alkyl, alkoxyalkyl, -C0-C4 alkylene-cycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-cycloalkenyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spirocycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheteroalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-heteroalkyl optionally substituted by 1-3 J 4 groups and -C0-C4 alkylene-aryl optionally substituted by 1-3 J 4Group-substituted -C0-C4 alkylene-heterocyclenyl;

[0114] or -L 2 -R is -C=N-OH;

[0115] Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy and alkoxyalkyl;

[0116] Each J 2 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl;

[0117] Each J 3 is attached to a carbon atom and is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl, or two of said optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optional 1-4 J 3 groups are on different ring carbons and together form a 1-3 carbon bridge;

[0118] Each J 4 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0119] R a and R b are each independently selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and -C0-C3 alkylene-alkynyl optionally substituted by alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; and

[0120] R c is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally substituted by 1-3 groups selected from halogen, alkyl, alkoxy and alkoxyalkyl; and

[0121] R d is selected from H, alkyl and haloalkyl.

[0122] Embodiment 1(a) of the present disclosure relates to a compound according to Embodiment 1, wherein G is -L1 -R 3 。

[0123] Embodiment 1(b) of the present disclosure relates to a compound according to Embodiment 1, wherein G is -L 1a -R 3a 。In other embodiments of Embodiment 1(b), L 1a is C0-C3 alkylene-C(O)N(H)-. In other aspects of Embodiment 1(b), R 3 is -C1-C4 alkylene-NR a R b wherein R a and R b are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In other aspects of Embodiment 1(b), R 3 is -C1-C3 alkylene-NR a R b wherein: R a and R b are each C1-C3 alkyl.

[0124] Embodiment 1(c) of the present disclosure relates to a compound according to Embodiment 1, wherein G is -W-X-Y

[0125] Embodiment 2 of the present disclosure relates to a compound according to Embodiment 1, wherein:

[0126] R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen;

[0127] R 2 is -O-(5-10 membered) aryl, -O-(5-10 membered) heteroaryl, -O-(4-7 membered) cycloalkyl, -O-(4-7 membered) heterocycloalkyl, -O-(5-10 membered) heteroaryl-C1-C4 alkylene-phenyl, -NH-(5-10 membered) aryl, or -NH--(5-10 membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties is optionally substituted with 1-3 J 1 groups;

[0128] or R 1 and R 2 together with the carbon atom to which they are attached form a ring selected from 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, wherein each ring is optionally substituted with 1-3 J 1 groups;

[0129] G is -L 1 -R 3or -W-X-Y;

[0130] L 1 is a bond, -C(O)-, -S(O)2-, -N(H)-, -N(C1-C6 alkyl)-, C1-C3 alkylene, 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl or 4-7 membered cycloalkyl, wherein the C1-C3 alkylene, 5-10 membered aryl, 5-10 membered heteroaryl, 5-7 membered heterocycloalkyl and 5-7 membered cycloalkyl are each optionally substituted by 1-3 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to the carbon or nitrogen of a saturated ring;

[0131] R 3 is a 4-7 membered heterocycle containing at least one nitrogen ring atom, wherein the 4-7 membered heterocycle containing at least one nitrogen ring atom is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of the 4-7 membered heterocycle is substituted by -L 2 -R;

[0132] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, wherein the 7-11 membered spiro group is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R;

[0133] W is a bond, -C(O)- or -S(O)2-;

[0134] X is 5-10 membered aryl, 5-10 membered heteroaryl, 5-7 membered heterocycloalkyl or 5-7 membered cycloalkyl, wherein the 5-10 membered aryl, 5-10 membered heteroaryl, 5-7 membered heterocycloalkyl and 5-7 membered cycloalkyl are optionally substituted by 1-3 J 2 groups;

[0135] Y is -C0-C4 alkylene-N(R d )-L 2 -R, a -C(O)-4-6 membered heterocycloalkyl containing one nitrogen atom and substituted by 1-2 oxo groups, -4-7 membered heterocycloalkyl-L 2R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4 ethynyl, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the -C0-C4 alkylene moiety is optionally independently substituted by 1-4 groups selected from halogen, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl-C1-C6 alkoxy or hydroxy;

[0136] R 4 is H, halo, C0-C4 alkyl or -O-C0-C4 alkyl;

[0137] L 2 is -SO2- or -C(O)-;

[0138] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q, C1-C4 alkylene-NR a R b 、-CH2-CN or C1-C6 haloalkyl, wherein one halogen of the C1-C6 haloalkyl is on the carbon atom adjacent to L 2 ;

[0139] Each Q is independently selected from halogen, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b 、cyano, C1-C6 hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-C1-C6 alkyl, -C1-C4 alkylene-C1-C6 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkenyl optionally substituted by 1-3 J 4Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkyl and optionally substituted by 1-3 Js 4 Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkenyl;

[0140] Or -L 2 -R is -C=N-OH;

[0141] Each J 1 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0142] Each J 2 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0143] Each J 3 Attached to the carbon atom of R 3 And independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy, or two of the optionally 1-4 Js 3 Groups form an oxo group or a 3-6-membered spiro group, or two of the optionally 1-4 Js 3 Groups are on different ring carbons and together form a 1-3 carbon bridge;

[0144] Each J 4 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 Groups can only include at most two oxo groups and at most one -C0-C4 alkylene-NR a R b Groups;

[0145] R a And R b Each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy and C0-C3 alkylene-C2-C6 alkynyl optionally substituted by alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C1-C6 alkoxy C1-C6 alkyl; And

[0146] R c selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl; and

[0147] R d selected from H, C1-C6 alkyl and C1-C6 haloalkyl.

[0148] Embodiment 3 of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has one of the following formulas:

[0149]

[0150] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds. Another aspect of Embodiment 3 of the present disclosure relates to a compound according to any one of Embodiments 1 or 2, which has one of the formulas (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof. Embodiment 4 of the present disclosure relates to Embodiment 3, which has formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa) or (IIb).

[0151] Embodiment 4(a) of the present disclosure relates to Embodiment 4, which has formula (IIa) or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa).

[0152] Embodiment 4(b) of the present disclosure relates to Embodiment 4, which has formula (IIb) or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIb).

[0153] Embodiment 5 of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has one of the following formulas:

[0154]

[0155] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds. Another aspect of Embodiment 5 of the present disclosure relates to a compound according to any one of Embodiments 1 or 2, which has one of the formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof.

[0156] Embodiment 5(a) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIIa).

[0157] Embodiment 5(b) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIIb).

[0158] Embodiment 5(c) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIIc).

[0159] Embodiment 5(d) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIId).

[0160] Embodiment 5(e) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIIe).

[0161] Embodiment 5(f) of the present disclosure relates to a compound according to any one of Embodiments 1, 1(a), 1(b), 1(c) or 2, which has the formula (IIIf).

[0162] Embodiment 6 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4(a), 4(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein G is -L 1 -R 3 . Another aspect of Embodiment 6 of the present disclosure relates to any one of Embodiments 1, 2, 3, 4 or 5, wherein G is -L 1 -R 3 . Embodiment 7 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4(a), 4(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f) or 6, wherein G is

[0163] Wherein:

[0164] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl are each optionally substituted by 1-2 J 2 groups, provided that when L 1 is CH2, Z 1 is not CH2 or N;

[0165] L 2 is -SO2- or -C(O)-;

[0166] Z 1 is -N(H)-, -C(R 5 )- or a 4-7 membered spiro ring group optionally containing 1-2 nitrogen atoms;

[0167] R 5 is H, halogen, C1-C3 alkyl or CN;

[0168] Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, wherein -C1-C3 alkylene and -C2-C3 alkenylene are each optionally substituted by 1-4 J 3 groups;

[0169] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q groups, C1-C4 alkylene-NR a R b , -CH2-CN or C1-C4 haloalkyl, wherein one halogen of C1-C4 haloalkyl is on the carbon atom adjacent to L 2 ;

[0170] Each Q is independently selected from halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b , -C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted by 1-3 J 4Group-substituted -C0-C4 alkylene-7-11-membered spiroheterocycloalkyl, optionally substituted by 1-3 J 4 Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkyl and optionally substituted by 1-3 J 4 Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkenyl;

[0171] Each J 2 Independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and -C1-C4 alkyl-C1-C4 alkoxy;

[0172] Each J 3 Independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and -C1-C4 alkyl-C1-C4 alkoxy, or two of the optionally 1-4 J 3 Groups form an oxo group or a 3-6-membered spiro group, or two of the optionally 1-4 J 3 Groups are on different ring carbon atoms and together form a 1-3 carbon bridge; and

[0173] Each J 4 Independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo, and -C0-C4 alkylene-NR a R b , provided that the J 4 Group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b Group. Another aspect of embodiment 7 of the present disclosure relates to any one of embodiments 1, 2, 3, 4, 5, or 6, wherein G is

[0174] Wherein:

[0175] L 1 Is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocycloalkyl, or 4-6-membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocycloalkyl, or 4-6-membered cycloalkyl is each optionally substituted by 1-2 J 2 Groups, provided that when L 1 Is CH2, Z 1 Is not CH2 or N;

[0176] L 2is -SO2- or -C(O)-;

[0177] Z 1 is -N(H)-, -C(R 5 )- or a 4- to 7-membered spirocyclic group optionally containing 1 to 2 nitrogen atoms;

[0178] R 5 is H, halogen, C1-C3 alkyl or CN;

[0179] Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, wherein -C1-C3 alkylene and -C2-C3 alkenylene are each optionally substituted by 1 to 4 J 3 groups;

[0180] R is vinyl optionally substituted by 1 to 3 Q groups, ethynyl optionally substituted by Q groups, -CH2-CN or C1-C4 haloalkyl, wherein one halogen of C1-C4 haloalkyl is on the carbon atom adjacent to L 2 ;

[0181] Each Q is independently selected from halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b , -C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 1 to 3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 1 to 3 J 4 groups, -C0-C4 alkylene-7- to 11-membered spirocyclic heteroalkyl optionally substituted by 1 to 3 J 4 groups, -C0-C4 alkylene-4- to 7-membered heteroalkyl optionally substituted by 1 to 3 J 4 groups and -C0-C4 alkylene-4- to 7-membered heteroalkenyl optionally substituted by 1 to 3 J 4 groups;

[0182] Each J 2 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy;

[0183] Each J 3Independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and -C1-C4 alkyl-C1-C4 alkoxy, or two of said optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optional 1-4 J 3 groups are on different ring carbon atoms and together form a 1-3 carbon bridge; and

[0184] Each J 4 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo, and -C0-C4 alkylene-NR a R b , provided that the J 4 group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group.

[0185] Embodiment 8 of the present disclosure relates to the compound according to Embodiment 7, wherein G is

[0186] wherein:

[0187] Z 1 is -N(H)-, -C(R 5 )-, or a 4-6 membered spiro group optionally containing 1-2 nitrogen atoms;

[0188] R 5 is H, halogen, C1-C3 alkyl, or CN;

[0189] Z 2 is -C1-C3 alkylene or -C2-C3 alkenylene, each of which is optionally substituted by 1-2 J 3 groups;

[0190] Z 3 is -C1-C2 alkylene optionally substituted by 1-2 J 3 groups;

[0191] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q groups, C1-C4 alkylene-NR a R b , -CH2-CN, or C1-C3 haloalkyl, wherein one halogen of the C1-C3 haloalkyl is on the carbon atom adjacent to -C(O)-;

[0192] Each Q is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b 、-C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C(O)OH, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C0-C3 alkylene-C1-C3 alkoxy, -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C3 alkylene-4-6 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups;

[0193] Each J 2 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy;

[0194] Each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy, or two of the optional J 3 groups are on different ring carbon atoms and together form a 1-2 carbon bridge and

[0195] Each J 4 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C1-C3 alkyl-C1-C3 alkoxy, oxo and -C0-C3 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C3 alkylene-NR a R b group.

[0196] Embodiment 9 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4(a), 4(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f) or 6, wherein R 3 is

[0197]

[0198] which contains R 3 said heterocycle containing at least one nitrogen ring atom of R is optionally substituted by 1 - 3 J 3 groups; and

[0199] each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy.

[0200] Another aspect of Embodiment 9 relates to a compound according to any one of Embodiments 1 - 6, wherein R 3 is

[0201]

[0202]

[0203] which contains R 3 said heterocycle containing at least one nitrogen ring atom of R is optionally substituted by 1 - 3 J 3 groups; and

[0204] each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy.

[0205] Embodiment 9(a) of the present disclosure relates to a compound according to Embodiment 9, wherein R 3 is

[0206] Embodiment 9(b) of the present disclosure relates to a compound according to Embodiment 9, wherein R 3 is

[0207] Embodiment 9(c) of the present disclosure relates to a compound according to Embodiment 9, wherein R 3 is

[0208] Embodiment 9(d) of the present disclosure relates to a compound according to Embodiment 9, wherein R 3 is

[0209] Embodiment 9(e) of the present disclosure relates to a compound according to Embodiment 9, wherein R 3 is

[0210] Embodiment 9(f) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0211] Embodiment 9(g) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0212] Embodiment 9(h) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0213] Embodiment 9(i) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0214] Embodiment 9(j) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0215] Embodiment 9(k) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0216] Embodiment 9(l) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0217] Embodiment 9(m) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0218] Embodiment 9(n) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0219] Embodiment 9(o) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0220] Embodiment 9(p) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is

[0221] Embodiment 9(q) of the present disclosure relates to the compound according to Embodiment 9, wherein R 3 is Embodiment(s) 9(s) of the present disclosure relate to a compound according to Embodiment 9, wherein R 3 is

[0222] Embodiment(s) 9(t) of the present disclosure relate to a compound according to Embodiment 9, wherein R 3 is

[0223] Embodiment 10 of the present disclosure relates to a compound according to any one of Embodiments 1-5, wherein G is -X-Y.

[0224] Embodiment 11 of the present disclosure relates to a compound according to Embodiment 10, wherein X is a 5-10 membered heteroaryl optionally substituted with 1-3 J 2 groups and Y is -C0-C4 alkylene-N(H)-L 2 -R.

[0225] Embodiment 12 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4(a), 4(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 6, 7, 8, 9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(l), 9(m), 9(n), 9(o), 9(p), 9(q), 9(r), 9(s), 9(t) or 11, wherein R is a vinyl optionally substituted with 1-2 groups independently selected from: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b 、-C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with 1-3 J 4 groups, -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with 1-3 J 4 groups, -C1-C3 alkylene-4-6 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C1-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0226] Another aspect of Embodiment 12 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4, 5, 6, 7, 8, 9 or 11, wherein R is a vinyl group optionally substituted by 1 to 2 groups independently selected from the following: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b 、-C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted by 1 to 3 J 4 groups, -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted by 1 to 3 J 4 groups, -C1-C3 alkylene-4-6 membered heterocycloalkyl optionally substituted by 1 to 3 J 4 groups and -C1-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted by 1 to 3 J 4 groups.

[0227] Embodiment 13 of the present disclosure relates to a compound according to any one of Embodiments 1, 2, 3, 4, 4(a), 4(b), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 6, 7, 8, 9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(l), 9(m), 9(n), 9(o), 9(p), 9(q), 9(r), 9(s), 9(t) or 11, wherein R is

[0228]

[0229] wherein:

[0230] each Q 1 is independently selected from H, F and Cl; and

[0231] Q 2 is selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b 、-C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted by 1 to 3 J 4 groups and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted by 1 to 3 J 4 groups.

[0232] Another aspect of Embodiment 13 of the present disclosure relates to a compound according to any one of Embodiments 1-9 or 11, wherein R is

[0233]

[0234] Wherein:

[0235] Each Q 1 is independently selected from H, F, and Cl; and

[0236] Q 2 is selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , -C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups, and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0237] Embodiment 13(a) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is H.

[0238] Embodiment 13(b) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is C1-C6 haloalkyl.

[0239] Embodiment 13(c) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is C1-C6 alkyl.

[0240] Embodiment 13(d) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is C1-C4 alkylene-NR a R b .

[0241] Embodiment 13(e) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is -C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups.

[0242] Embodiment 13(f) of the present disclosure relates to the compound according to Embodiment 13, wherein Q 2 is -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0243] Embodiment 14 of the present disclosure relates to the compound according to any one of the foregoing embodiments, wherein R 2is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted with 1-3 J 1 groups.

[0244] Embodiment 15 of the present disclosure relates to a compound according to one of the foregoing embodiments, wherein R 2 is -O-(5-10 membered) heteroaryl containing at least one nitrogen atom and optionally substituted with 1-2 J 1 groups.

[0245] Embodiment 16 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0246]

[0247] each of which is optionally substituted with 1-2 J 1 groups.

[0248] Embodiment 17 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0249]

[0250] each of which is optionally substituted with 1-2 J 1 groups, wherein:

[0251] each J 1 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, -C0-C3 alkylene-N(H)R c , C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy; and

[0252] R c is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl.

[0253] Embodiment 18 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0254]

[0255] Embodiment 19 of the present disclosure relates to a compound according to Embodiment 1, which has one of the following formulas:

[0256]

[0257]

[0258] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0259] Each Q 1 is independently selected from H, F and Cl; and

[0260] Q 2 is independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups. Or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein each Q 1 is independently selected from H, F and Cl; and

[0261] Q 2 is independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0262] Embodiment 20 of the present disclosure relates to a compound according to Embodiment 1, which has one of the following formulas:

[0263]

[0264]

[0265]

[0266] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0267] Each Q 1independently selected from H, F, and Cl; and

[0268] Q 2 is selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7-membered heterocycloalkyl optionally substituted with 1-3 J 4 groups, and -C0-C3 alkylene-4-7-membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0269] Embodiment 21 of the present disclosure relates to a compound according to any one of Embodiments 19 or 20, wherein at least one Q 2 is H.

[0270] Embodiment 22 of the present disclosure relates to a compound according to any one of Embodiments 19 or 20, wherein one Q 2 is -C1-C3 alkylene-NR a R b .

[0271] Embodiment 23 of the present disclosure relates to a compound according to any one of Embodiments 19 or 20, wherein one Q 2 is C0-C3 alkylene-4-7-membered heterocycloalkyl optionally substituted with 1-3 J 4 groups.

[0272] Embodiment 24 of the present disclosure relates to a compound according to Embodiment 1, selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0273] Other embodiments of the present disclosure relate to any one of the foregoing embodiments, wherein the compound is selected from Table 1.

[0274] Embodiments P1 - P14

[0275] Embodiment P1 of the present disclosure relates to a compound having the formula (I):

[0276]

[0277] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, wherein:

[0278] A is N or CH;

[0279] E 1 is N or C(CN);

[0280] E 2 is C(R 4 ) or N;

[0281] R 1 is an alkyl, haloalkyl or halogen;

[0282] R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl moieties is optionally substituted by 1-4 J 1 groups;

[0283] or R 1 and R 2 together with the carbon atom to which it is attached form a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted by 1-4 J 1 groups;

[0284] G is -L 1 -R 3 or X-Y;

[0285] L 1 is a bond, -C(O)-, -S(O)2-, alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein each of the alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is optionally substituted by 0-4 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0286] R 3 is a 4-8 membered heterocycle containing at least one nitrogen ring atom, wherein R 3 is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R;

[0287] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, wherein the 7-11 membered spiro group containing at least one nitrogen ring atom is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of the 7-11 membered spiro group is substituted by -L 2 -R;

[0288] X is aryl, heteroaryl, heterocycloalkyl or cycloalkyl, each of which is optionally substituted by 1-4 J 2 groups;

[0289] Y is -C0-C4 alkylene -N(H)-L 2-R, -C0-C4 alkylene -O-C(O)-C(H)=CH2, -C0-C4 alkylene -O-C(O)-ethynyl, -C0-C4 alkylene -C(H)=C(CN)-C(O)-NH2, -4-7 membered heterocycloalkyl -L 2 R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene -C(H)=C(O)-NH2, -C0-C4 alkylene -C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene -subethynyl-C(O)-O-alkyl, -C0-C4 alkylene -C(H)=C(H)-CN, -C0-C4 alkylene -N=C=S, -C0-C4-etheyny, -C0-C4 alkylene -ethynyl, -C0-C4 alkylene -CN, -C0-C4 alkylene -C(H)=N-N(H)Boc, -C0-C4 alkylene -C(O)-CH2-Br, -C0-C4 alkylene -CH2-Cl, -C0-C4 alkylene -oxiranyl, -C0-C4 alkylene -SH, -C0-C4 alkylene -F and -C0-C4 alkylene -C(H)=O, where the C0-C4 alkylene moiety is optionally independently substituted by 1-4 groups selected from halogen, cycloalkyl, alkoxyalkoxyalkyl or hydroxy;

[0290] R 4 is H, halo, alkyl or -O-alkyl;

[0291] L 2 is -SO2- or -C(O)-;

[0292] R is vinyl, ethynyl, -CH2-CN or haloalkyl where one halogen of the haloalkyl is on the carbon atom adjacent to L 2 and where the vinyl and ethynyl are each optionally independently substituted by 1-3 groups selected from: halogen, haloalkyl, alkyl, -C1-C6 alkylene -NR a R b , cyano, hydroxyalkyl, -C1-C6 alkylene -C(O)OH, -C1-C6 alkylene -C(O)O-alkyl, alkoxyalkyl, -C0-C4 alkylene -cycloalkyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene -cycloalkenyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene -heterocycloalkyl optionally substituted by 0-3 J 4 groups and -C0-C4 alkylene -heterocycloalkenyl optionally substituted by 0-3 J 4 groups;

[0293] or -L 2-R is -C=N-OH;

[0294] Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy and alkoxyalkyl;

[0295] Each J 2 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl;

[0296] Each J 3 is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl and alkoxy and alkoxyalkyl, provided that J 3 is attached to carbon;

[0297] Each J 4 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo and -C0-C4 alkylene-NR a R b , provided that J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0298] R a and R b are each independently selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and -C0-C3 alkylene-alkynyl optionally substituted by alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; and

[0299] R c is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally substituted by 1-3 groups selected from halogen, alkyl, alkoxy and alkoxyalkyl.

[0300] Embodiment P2 of the present disclosure relates to the compound according to Embodiment P1, wherein:

[0301] R 1 is C1-C4 alkyl, C1-C4 haloalkyl or halogen;

[0302] R 2is -O-(5- to 10-membered) aryl, -O-(5- to 10-membered) heteroaryl, -O-(4- to 7-membered) cycloalkyl, -O-(4- to 7-membered) heterocycloalkyl, -NH-(5- to 10-membered) aryl or -NH-(5- to 10-membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties is optionally substituted by 1 to 3 J 1 groups;

[0303] or R 1 and R 2 together with the carbon atom to which it is attached form a ring selected from 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein each ring is optionally substituted by 1 to 3 J 1 groups;

[0304] G is -L 1 -R 3 or X-Y;

[0305] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl or 4- to 7-membered cycloalkyl, wherein C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are each optionally substituted by 0 to 3 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0306] R 3 is a 4- to 7-membered heterocycle containing at least one nitrogen ring atom, wherein the 4- to 7-membered heterocycle containing at least one nitrogen ring atom is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of the 4- to 7-membered heterocycle is substituted by -L 2 -R;

[0307] or R 3 is a 7- to 11-membered spiro group containing at least one nitrogen ring atom, wherein the 7- to 11-membered spiro group is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R;

[0308] X is 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl or 5- to 7-membered cycloalkyl, wherein the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are each optionally substituted by 1 to 3 J 2 groups;

[0309] Y is -C0-C4 alkylene-N(H)-L 2 -R, -C0-C4 alkylene-O-C(O)-C(H)=CH2, -C0-C4 alkylene-O-C(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -4-7 membered heterocycloalkyl-L 2 R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-subethynyl-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4-etheyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, where the C0-C4 alkylene moiety is optionally independently substituted by 1-4 groups selected from halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy or hydroxy;

[0310] R 4 is H, halo, C0-C4 alkyl or -O-C0-C4 alkyl;

[0311] L 2 is -SO2- or -C(O)-;

[0312] R is vinyl, ethynyl, -CH2-CN or C1-C6 haloalkyl, where one halogen of the C1-C6 haloalkyl is on the carbon atom adjacent to L 2 and where each of the vinyl and ethynyl is optionally independently substituted by 1-3 groups selected from the following: halogen, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b 、cyano, C1-C6 hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-C1-C6 alkyl, -C1-C4 alkylene-C1-C6 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 0-3 J4 Group-substituted -C0-C4 alkylene-4-7 membered heterocycloalkyl and optionally 0-3 J 4 Group-substituted -C0-C4 alkylene-4-7 membered heterocycloalkenyl;

[0313] Or -L 2 -R is -C=N-OH;

[0314] Each J 1 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0315] Each J 2 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0316] Each J 3 Independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy, provided that J 3 Is attached to carbon;

[0317] Each J 4 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that J 4 Groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b Groups;

[0318] R a And R b Each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy and C0-C3 alkylene-C2-C6 alkynyl optionally substituted by alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C1-C6 alkoxy C1-C6 alkyl; and

[0319] R cselected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl.

[0320] Embodiment P3 of the present disclosure relates to a compound according to any one of Embodiments P1 or P2, having one of the following formulas:

[0321]

[0322] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above compounds.

[0323] Embodiment P4 of the present disclosure relates to Embodiment P3, having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa) or (IIb).

[0324] Embodiment P5 of the present disclosure relates to a compound according to any one of Embodiments P1-P5, wherein G is -L 1 -R 3 .

[0325] Embodiment P6 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 3 is:

[0326] wherein:

[0327] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroalkyl or 4-6 membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroalkyl or 4-6 membered cycloalkyl are each optionally substituted with 0-2 J 2 groups, provided that when L 1 is CH2, Z 1 is not CH2 or N;

[0328] L 2 is -SO2- or -C(O)-;

[0329] Z 1 is -N(H)-, -C(R 5) - or optionally a 4- to 7-membered spirocyclic group containing 1 to 2 nitrogen atoms;

[0330] R 5 is H, halogen, C1-C3 alkyl or CN;

[0331] Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, where -C1-C3 alkylene and -C2-C3 alkenylene are each optionally substituted by 1 to 4 J 3 groups;

[0332] R is vinyl, ethynyl, -CH2-CN or C1-C4 haloalkyl, where one halogen of C1-C4 haloalkyl is on the carbon atom adjacent to L 2 and where said vinyl and ethynyl are each optionally substituted independently by 1 to 3 groups selected from: halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b 、-C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 0 to 3 J 4 groups, -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted by 0 to 3 J 4 groups, -C0-C4 alkylene-4- to 7-membered heterocycloalkyl optionally substituted by 0 to 3 J 4 groups and -C0-C4 alkylene-4- to 7-membered heterocycloalkenyl optionally substituted by 0 to 3 J 4 groups;

[0333] Each J 2 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy;

[0334] Each J 3 is independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy, provided that J 3 is attached to carbon; and

[0335] Each J 4Independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo, and -C0-C4 alkylene-NR a R b , provided that the J 4 group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group.

[0336] An embodiment P7 of the present disclosure relates to a compound according to embodiment P6, wherein R 3 is:

[0337] Wherein:

[0338] Z 1 is -N(H)-, -C(R 5 )-, or a 4-6 membered spiro group optionally containing 1-2 nitrogen atoms;

[0339] R 5 is H, halogen, C1-C3 alkyl, or CN;

[0340] Z 2 is -C1-C3 alkylene or -C2-C3 alkenylene, each of which is optionally substituted with 1-2 J 3 groups;

[0341] Z 3 is -C1-C2 alkylene optionally substituted with 1-2 J 3 groups;

[0342] R is vinyl, ethynyl, -CH2-CN, or C1-C3 haloalkyl, wherein one halogen of the C1-C3 haloalkyl is on the carbon atom adjacent to -C(O)-, and wherein each of the vinyl and ethynyl is optionally substituted with 1-3 groups independently selected from: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C(O)OH, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C0-C3 alkylene-C1-C3 alkoxy, -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with 0-3 J 4 groups, -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with 0-3 J 4 groups, -C0-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with 0-3 J 4Group-substituted -C0-C3 alkylene-4-6 membered heterocycloalkyl and optionally substituted by 0-3 J 4 Group-substituted -C0-C3 alkylene-4-6 membered heterocycloalkenyl;

[0343] Each J 2 Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy;

[0344] Each J 3 Independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy, provided that J 3 Is attached to carbon; and

[0345] Each J 4 Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C1-C3 alkyl-C1-C3 alkoxy, oxo and -C0-C3 alkylene-NR a R b Provided that J 4 The group may include only up to two oxo groups and up to one -C0-C3 alkylene-NR a R b Group.

[0346] Embodiment P8 of the present disclosure relates to a compound according to any one of embodiments P1-P7, wherein R is vinyl optionally substituted by 1-2 groups independently selected from: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, optionally substituted by 0-3 J 4 Group-substituted -C1-C3 alkylene-C3-C6 cycloalkyl, optionally substituted by 0-3 J 4 Group-substituted -C1-C3 alkylene-C3-C6 cycloalkenyl, optionally substituted by 0-3 J 4 Group-substituted -C1-C3 alkylene-4-6 membered heterocycloalkyl and optionally substituted by 0-3 J 4 Group-substituted -C1-C3 alkylene-4-6 membered heterocycloalkenyl.

[0347] Embodiment P9 of the present disclosure relates to a compound according to any one of embodiments P1 - P4, wherein G is -X-Y.

[0348] Embodiment P10 of the present disclosure relates to a compound according to any one of embodiments P1 - P4 and P9, wherein X is a 5 - 10 membered heteroaryl optionally substituted with 1 - 3 J 2 groups and Y is -C0-C4 alkylene -N(H)-L 2 -R,

[0349] Embodiment P11 of the present disclosure relates to a compound according to any one of embodiments P1 - P10, wherein R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted with 1 - 3 J 1 groups.

[0350] Embodiment P12 of the present disclosure relates to a compound according to any one of embodiments P1 - P11, wherein R 2 is -O-(5 - 10 membered) heteroaryl containing at least one nitrogen atom and optionally substituted with 1 - 2 J 1 groups.

[0351] Embodiment P13 of the present disclosure relates to a compound according to any one of embodiments P1 - P12, wherein R 2 is

[0352] each of which is optionally substituted with 1 - 2 J 1 groups.

[0353] Embodiment P14 of the present disclosure relates to a compound according to any one of embodiments P1 - P13, wherein R 2 is

[0354]

[0355] Embodiment 101 of the present disclosure relates to a compound of formula (I):

[0356]

[0357] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0358] A is N or CH;

[0359] E 1 is N or C(CN);

[0360] E 2is C(R 4 ) or N;

[0361] R 1 is alkyl, haloalkyl or halogen;

[0362] R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl moieties is optionally substituted by 1-4 J 1 groups;

[0363] or R 1 and R 2 together with the carbon atom to which it is attached form a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted by 1-4 J 1 groups;

[0364] G is -L 1 -R 3 or X-Y;

[0365] L 1 is a bond, -C(O)-, -S(O)2-, alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein each of the alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is optionally substituted by 0-4 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0366] R 3 is a 4-8 membered heterocycle containing at least one nitrogen ring atom, wherein R 3 is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R;

[0367] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, wherein the 7-11 membered spiro group containing at least one nitrogen ring atom is optionally substituted by 1-4 J 3 groups, and wherein one nitrogen atom of the 7-11 membered spiro group is substituted by -L 2 -R;

[0368] X is aryl, heteroaryl, heterocycloalkyl or cycloalkyl, each of which is optionally substituted by 1-4 J 2 groups;

[0369] Y is -C0-C4 alkylene -N(H)-L 2 -R, -C0-C4 alkylene -O-C(O)-C(H)=CH2,,-C0-C4 alkylene -O-C(O)-ethynyl, -C0-C4 alkylene -C(H)=C(CN)-C(O)-NH2, -C0-C4 alkylene -1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene -C(H)=C(O)-NH2, -C0-C4 alkylene -C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene -subethynyl-C(O)-O-alkyl, -C0-C4 alkylene -C(H)=C(H)-CN, -C0-C4 alkylene -N=C=S, -C0-C4-ethyny, -C0-C4 alkylene -ethynyl, -C0-C4 alkylene -CN, -C0-C4 alkylene -C(H)=N-N(H)Boc, -C0-C4 alkylene -C(O)-CH2-Br, -C0-C4 alkylene -CH2-Cl, -C0-C4 alkylene -oxiranyl, -C0-C4 alkylene -SH, -C0-C4 alkylene -F and -C0-C4 alkylene -C(H)=O, wherein the C0-C4 alkylene moiety is optionally substituted by 1-4 groups independently selected from halogen, cycloalkyl, alkoxyalkoxyalkyl or hydroxy;

[0370] R 4 is H, alkyl or -O-alkyl;

[0371] L 2 is -SO2- or -C(O)-;

[0372] R is vinyl, ethynyl, -CH2-CN or a haloalkyl in which one halogen of the haloalkyl is on the carbon atom adjacent to L 2 and wherein the vinyl and ethynyl are each optionally substituted by 1-3 groups independently selected from the following: halogen, haloalkyl, alkyl, -C1-C6 alkylene -NR a R b 、cyano, hydroxyalkyl, -C1-C6 alkylene -C(O)OH, -C1-C6 alkylene -C(O)O-alkyl, alkoxyalkyl, -C0-C4 alkylene -cycloalkyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene -cycloalkenyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene -heterocycloalkyl optionally substituted by 0-3 J 4 groups and -C0-C4 alkylene -heterocycloalkenyl optionally substituted by 0-3 J 4 groups;

[0373] or -L 2-R is -C=N-OH;

[0374] Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl;

[0375] Each J 2 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl;

[0376] Each J 3 and is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, provided that J 3 is attached to carbon;

[0377] Each J 4 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and -C0-C4 alkylene-NR a R b , provided that J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0378] R a and R b are each independently selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -C0-C3 alkylene-alkynyl optionally substituted by alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; and

[0379] R c is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted by 1-3 groups selected from halogen, alkyl, alkoxy, and alkoxyalkyl.

[0380] Embodiment 102 of the present disclosure relates to the compound according to Embodiment 101, wherein:

[0381] R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen;

[0382] R 2is -O-(5- to 10-membered) aryl, -O-(5- to 10-membered) heteroaryl, -O-(4- to 7-membered) cycloalkyl, -O-(4- to 7-membered) heterocycloalkyl, -NH-(5- to 10-membered) aryl or -NH-(5- to 10-membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties is optionally substituted by 1 to 3 J 1 groups;

[0383] or R 1 and R 2 together with the carbon atom to which it is attached forms a ring selected from 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein each ring is optionally substituted by 1 to 3 J 1 groups;

[0384] G is -L 1 -R 3 or X-Y;

[0385] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl or 4- to 7-membered cycloalkyl, wherein C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are each optionally substituted by 0 to 3 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0386] R 3 is a 4- to 7-membered heterocycle containing at least one nitrogen ring atom, wherein the 4- to 7-membered heterocycle containing at least one nitrogen ring atom is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of the 4- to 7-membered heterocycle is substituted by -L 2 -R;

[0387] or R 3 is a 7- to 11-membered spiro group containing at least one nitrogen ring atom, wherein the 7- to 11-membered spiro group is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R;

[0388] X is 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl or 5- to 7-membered cycloalkyl, wherein the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are optionally substituted by 1 to 3 J 2 groups;

[0389] Y is -C0-C4 alkylene-N(H)-L 2 -R, -C0-C4 alkylene-O-C(O)-C(H)=CH2, -C0-C4 alkylene-O-C(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-subethynyl-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4-ethyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the C0-C4 alkylene moiety is optionally substituted by 1-4 groups independently selected from halogen, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl-C1-C6 alkoxy or hydroxy;

[0390] R 4 is H, C0-C4 alkyl or -O-C0-C4 alkyl;

[0391] L 2 is -SO2- or -C(O)-;

[0392] R is vinyl, ethynyl, -CH2-CN or C1-C6 haloalkyl, wherein one halogen of the C1-C6 haloalkyl is on the carbon atom adjacent to L 2 and wherein each of the vinyl and ethynyl is optionally substituted by 1-3 groups independently selected from the following: halogen, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b 、cyano, C1-C6 hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-C1-C6 alkyl, -C1-C4 alkylene-C1-C6 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 0-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 0-3 J 4Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkyl and optionally substituted by 0-3 J 4 Group-substituted -C0-C4 alkylene-4-7-membered heterocycloalkenyl;

[0393] or -L 2 -R is -C=N-OH;

[0394] Each J 1 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0395] Each J 2 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy;

[0396] Each J 3 Independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy, provided that J 3 Is attached to carbon;

[0397] Each J 4 Independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that J 4 The group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0398] R a and R b Each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy and C0-C3 alkylene-C2-C6 alkynyl optionally substituted by alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C1-C6 alkoxy C1-C6 alkyl; and

[0399] R cSelected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl.

[0400] Embodiment 103 of the present disclosure relates to a compound according to any one of Embodiments 101 or 102, which has one of the following formulas:

[0401]

[0402] Or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds.

[0403] Embodiment 104 of the present disclosure relates to a compound according to Embodiment 103, which has formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa) or (IIb).

[0404] Embodiment 105 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein G is -L 1 -R 3 .

[0405] Embodiment 106 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 3 is:

[0406] Wherein:

[0407] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroalkyl or 4-6 membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroalkyl or 4-6 membered cycloalkyl are each optionally substituted with 0-2 J 2 groups, provided that when L 1 is CH2, Z 1 is not CH2 or N;

[0408] L 2 is -SO2- or -C(O)-;

[0409] Z 1 is -N(H)-, -C(R5 ) - or an optionally 4- to 7-membered spirocyclic group containing 1 to 2 nitrogen atoms;

[0410] R 5 is H, halogen, C1-C3 alkyl or CN;

[0411] Z 2 and Z 3 each independently is -C1-C3 alkylene or -C2-C3 alkenylene, wherein -C1-C3 alkylene and -C2-C3 alkenylene are each optionally substituted by 1 to 4 J 3 groups;

[0412] R is vinyl, ethynyl, -CH2-CN or C1-C4 haloalkyl, wherein one halogen of C1-C4 haloalkyl is on the carbon atom adjacent to L 2 , and wherein said vinyl and ethynyl are optionally substituted by 1 to 3 groups each independently selected from the following: halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b , -C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 0 to 3 J 4 groups, -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted by 0 to 3 J 4 groups, -C0-C4 alkylene-4- to 7-membered heterocycloalkyl optionally substituted by 0 to 3 J 4 groups and -C0-C4 alkylene-4- to 7-membered heterocycloalkenyl optionally substituted by 0 to 3 J 4 groups;

[0413] Each J 2 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy;

[0414] Each J 3 is independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy, provided that J 3 is attached to carbon; and

[0415] Each J 4Independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group.

[0416] Embodiment 107 of the present disclosure relates to a compound according to Embodiment 106, wherein R 3 is:

[0417] wherein:

[0418] Z 1 is -N(H)-, -C(R 5 )- or a 4-6 membered spiro group optionally containing 1-2 nitrogen atoms;

[0419] R 5 is H, halogen, C1-C3 alkyl or CN;

[0420] Z 2 is -C1-C3 alkylene or -C2-C3 alkenylene, each of which is optionally substituted by 1-2 J 3 groups;

[0421] Z 3 is -C1-C2 alkylene optionally substituted by 1-2 J 3 groups;

[0422] R is vinyl, ethynyl, -CH2-CN or C1-C3 haloalkyl, wherein one halogen of the C1-C3 haloalkyl is on the carbon atom adjacent to -C(O)-, and wherein the vinyl and ethynyl are optionally substituted by 1-3 groups independently selected from the following: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C(O)OH, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C0-C3 alkylene-C1-C3 alkoxy, -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted by 0-3 J 4 groups, -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted by 0-3 J 4 groups, -C0-C3 alkylene-C1-C3 alkoxy optionally substituted by 0-3 J 4Group-substituted -C0-C3 alkylene-4-6-membered heterocycloalkyl and optionally substituted by 0-3 Js 4 Group-substituted -C0-C3 alkylene-4-6-membered heterocycloalkenyl;

[0423] Each J 2 Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy;

[0424] Each J 3 Independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy, provided that J 3 Is attached to carbon; and

[0425] Each J 4 Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C1-C3 alkyl-C1-C3 alkoxy, oxo, and -C0-C3 alkylene-NR a R b Provided that J 4 The group may include only up to two oxo groups and up to one -C0-C3 alkylene-NR a R b Group.

[0426] Embodiment 108 of the present disclosure relates to a compound according to any of the foregoing embodiments, wherein R is vinyl optionally substituted by 1-2 groups independently selected from: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b ,-C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, optionally substituted by 0-3 Js 4 Group-substituted -C1-C3 alkylene-C3-C6 cycloalkyl, optionally substituted by 0-3 Js 4 Group-substituted -C1-C3 alkylene-C3-C6 cycloalkenyl, optionally substituted by 0-3 Js 4 Group-substituted -C1-C3 alkylene-4-6-membered heterocycloalkyl and optionally substituted by 0-3 Js 4 Group-substituted -C1-C3 alkylene-4-6-membered heterocycloalkenyl.

[0427] Embodiment 109 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein G is -X-Y.

[0428] Embodiment 110 of the present disclosure relates to a compound according to any one of Embodiments 101-104 and 109, wherein X is a 5-10 membered heteroaryl optionally substituted with 1-3 J 2 groups and Y is -C0-C4 alkylene-N(H)-L 2 -R.

[0429] Embodiment 111 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted with 1-3 J 1 groups.

[0430] Embodiment 112 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-(5-10 membered) heteroaryl containing at least one nitrogen atom and optionally substituted with 1-2 J 1 groups.

[0431] Embodiment 113 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0432] each of which is optionally substituted with 1-2 J 1 groups.

[0433] Embodiment 114 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0434]

[0435] Embodiment 115 of the present disclosure relates to a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0436] Embodiment 116 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0437] Embodiment 117 of the present disclosure relates to the pharmaceutical composition of Embodiment 113, further comprising a second agent.

[0438] Embodiment 118 of the present disclosure relates to a method for treating a subject suffering from a Her2-mediated disease or condition, the method comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt, deuterated analogue, tautomer or stereoisomer thereof as described in any one of Embodiments 1-15, or the pharmaceutical composition as described in any one of Embodiments 16-17.

[0439] Embodiment 119 of the present disclosure relates to the method according to Embodiment 118, wherein the disease or condition is a cancer having a Her2 YVMA insertion mutation.

[0440] Embodiment 120 of the present disclosure relates to the method for treating a disease or condition according to Embodiment 118, wherein the disease or condition is a cancer selected from the following: lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma.

[0441] Embodiment 121 of the present disclosure relates to the method for treating a disease or condition according to any one of Embodiments 118-120, wherein the disease or condition is non-small cell lung cancer.

[0442] Embodiment 122 of the present disclosure relates to the method according to any one of Embodiments 118-121, further comprising administering one or more additional therapeutic agents.

[0443] Embodiment 123 of the present disclosure relates to the method according to Embodiment 122, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, iproplatin, ilofosine, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and CTLA4 inhibitors; v) antibody-drug conjugates selected from ado-trastuzumab emtansine and deruxtecan; vi) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, megestrol acetate, raloxifene, tamoxifen, and toremifene; vii) taxanes selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; viii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; x) antiangiogenic agents selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidine, and thalidomide; xi) topoisomerase inhibitors selected from amsacrine, edotecarin, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiv) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xv) IDO inhibitors;xvi) Chemotherapeutic agents selected from 3-AP (3-amino-2-formyl thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elisom, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, testolactone, thiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors and aromatase inhibitors (anastrozole, letrozole, exemestane); xvii) BRAF inhibitors; xviii) Mek inhibitors; xix) c-Kit mutant inhibitors; xx) EGFR inhibitors; xxi) epigenetic regulators; xxii) other adenosine axis blockers selected from CD39, CD38, A2AR and A2BR; or xxiii) agonists of TNFA superfamily members; and xxiv) anti-ErbB2 mAb.;

[0444] Embodiment 124 of the present disclosure relates to the method according to Embodiment 122, wherein the one or more additional therapeutic agents are ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0445] Embodiment 201 of the present disclosure relates to a compound of formula (I):

[0446]

[0447] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0448] A is N or CH;

[0449] E 1 is N or C(CN);

[0450] E 2 is C(R 4 ) or N;

[0451] R 1 is alkyl, haloalkyl or halogen;

[0452] R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -O-heteroaryl-alkylene-aryl, -NH-alkyl, -NH-aryl or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl moieties is optionally substituted by 1-4 J 1 groups;

[0453] or R 1 and R 2 forms, together with the carbon atom to which it is attached, a saturated or unsaturated carbocyclic or heterocyclic ring, where the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted with 1-4 J 1 groups;

[0454] G is -L 1 -R 3 or -W-X-Y;

[0455] L 1 is a bond, -C(O)-, -S(O)2-, -N(R c ), alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, where each of the alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is optionally substituted with 1-4 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0456] R 3 is a 4-9 membered heterocycle containing at least one nitrogen ring atom, where R 3 is optionally substituted with 1-4 J 3 groups, and where one nitrogen atom of R 3 is substituted with -L 2 -R;

[0457] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, where the 7-11 membered spiro group containing at least one nitrogen ring atom is optionally substituted with 1-4 J 3 groups, and where one nitrogen atom of the 7-11 membered spiro group is substituted with -L 2 -R;

[0458] W is a bond, -C(O)- or -S(O)2-;

[0459] X is aryl, heteroaryl, heterocycloalkyl or cycloalkyl, each of which is optionally substituted with 1-4 J 2 groups;

[0460] Y is -C0-C4 alkylene-N(R d ))-L 2-R, -C(O)-4- to 7-membered heterocycloalkyl containing at least one nitrogen atom and substituted with 1 or 2 oxo groups, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4 ethenynyl, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the C0-C4 alkylene moiety is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxyalkoxyalkyl or hydroxy;

[0461] R 4 is H, alkyl or -O-alkyl;

[0462] L 2 is -SO2- or -C(O)-;

[0463] R is vinyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, -CH2-CN or a haloalkyl in which one halogen of the haloalkyl is on the carbon atom adjacent to L 2 ;

[0464] Each Q is independently selected from halogen, haloalkyl, alkyl, alkene, alkyne, -C1-C6 alkylene-NR a R b , -C1-C6 alkylene-OR c , cyano, hydroxyalkyl, -C0-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-alkyl, alkoxyalkyl, -C0-C4 alkylene-cycloalkyl optionally substituted with 1 to 3 J 4 groups, -C0-C4 alkylene-cycloalkenyl optionally substituted with 1 to 3 J 4 groups, -C0-C4 alkylene-7- to 11-membered spirocycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 J 4 groups, -C0-C4 alkylene-heterocycloalkyl optionally substituted with 1 to 3 J 4 groups and -C0-C4 alkylene-heterocycloalkenyl optionally substituted with 1 to 3 J 4 groups;

[0465] or -L 2 -R is -C=N-OH;

[0466] Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy and alkoxyalkyl;

[0467] Each J 2 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl;

[0468] Each J 3 is attached to a carbon atom and is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl,, or two of the optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of the optional 1-4 J 3 groups are on different ring carbons and together form a 1-3 carbon bridge;

[0469] Each J 4 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0470] R a and R b are each independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and -C0-C3 alkylene-alkynyl optionally substituted by alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; and

[0471] R c is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally substituted by 1-3 groups selected from halogen, alkyl, alkoxy and alkoxyalkyl; and

[0472] R d is selected from H, alkyl and haloalkyl.

[0473] Embodiment 202 of the present disclosure relates to the compound according to Embodiment 201, wherein:

[0474] R 1 is a C1-C4 alkyl, C1-C4 haloalkyl or halogen;

[0475] R 2 is -O-(5-10 membered) aryl, -O-(5-10 membered) heteroaryl, -O-(4-7 membered) cycloalkyl, -O-(4-7 membered) heterocycloalkyl, -O-(5-10 membered) heteroaryl-C1-C4 alkylene-phenyl, -NH-(5-10 membered) aryl or -NH--(5-10 membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties is optionally substituted with 1-3 J 1 groups;

[0476] or R 1 and R 2 together with the carbon atom to which it is attached forms a ring selected from 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl and 4-7 membered heterocycloalkyl, wherein each ring is optionally substituted with 1-3 J 1 groups;

[0477] G is -L 1 -R 3 or -W-X-Y;

[0478] L 1 is a bond, -C(O)-, -S(O)2-, -N(H)-, -N(C1-C6 alkyl)-, C1-C3 alkylene, 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl or 4-7 membered cycloalkyl, wherein C1-C3 alkylene, 5-10 membered aryl, 5-10 membered heteroaryl, 5-7 membered heterocycloalkyl and 5-7 membered cycloalkyl are each optionally substituted with 1-3 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring;

[0479] R 3 is a 4-7 membered heterocycle containing at least one nitrogen ring atom, wherein the 4-7 membered heterocycle containing at least one nitrogen ring atom is optionally substituted with 1-4 J 3 groups, and wherein one nitrogen atom of the 4-7 membered heterocycle is substituted with -L 2 -R;

[0480] or R 3 is a 7-11 membered spiro group containing at least one nitrogen ring atom, wherein the 7-11 membered spiro group is optionally substituted with 1-4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted with -L 2 -R;

[0481] W is a 9a-bond, -C(O)- or -S(O)2-;

[0482] X is a 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl or 5- to 7-membered cycloalkyl, wherein the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are optionally substituted by 1 to 3 J 2 groups;

[0483] Y is -C0-C4 alkylene-N(R d )-L 2 -R, a -C(O)-4- to 6-membered heterocycloalkyl containing one nitrogen atom and substituted by 1 to 2 oxo groups, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4-ethyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the -C0-C4 alkylene moiety is optionally independently substituted by 1 to 4 groups selected from halogen, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl-C1-C6 alkoxy or hydroxy;

[0484] R 4 is H, C0-C4 alkyl or -O-C0-C4 alkyl;

[0485] L 2 is -SO2- or -C(O)-;

[0486] R is vinyl optionally substituted by 1 to 3 Q groups, ethynyl optionally substituted by Q, -CH2-CN or C1-C6 haloalkyl, wherein one halogen of the C1-C6 haloalkyl is on the carbon atom adjacent to L 2 ;

[0487] Each Q is independently selected from halogen, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b, cyano, C1-C6 hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-C1-C6 alkyl, -C1-C4 alkylene-C1-C6 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-4-7 membered heterocycloalkyl and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups; 4 or -L

[0488] -R is -C=N-OH; 2

[0489] Each J 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy and C1-C6 alkyl-C1-C6 alkoxy;

[0490] Each J 2 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 alkyl-C1-C6 alkoxy;

[0491] Each J 3 attached to the carbon atom of R 3 and is independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 alkyl-C1-C6 alkoxy, or two of said optionally 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optionally 1-4 J 3 groups are on different ring carbons and together form a 1-3 carbon bridge;

[0492] Each J 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that J 4The group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group;

[0493] R a and R b are each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, and C0-C3 alkylene-C2-C6 alkynyl optionally substituted by alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -C1-C6 alkoxy-C1-C6 alkyl; and

[0494] R c is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl groups are each optionally substituted by 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkoxy-C1-C6 alkyl; and

[0495] R d is selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0496] Embodiment 203 of the present disclosure relates to a compound according to any one of Embodiments 201 or 202, which has one of the following formulas:

[0497]

[0498] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the above-mentioned compounds.

[0499] Embodiment 204 of the present disclosure relates to a compound according to Embodiment 203, which has formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of formula (IIa) or (IIb).

[0500] Embodiment 205 of the present disclosure relates to a compound according to any one of Embodiments 201 or 202, which has one of the following formulas:

[0501]

[0502] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the above-mentioned compounds.

[0503] Embodiment 206 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein G is -L 1 -R 3 .

[0504] Embodiment 207 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein G is

[0505] wherein:

[0506] L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl are each optionally substituted by 1-2 J 2 groups, provided that when L 1 is CH2, Z 1 is not CH2 or N;

[0507] L 2 is -SO2- or -C(O)-;

[0508] Z 1 is -N(H)-, -C(R 5 )- or a 4-7 membered spiro group optionally containing 1-2 nitrogen atoms;

[0509] R 5 is H, halogen, C1-C3 alkyl or CN;

[0510] Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, wherein -C1-C3 alkylene and -C2-C3 alkenylene are each optionally substituted by 1-4 J 3 groups;

[0511] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q groups, -CH2-CN or C1-C4 haloalkyl, wherein one halogen of the C1-C4 haloalkyl is on the carbon atom adjacent to L 2 ;

[0512] Each Q is independently selected from halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b, -C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 1-3 J 4 -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted by 1-3 J 4 -C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted by 1-3 J 4 and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted by 1-3 J; 4

[0513] Each J 2 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy;

[0514] Each J 3 is independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy, or two of the optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of the optional 1-4 J 3 groups are on different ring carbon atoms and together form a 1-3 carbon bridge; and

[0515] Each J 4 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo and -C0-C4 alkylene-NR a R b 4 , provided that the J a group may include only up to two oxo groups and up to one -C0-C4 alkylene-NR b R 1 group.

[0516] Embodiment 208 of the present disclosure relates to the compound according to Embodiment 207, wherein G is

[0517] wherein:

[0518] Z 1 is -N(H)-, -C(R 5 )- or a 4-6 membered spiro group optionally containing 1-2 nitrogen atoms;

[0519] R 5 is H, halogen, C1-C3 alkyl or CN;

[0520] Z 2 is -C1-C3 alkylene or -C2-C3 alkenylene, each of which is optionally substituted by 1-2 J 3 groups;

[0521] Z 3 is -C1-C2 alkylene optionally substituted by 1-2 J 3 groups;

[0522] R is vinyl optionally substituted by 1-3 Q groups, ethynyl optionally substituted by Q groups, -CH2-CN or C1-C3 haloalkyl, where one halogen of the C1-C3 haloalkyl is on the carbon atom adjacent to -C(O)-;

[0523] Each Q is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b 、-C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C(O)OH, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C0-C3 alkylene-C1-C3 alkoxy, -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted by 1-3 J 4 groups, -C0-C3 alkylene-4-6 membered heterocycloalkyl optionally substituted by 1-3 J 4 groups and -C0-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted by 1-3 J 4 groups;

[0524] Each J 2 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy;

[0525] Each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy, or two of the optional J 3 groups are on different ring carbon atoms and together form a 1-2 carbon bridge and

[0526] Each J 4Independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C1-C3 alkyl-C1-C3 alkoxy, oxo and -C0-C3 alkylene-NR a R b , provided that the J 4 group may include only up to two oxo groups and up to one -C0-C3 alkylene-NR a R b group.

[0527] Embodiment 209 of the present disclosure relates to a compound according to any one of embodiments 201-206, wherein R 3 is

[0528]

[0529]

[0530] wherein the heterocycle containing at least one nitrogen ring atom of R 3 is optionally substituted by 1-3 J 3 groups; and

[0531] each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy.

[0532] Embodiment 210 of the present disclosure relates to a compound according to any one of embodiments 201-205, wherein G is -X-Y.

[0533] Embodiment 211 of the present disclosure relates to a compound according to embodiment 210, wherein X is a 5-10 membered heteroaryl optionally substituted by 1-3 J 2 groups and Y is -C0-C4 alkylene-N(H)-L 2 -R.

[0534] Embodiment 212 of the present disclosure relates to a compound according to any one of embodiments 201-209 and 211, wherein R is a vinyl optionally substituted by 1-2 groups independently selected from: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, optionally substituted by 1-3 J 4Group-substituted -C1-C3 alkylene-C3-C6 cycloalkyl, optionally substituted by 1-3 J 4 Group-substituted -C1-C3 alkylene-C3-C6 cycloalkenyl, optionally substituted by 1-3 J 4 Group-substituted -C1-C3 alkylene-4-6 membered heterocycloalkyl and optionally substituted by 1-3 J 4 Group-substituted -C1-C3 alkylene-4-6 membered heterocyclenyl.

[0535] Embodiment 213 of the present disclosure relates to a compound according to any one of Embodiments 201-209 and 211, wherein R is

[0536]

[0537] wherein:

[0538] Each Q 1 is independently selected from H, F, and Cl; and

[0539] Q 2 is independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b and is optionally substituted by 1-3 J 4 group-substituted -C0-C4 alkylene-4-7 membered heterocycloalkyl and optionally substituted by 1-3 J 4 group-substituted -C0-C4 alkylene-4-7 membered heterocyclenyl.

[0540] Embodiment 214 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted by 1-3 J 1 groups.

[0541] Embodiment 215 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-(5-10 membered) heteroaryl containing at least one nitrogen atom and optionally substituted by 1-2 J 1 groups.

[0542] Embodiment 216 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0543]

[0544] each of which is optionally substituted by 1-2 J 1 groups.

[0545] Embodiment 217 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0546]

[0547] each of which is optionally substituted with 1 - 2 J 1 groups, wherein:

[0548] each J 1 is independently selected from halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, hydroxy, C1 - C3 hydroxyalkyl, -C0 - C3 alkylene - N(H)R c , C1 - C6 alkoxy, and -C1 - C6 alkyl - C1 - C6 alkoxy; and

[0549] R c is selected from H, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, -C1 - C6 alkyl - C1 - C6 alkoxy, C3 - C7 cycloalkyl, 4 - 7 - membered heteroalkyl, 6 - 10 - membered aryl, and 5 - 10 - membered heteroaryl, wherein the C3 - C7 cycloalkyl, 4 - 7 - membered heteroalkyl, 6 - 10 - membered aryl, and 5 - 10 - membered heteroaryl groups are each optionally substituted with 1 - 3 groups selected from halogen, C1 - C6 alkyl, C1 - C6 alkoxy, and C1 - C6 alkoxy - C1 - C6 alkyl.

[0550] Embodiment 218 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0551]

[0552] Embodiment 219 of the present disclosure relates to a compound according to Embodiment 201, which has one of the following formulas:

[0553]

[0554]

[0555] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, wherein:

[0556] each Q 1 is independently selected from H, F, and Cl; and

[0557] Q 2 is independently selected from H, C1 - C6 haloalkyl, C1 - C6 alkyl, -C1 - C3 alkylene - NR a Rb , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein

[0558] each Q 1 is independently selected from H, F and Cl; and

[0559] Q 2 is independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0560] Embodiment 220 of the present disclosure relates to a compound according to Embodiment 201, which has one of the following formulas:

[0561]

[0562]

[0563]

[0564] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein:

[0565] each Q 1 is independently selected from H, F and Cl; and

[0566] Q 2 is independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups. Or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein

[0567] each Q 1 is independently selected from H, F and Cl; and

[0568] Q 2Independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

[0569] Embodiment 221 of the present disclosure relates to a compound according to any one of Embodiments 219 or 220, wherein Q 2 is H.

[0570] Embodiment 222 of the present disclosure relates to a compound according to any one of Embodiments 219 or 220, wherein Q 2 is -C1-C3 alkylene-NR a R b .

[0571] Embodiment 223 of the present disclosure relates to a compound according to any one of Embodiments 219 or 220, wherein Q 2 is C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups.

[0572] Embodiment 224 of the present disclosure relates to a compound according to Embodiment 201, selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0573] Embodiment 225 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0574] Embodiment 226 of the present disclosure relates to the pharmaceutical composition according to Embodiment 225, further comprising a second agent.

[0575] Embodiment 227 of the present disclosure relates to a method for treating a subject suffering from a Her2-mediated disease or condition, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 201-224 or a pharmaceutically acceptable salt, deuterated analogue, tautomer or stereoisomer thereof, or a pharmaceutical composition according to any one of Embodiments 225-226.

[0576] Embodiment 228 of the present disclosure relates to the method according to Embodiment 227, wherein the disease or condition is cancer having a Her2 YVMA insertion mutation.

[0577] Embodiment 229 of the present disclosure relates to the method according to Embodiment 227, wherein the disease or condition is cancer selected from the following: lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma.

[0578] Embodiment 230 of the present disclosure relates to the method for treating a disease or condition according to any one of Embodiments 227-229, wherein the disease or condition is non-small cell lung cancer.

[0579] Embodiment 231 of the present disclosure relates to the method according to any one of Embodiments 227-230, further comprising administering one or more additional therapeutic agents.

[0580] Embodiment 232 of the present disclosure relates to the method according to Embodiment 231, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, 1,7-heptanediol bis(amino sulfonate), ifosfamide, iproplatin, ilofosine, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and CTLA4 inhibitors; v) antibody-drug conjugates selected from ado-trastuzumab emtansine and deruxtecan; vi) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, megestrol acetate, raloxifene, tamoxifen, and toremifene; vii) taxanes selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; viii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; x) antiangiogenic agents selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, lenalidine, and thalidomide; xi) topoisomerase inhibitors selected from amsacrine, edotecarin, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiv) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xv) IDO inhibitors;xvi) A chemotherapeutic agent selected from 3-AP (3-amino-2-formyl thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elisidepsin, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, testolactone, thiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors, and aromatase inhibitors (anastrozole, letrozole, exemestane); xvii) BRAF inhibitors; xviii) Mek inhibitors; xix) c-Kit mutant inhibitors; xx) EGFR inhibitors; xxi) epigenetic regulators; xxii) other adenosine axis blockers selected from CD39, CD38, A2AR, and A2BR; or xxiii) agonists of TNFA superfamily members; and xxiv) anti-ErbB2 mAb.;

[0581] Embodiment 233 of the present disclosure relates to the method according to Embodiment 232, wherein the one or more additional therapeutic agents are ado-trastuzumab emtansine or deruxtecan.

[0582] Embodiment 234 of the present disclosure relates to the method according to Embodiment 232, wherein the one or more additional therapeutic agents are pembrolizumab or nivolumab.

[0583] Embodiment 301 of the present disclosure relates to a compound of formula (I):

[0584]

[0585] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, wherein:

[0586] A is N or CH;

[0587] E 1 is N or C(CN);

[0588] E 2 is C(R 4 ) or N;

[0589] R 1 is alkyl, haloalkyl, or halogen;

[0590] R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl, or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties is optionally substituted with 1-4 J 1 groups;

[0591] or R 1 and R 2 together with the carbon atom to which it is attached forms a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted with 1-4 J 1 groups;

[0592] G is -L 1 -R 3 ;

[0593] L 1 is -C0-C6 alkylene-C(O)N(H)- or -C0-C6 alkylene-S(O)2N(H)-;

[0594] R 3 is -C1-C6 alkylene-NR 2 optionally substituted with 1-4 J a R b ;

[0595] R 4 is H, alkyl or -O-alkyl;

[0596] Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy and alkoxyalkyl;

[0597] Each J 2 is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl and alkoxy and alkoxyalkyl, provided that J 3 is attached to carbon; and

[0598] R a and R b are each independently selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and -C0-C3 alkylene-alkynyl optionally substituted with alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl; and

[0599] Embodiment 302 of the present disclosure relates to a compound according to Embodiment 301, wherein:

[0600] R 1 is C1-C4 alkyl, C1-C4 haloalkyl or halogen;

[0601] R 2is -O-(5- to 10-membered) aryl, -O-(5- to 10-membered) heteroaryl, -O-(4- to 7-membered) cycloalkyl, -O-(4- to 7-membered) heterocycloalkyl, -NH-(5- to 10-membered) aryl or -NH-(5- to 10-membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties is optionally substituted with 1 to 3 J 1 groups;

[0602] or R 1 and R 2 together with the carbon atom to which it is attached form a ring selected from 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein each ring is optionally substituted with 1 to 3 J 1 groups;

[0603] L 1 is -C0-C3 alkylene-C(O)N(H)- or -C0-C3 alkylene-S(O)2N(H)-;

[0604] R 3 is -C1-C4 alkylene-NR 2 optionally substituted with 1 to 2 J a R b ;

[0605] R 4 is H, C0-C4 alkyl or -O-C0-C4 alkyl;

[0606] Each J 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c and C1-C6 alkoxy and -C1-C6 alkoxy-C1-C6 alkyl;

[0607] Each J 2 is independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkoxy-C1-C6 alkyl, provided that J 2 is attached to carbon; and

[0608] R a and R b are each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy and C0-C3 alkylene-C2-C6 alkynyl optionally substituted with alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -C1-C6 alkoxyC1-C6 alkyl.

[0609] Embodiment 303 of the present disclosure relates to a compound according to any one of Embodiments 301 or 302, which has one of the following formulas:

[0610]

[0611] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds.

[0612] Embodiment 304 of the present disclosure relates to a compound according to Embodiment 303, which has formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa) or (IIb).

[0613] Embodiment 305 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein L 1 is -C0-C3 alkylene-C(O)N(H)-.

[0614] Embodiment 306 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 3 is -C1-C4 alkylene-NR a R b , wherein:

[0615] R a and R b are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl.

[0616] Embodiment 307 of the present disclosure relates to a compound according to Embodiment 306, wherein R 3 is -C1-C3 alkylene-NR a R b , wherein: R a and R b are each C1-C3 alkyl.

[0617] Embodiment 308 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted with 1-3 J 1 groups.

[0618] Embodiment 309 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is -O-(5-10 membered) heteroaryl containing at least one nitrogen atom and optionally substituted with 1-2 J 1 groups.

[0619] Embodiment 310 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0620] each of which is optionally substituted with 1 - 2 J 1 groups.

[0621] Embodiment 311 of the present disclosure relates to a compound according to any one of the foregoing embodiments, wherein R 2 is

[0622] Embodiment 312 of the present disclosure relates to a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0623] Embodiment 313 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0624] Embodiment 314 of the present disclosure relates to the pharmaceutical composition of Embodiment 313, further comprising a second agent.

[0625] Embodiment 315 of the present disclosure relates to a method for treating a subject having a Her2-mediated disease or condition, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 301 - 312 or a pharmaceutically acceptable salt, deuterated analogue, tautomer or stereoisomer thereof, or a pharmaceutical composition according to any one of Embodiments 313 - 314.

[0626] Embodiment 316 of the present disclosure relates to the method according to Embodiment 315, wherein the disease or condition is a cancer having a Her2 YVMA insertion mutation.

[0627] Embodiment 317 of the present disclosure relates to a method for treating a disease or condition according to Embodiment 315, wherein the disease or condition is a cancer selected from the following: lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma.

[0628] Embodiment 318 of the present disclosure relates to a method for treating a disease or condition according to any one of Embodiments 315 - 317, wherein the disease or condition is non-small cell lung cancer.

[0629] Embodiment 319 of the present disclosure relates to the method according to any one of Embodiments 315 - 318, further comprising administering one or more additional therapeutic agents.

[0630] Embodiment 320 of the present disclosure relates to the method according to Embodiment 319, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, heptamethylenediamine disulfonate, ifosfamide, iproplatin, ilofosine, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and CTLA4 inhibitors; v) antibody-drug conjugates selected from ado-trastuzumab emtansine and deruxtecan; vi) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, megestrol acetate, raloxifene, tamoxifen, and toremifene; vii) taxanes selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; viii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; x) antiangiogenic agents selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, lenalidine, and thalidomide; xi) topoisomerase inhibitors selected from amsacrine, edotecarin, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiv) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xv) IDO inhibitors;xvi) chemotherapeutic agents selected from 3-AP (3-amino-2-formyl thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elisidepsin, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, testolactone, thiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors and aromatase inhibitors (anastrozole, letrozole, exemestane); xvii) BRAF inhibitors; xviii) Mek inhibitors; xix) c-Kit mutant inhibitors; xx) EGFR inhibitors; xxi) epigenetic regulators; xxii) other adenosine axis blockers selected from CD39, CD38, A2AR and A2BR; or xxiii) agonists of TNFA superfamily members; and xxiv) anti-ErbB2 mAb.;

[0631] Embodiment 321 of the present disclosure relates to the method according to Embodiment 319, wherein the one or more additional therapeutic agents are ado-trastuzumab emtansine or deruxtecan.

[0632] The compounds contemplated herein are described with reference to general formulas and specific compounds. In addition, the compounds described herein may exist in a variety of different forms or derivatives, all of which are within the scope of the present disclosure. For example, these include tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g., carboxylic acid esters) and active metabolites.

[0633] It is understood that some compounds may exhibit tautomerism. In such cases, the formulas provided herein only explicitly depict one possible tautomeric form. Therefore, it should be understood that the formulas provided herein are intended to represent any tautomeric form of the depicted compound, not limited solely to the specific tautomeric form depicted in the figure of the formula.

[0634] Similarly, some compounds according to the present disclosure may exist as stereoisomers as defined herein. All such individual stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present disclosure. Unless otherwise stated, all such stereoisomeric forms are included in the formulas provided herein.

[0635] In some embodiments, the chiral compounds of the present disclosure are in a form containing at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.) or 99% (98% e.e. or d.e.). As generally understood by those skilled in the art, an optically pure compound having one chiral center is a compound consisting essentially of one of the two possible enantiomers (i.e., is enantiopure), and an optically pure compound having more than one chiral center is a compound having both diastereopurity and enantiopurity. In some embodiments, the compound exists in an optically pure form.

[0636] For the synthesis of compounds involving the addition of a single group at a double bond (especially a carbon-carbon double bond), the addition can occur at the atoms to which the double bond is attached. For such compounds, the present disclosure includes both regioisomers.

[0637] In addition to the formulas and compounds described herein, the present disclosure also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolite derivatives (active metabolites) and pharmaceutically acceptable salts thereof.

[0638] Unless otherwise indicated, the description of compounds herein includes pharmaceutically acceptable salts of such compounds.

[0639] In some embodiments, the compounds of the present disclosure are complexed with an acid or a base, including base addition salts such as ammonium salts, diethylamine salts, ethanolamine salts, ethylenediamine salts, diethanolamine salts, tert-butylamine salts, piperazine salts, meglumine salts; acid addition salts such as acetate, acetylsalicylate, benzenesulfonate, camphorsulfonate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and toluenesulfonate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. In some cases, the amorphous form of the complex can be facilitated by additional processing such as by spray drying, mechanochemical methods (such as roller compaction) or microwave irradiation of the parent compound mixed with an acid or a base. Such methods may also include the addition of ionic and / or non-ionic polymer systems including, but not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copolymers of methacrylic acid (e.g., L100-55), which further stabilizes the amorphous nature of the complex. Such amorphous complexes offer several advantages. For example, reducing the melting temperature relative to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. In addition, the amorphous complex is readily friable, which provides improved compression for loading the solid into capsule or tablet forms.

[0640] III. Formulations and Administration

[0641] Embodiment 25 of the present disclosure relates to a pharmaceutical composition comprising the compound described in any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0642] Embodiment 26 of the present disclosure relates to the pharmaceutical composition according to Embodiment 25, further comprising a second agent.

[0643] Suitable dosage forms depend in part on the use or route of administration, such as oral, transdermal, transmucosal, inhalation, or by injection (parenteral). Such dosage forms should allow the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effect. Techniques and formulations generally can be found in The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (which is hereby incorporated by reference herein).

[0644] The compounds of the present disclosure (i.e., any compound described in Embodiments 1-24, including any sub-embodiments thereof) can be formulated as pharmaceutically acceptable salts.

[0645] Carriers or excipients can be used to produce the composition. The carrier or excipient can be selected to facilitate the administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or various types of starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. Examples of physiologically compatible solvents include water for injection (WFI), normal saline, and sterile solutions of glucose.

[0646] The compound can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalation. In some embodiments, the compound can be administered by oral administration. For oral administration, for example, the compound can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.

[0647] For inhalants, the compounds of the present disclosure can be formulated as dry powders or suitable solutions, suspensions, or aerosols. Powders and solutions can be formulated with suitable additives known in the art. For example, powders can include suitable powder matrices such as lactose or starch, and solutions can include propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, bases, and buffer salts. Such solutions or suspensions can be administered by inhalation via, for example, spraying, pumping, nebulizing, or atomizing. The compounds of the present disclosure can also be used in combination with other inhalation therapies, such as corticosteroids, such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; β-agonists, such as albuterol, salmeterol, and formoterol; anticholinergics, such as ipratropium bromide or tiotropium bromide; vasodilators, such as treprostinal and iloprost; enzymes, such as DNase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides, such as single-stranded or double-stranded DNA or RNA, siRNA; antibiotics, such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocromil sodium; and sodium cromoglycate.

[0648] Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable auxiliaries, if desired, to obtain tablet or lozenge cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: polyvidone). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or salts thereof such as sodium alginate, can be added.

[0649] The lozenge cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain, for example, gum-100-yridi, talc, polyvinylpyrrolidone, -100-yridine gum, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or lozenge coatings for identification or characterization of different combinations of the active compound dosage.

[0650] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin ("gelcaps"), and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol (PEG). In addition, a stabilizer can be added.

[0651] Alternatively, injection (parenteral administration) can be used, for example intramuscular, intravenous, intraperitoneal and / or subcutaneous. For injection, the compounds of the present disclosure are formulated in a sterile liquid solution, such as in a physiologically compatible buffer or solution such as saline, Hank's solution or Ringer's solution. In addition, the compounds can be formulated in solid form and redissolved or suspended immediately before use. A lyophilized form can also be produced.

[0652] Administration can also be by transmucosal, topical, transdermal or inhalation routes. For transmucosal, topical or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are well known in the art and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to facilitate penetration. For example, transmucosal administration can be by nasal spray or suppository (rectal or vaginal).

[0653] The topical compositions of the present disclosure are formulated as oils, creams, emulsions, ointments, etc. by selecting suitable carriers known in the art. Suitable carriers include vegetable oils or mineral oils, white petrolatum (white soft paraffin), branched-chain fats or oils, animal fats and high molecular weight alcohols (greater than C 12 ). In another embodiment, the carrier is one in which the active ingredient is soluble. If desired, emulsifiers, stabilizers, humectants and antioxidants, as well as agents imparting color or fragrance, can also be included. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. In addition, transdermal administration can include transdermal patches or dressings such as bandages impregnated with the active ingredient and one or more carriers or diluents known in the art. Of course, when administered in the form of a transdermal delivery system, the dose administration will be continuous rather than intermittent throughout the dosing regimen.

[0654] Taking into account such as compound IC 50、The amount of the compound to be administered can be determined for each case through standard procedures, taking into account factors such as the biological half-life of the compound, the age, size, and weight of the subject, and the indication being treated. The significance of these and other factors is well known to those of ordinary skill in the art. Generally, the dose will be between about 0.01 and 50 mg / kg or 0.1 and 20 mg / kg of the subject being treated. Multiple doses can be used.

[0655] The compounds of the present disclosure can also be used in combination with other therapies for treating the same disease. Such combinations include administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapies. In some embodiments, the doses of the compounds of the present disclosure or one or more of the other therapeutic agents used in combination can be modified by methods well known to those of ordinary skill in the art, for example, reducing the amount of drug administered relative to the compound or therapy used alone.

[0656] It is understood that combination use includes use in combination with other therapies, drugs, medical procedures, etc., where the other therapies or procedures can be administered at a different time from the compounds of the present disclosure (e.g., within a short time, such as within several hours (e.g., 1, 2, 3, 4 - 24 hours) or within a longer time (e.g., 1 - 2 days, 2 - 4 days, 4 - 7 days, 1 - 4 weeks)), or administered simultaneously with the compounds of the present disclosure. Combination use also includes use with therapies or medical procedures administered once or infrequently (such as surgery), and the compounds of the present disclosure administered within a short or long time before or after the other therapies or procedures. In some embodiments, the present disclosure provides for delivering the compounds of the present disclosure and one or more other pharmaceutical therapeutic agents by different administration routes or by the same administration route. Combination use for any administration route includes delivering the compounds of the present disclosure and one or more other pharmaceutical therapeutic agents delivered by the same administration route in any formulation, including formulations in which the two compounds are chemically linked and maintain their therapeutic activity upon administration. In one aspect, other pharmaceutical therapies can be co - administered with one or more compounds of the present disclosure. Combination use by co - administration includes administering co - formulations or formulations of chemically - bound compounds by the same or different routes, or administering two or more compounds in separate formulations within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours). Co - administration of separate formulations includes co - administering via one device (e.g., the same inhalation device, the same syringe, etc.) or administering from separate devices within a short time of each other. Co - formulations of the compounds of the present disclosure and one or more other pharmaceutical therapies delivered by the same route include preparing the materials together such that they can be administered by one device, including separate compounds combined in one formulation, or modified compounds such that they are chemically bound but still maintain their biological activity. Such chemically - bound compounds can have a bond that is substantially maintained in the body, or the bond can break down in the body, separating the two active components.

[0657] IV. Methods of Use

[0658] Disease Indications and Modulation of Her2

[0659] Exemplary Diseases Associated with Her2

[0660] Her2 overexpression has been reported in various tumors, including lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma [1]. In addition, comorbidities that can be associated with Her2-mediated tumors such as stage IV WT NSCLC include pulmonary conditions, hypertension, hypercholesterolemia, cardiovascular disease, renal function conditions, thyroid conditions, obesity, depressive anxiety, osteoporosis, liver conditions, autoimmune diseases, dementia, and Alzheimer's disease. It is expected that such comorbidities can also be treated with Her2 inhibitors such as the compounds of the present disclosure.

[0661] The methods and compounds are generally used for the therapy of human subjects. However, they can also be used to treat similar or the same indications in other animal subjects.

[0662] References:

[0663] 1. Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Molecular Biology International. 2014; 852748:2014.

[0664] In certain embodiments, the patient is 60 years of age or older and has relapsed after first-line cancer therapy. In certain embodiments, the patient is 18 years of age or older and has relapsed or is refractory after second-line cancer therapy. In certain embodiments, the patient is 60 years of age or older and is primarily refractory to first-line cancer therapy. In certain embodiments, the patient is 70 years of age or older and has not been previously treated. In certain embodiments, the patient is 70 years of age or older and is ineligible and / or unlikely to benefit from cancer therapy.

[0665] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg per day. In certain embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, or 2500 mg per day. In other embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg or more per day. In certain embodiments, -104-yridined is administered continuously.

[0666] In certain embodiments, provided herein is a method for treating a Her2-mediated disease or condition by administering to a mammal having the disease or condition any compound described in any of embodiments 1-24 or any sub-embodiment thereof, or a pharmaceutically acceptable salt, deuterated analogue, tautomer, or stereoisomer thereof, or a pharmaceutical composition in any of embodiments 25-26, in an amount of at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg per day, and wherein the compound is administered on an empty stomach.

[0667] Embodiment 27 of the present disclosure relates to a method for treating a subject having a Her2-mediated disease or condition, the method comprising administering to the subject an effective amount of a compound described in any of embodiments 1-24 or any sub-embodiment thereof, or a pharmaceutically acceptable salt, deuterated analogue, tautomer, or stereoisomer thereof, or a pharmaceutical composition in any of embodiments 25-26.

[0668] Embodiment 28 of the present disclosure relates to the method according to embodiment 27, wherein the disease or condition is a cancer having a Her2 YVMA insertion mutation.

[0669] Embodiment 29 of the present disclosure relates to the method according to Embodiment 27, wherein the disease or condition is cancer selected from the following: lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma.

[0670] Embodiment 30 of the present disclosure relates to the method according to any one of Embodiments 27-29, wherein the disease or condition is non-small cell lung cancer.

[0671] V. Combination Therapies

[0672] A Her2 modulator can be usefully combined with another pharmaceutically active compound or with two or more other pharmaceutically active compounds, particularly in the treatment of cancer. In one embodiment, the combination comprises any one or more of the compounds described herein and one or more compounds having therapeutic efficacy against the same disease indication, wherein the compounds are synergistic against the disease indication. In one embodiment, the combination comprises any one or more of the compounds described herein that are effective in the treatment of cancer and one or more other compounds that are effective in the treatment of the same cancer, further wherein the compounds are synergistically effective in the treatment of cancer.

[0673] Embodiment 31 of the present disclosure relates to the method according to any one of Embodiments 27-29, further comprising administering one or more additional therapeutic agents.

[0674] Embodiment 32 of the present disclosure relates to the method according to Embodiment 31, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, 1,7-heptanediol bis(aminosulfonate), ifosfamide, iproplatin, ilofosine, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and CTLA4 inhibitors; v) antibody-drug conjugates selected from ado-trastuzumab emtansine and deruxtecan; vi) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, megestrol acetate, raloxifene, tamoxifen, and toremifene; vii) taxanes selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; viii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; x) antiangiogenic agents selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, lenalidine, and thalidomide; xi) topoisomerase inhibitors selected from amsacrine, edotecarin, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxyellipticine, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiv) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xv) IDO inhibitors;xvi) Chemotherapeutic agents selected from 3-AP (3-amino-2-formyl thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elisomel, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, testolactone, thiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors and aromatase inhibitors (anastrozole, letrozole, exemestane); xvii) BRAF inhibitors; xviii) Mek inhibitors; xix) c-Kit mutant inhibitors; xx) EGFR inhibitors; xxi) epigenetic regulators; xxii) other adenosine axis blockers selected from CD39, CD38, A2AR and A2BR; or xxiii) agonists of TNFA superfamily members; and xxiv) anti-ErbB2 mAb.;

[0675] Her2 ubiquitination and internalization are key mechanisms underlying potential endocytosis and subsequent potency of anti-Her2 antibody-drug conjugates (ADCs). Non-limiting examples of anti-HER2 ADCs include (ado-trastuzumab emtansine) (T-DM1), which is approved for patients with Her2-positive, metastatic breast cancer and Her2-positive early breast cancer. Another ADC is (trastuzumab deruxtecan) (T-DXd) - which is currently in Phase 2 for previously treated Her-mutant NSCLC and is currently approved for (1) unresectable or metastatic HER2-positive breast cancer, (2) unresectable or metastatic HER2-low breast cancer, (3) unresectable or metastatic non-small cell lung cancer and (4) locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.

[0676] The irreversible Her2 kinase inhibitors of the present disclosure can enhance Her2 ubiquitination and internalization by disrupting the Her2:HSP90 chaperone molecule interaction, leading to degradation of the Her2 receptor. Thus, the Her2 kinase inhibitors of the present disclosure can enhance the potency of these ADC drugs, which require co-internalization with Her2 into lysosomes to release the tumor cell killing payload.

[0677] Embodiment 33 of the present disclosure relates to the method according to embodiment 32, wherein the one or more additional therapeutic agents are ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0678] Embodiment 34 of the present disclosure relates to the method according to embodiment 32, wherein the one or more additional therapeutic agents are pembrolizumab or nivolumab.

[0679] Embodiment 34 of the present disclosure relates to the method according to Embodiment 32, wherein the one or more additional therapeutic agents are pembrolizumab.

[0680] Non-limiting examples of PD-1 inhibitors that can be combined with the compounds of the present disclosure for the therapeutic methods of the present disclosure include pembrolizumab nivolumab, cemiplimab. Non-limiting examples of PD-L1 inhibitors that can be combined with the compounds of the present disclosure include atezolizumab, avelumab, and durvalumab. Non-limiting examples of CTLA4 inhibitors that can be combined with the compounds of the present disclosure include ipilimumab.

[0681] In another embodiment, the compounds of the present disclosure are combined with docetaxel or gemcitabine in the therapeutic methods of the present disclosure.

[0682] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof by administering to the subject an effective amount of a composition comprising any one or more of the compounds described herein, in combination with one or more other therapies or medical procedures effective in treating cancer. Other therapies or medical procedures include suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiotherapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, one or more suitable anti-cancer therapies or medical procedures are selected from treatment with chemotherapeutic agents (e.g., chemotherapeutic drugs), radiotherapy (e.g., x-rays, gamma rays or electron, proton, neutron or alpha particle beams), hyperthermia (e.g., microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma tumor vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF-secreting breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g., Ad5CMV-p53 vector, adenovirus vector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexatin lutetium), surgery or bone marrow and stem cell transplantation.

[0683] VI. Kits

[0684] In another aspect, the present disclosure provides a kit that includes one or more compounds as described in any one of embodiments 1-15, or a pharmaceutically acceptable salt, deuterated analogue, tautomer, or stereoisomer thereof, or a pharmaceutical composition in one of embodiments 16-17. In some embodiments, the compound or composition is packaged in, for example, a vial, bottle, flask, which can be further packaged in, for example, a box, envelope, or bag. The compound or composition can be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal (e.g., a human). The compound or composition can be approved for administration to a mammal (e.g., a human) for a Her2-mediated disease or condition. The kits described herein can include written instructions for use and / or other indications that the compound or composition is suitable or approved for administration to a mammal (e.g., a human) for a Her2-mediated disease or condition. The compound or composition can be packaged in unit dose or single-dose form, such as single-dose pills, capsules, etc.

[0685] VII. Binding Assays

[0686] The methods of the present disclosure can involve assays capable of detecting the binding of a compound to a target molecule. Such binding is at a statistically significant level, with a confidence level of at least 90%, or a confidence level of at least 95%, 97%, 98%, 99% or higher, i.e., the assay signal represents binding to the target molecule, i.e., distinguishable from the background. In some embodiments, a control is used to distinguish target binding from non-specific binding. For different target types, there are various assays known to indicate binding and can be used for the present disclosure.

[0687] A binding compound can be characterized by its effect on the activity of a target molecule. Thus, under standard conditions, the inhibitory concentration (IC 50 ) or effective concentration (EC 50 ) of a "low activity" compound is greater than 1 μM. "Very low activity" means that the IC 50 or EC 50 is higher than 100 μM under standard conditions. "Extremely low activity" means that the IC 50 or EC 50 is higher than 1 mM under standard conditions. "Moderate activity" means that the IC 50 or EC 50 is from 200 nM to 1 μM. "Moderately high activity" means that the IC 50 or EC 50 is from 1 nM to 200 nM. "High activity" means that the IC 50 or EC 50 is below 1 nM under standard conditions. The IC 50 or EC 50Defined as the concentration of a compound at which 50% loss or gain of activity of a measured target molecule (e.g., an enzyme or other protein) occurs relative to the range of activity observed when the compound is absent. Activity can be measured using methods known to those of ordinary skill in the art, e.g., by measuring any detectable product or signal generated by the occurrence of an enzymatic reaction, or by other activities of the measured protein.

[0688] “Background signal” for a binding assay means the signal recorded under the standard conditions of a particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule. Those of ordinary skill in the art will recognize that acceptable methods exist and are widely available for determining the background signal.

[0689] “Standard deviation” means the square root of the variance. Variance is a measure of the spread of a distribution. It is calculated as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2, and the variance is:

[0690]

[0691] Measuring enzymatic and binding reactions during a screening assay

[0692] Techniques for measuring the progress of enzymatic and binding reactions, e.g., in multi-well carriers, are known in the art and include, but are not limited to, the following.

[0693] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays to detect peroxide as described in Gordon, A.J. and Ford, R.A., (1972) The Chemist’s Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, N.Y., page 437.

[0694] Fluorescence spectroscopy can be used to monitor the formation of reaction products. Fluorescence methods are generally more sensitive than absorption methods. The use of fluorescent probes is well known to those of skill in the art. For a review, see Bashford et al., (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pages 91 - 114, IRL Press Ltd.; and Bell, (1981) Spectroscopy In Biochemistry, Volume I, pages 155 - 194, CRC Press.

[0695] In fluorescence spectrophotometric methods, an enzyme is exposed to a substrate that changes its intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is non-fluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, Smase activity can be detected using Red reagent (Molecular Probes, Eugene, OR). To measure sphingomyelinase activity using Red, the following reactions occur. First, Smase hydrolyzes sphingomyelin to produce ceramide and phosphocholine. Second, alkaline phosphatase hydrolyzes phosphocholine to produce choline. Third, choline is oxidized by choline oxidase to betaine. Finally, in the presence of horseradish peroxidase, H2O2 reacts with Red to produce the fluorescent product Resorufin, and its signal is detected using fluorescence spectrophotometry.

[0696] Fluorescence polarization (FP) is based on the decrease in the rotational speed of fluorophore molecules when bound to larger molecules such as receptor proteins, allowing the bound ligand to emit polarized fluorescence. FP is determined empirically by measuring the vertical and horizontal components of the fluorescence emitted by a fluorophore after excitation with plane-polarized light. When the molecular rotation of the fluorophore decreases, the polarized emission increases. When the fluorophore binds to a larger molecule (i.e., the receptor), the fluorophore produces a larger polarized signal, slowing the molecular rotation of the fluorophore. The magnitude of the polarized signal is quantitatively related to the extent of binding of the fluorescent ligand. Thus, the polarization of the "binding" signal depends on the maintenance of high-affinity binding.

[0697] FP is a homogeneous technique and the reaction is very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable and can be prepared in large batches, resulting in high reproducibility. Due to these properties, FP has proven to be highly automatable, typically using a single pre-mixed tracer-receptor reagent for a single incubation. For a review, see Owicki et al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27.

[0698] FP is particularly desirable because its readout is independent of emission intensity (Checovich, W.J., et al., (1995) Nature 375:254-256; Dandliker, W.B., et al., (1981) Methods in Enzymology 74:3-28), and is thus insensitive to the presence of colored compounds that quench fluorescent emission. FP and FRET (see below) are well suited for identifying compounds that block the interaction between sphingolipid receptors and their ligands. See, e.g., Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5:77-88.

[0699] Fluorophores derived from sphingolipids that can be used in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and a ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl) sphingomyelin phosphocholine ( FL C5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl) sphingomyelin phosphocholine ( FL C12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl) sphingosine ( FL C5-ceramide). U.S. Patent No. 4,150,949 (Immunoassay for gentamicin) discloses fluorescein-labeled gentamicin, including fluorescein thiocarbonyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled in the art.

[0700] Exemplary normal and polarization fluorometers include a fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). General purpose microplate readers for other assays are available, such as a reader and a microplate spectrophotometer (both from Molecular Devices).

[0701] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. See, e.g., Heim et al., (1996) Curr. Biol. 6:178-182; Mitra et al., (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects energy transfer between two fluorophores in close proximity with known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when the protein specifically interacts with a target molecule, resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample changes, which can be measured by a fluorometer, such as the fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

[0702] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interactions with target molecules. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., (1997) J. Lipid Res. 38:2365-2373; Kahl et al., (1996) Anal. Biochem. 243:282-283; Undenfriend et al., (1987) Anal. Biochem. 161:494-500). See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734. A commercially available system uses scintillant-coated plates (NEN LifeScience Products, Boston, MA).

[0703] The target molecule can be bound to the scintillation plate by a variety of well-known methods. The scintillation plate can be derivatized to bind to fusion proteins, such as GST, His6, or Flag fusion proteins. When the target molecule is a protein complex or multimer, one protein or subunit can first be attached to the plate and then the other components of the complex are added under binding conditions, resulting in a bound complex.

[0704] In a typical SPA assay, the gene product in the expression pool will be radiolabeled and added to the wells and allowed to interact with the solid phase, which is the immobilized target molecule and scintillant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when the radiolabel is close enough to the scintillant coating, it produces a signal detected by a device such as TOPCOUNT Signals detectable by a microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If the radiolabeled expression product binds to the target molecule, the radiolabel remains near the scintillant long enough to generate a detectable signal.

[0705] In contrast, labeled proteins that do not bind to the target molecule or bind only transiently will not remain near the scintillant long enough to generate a signal above background. Any time spent near the scintillant due to random Brownian motion will also not generate a significant signal. Similarly, residual unincorporated radiolabel used during the expression step may be present, but will not generate a significant signal because it will be in solution rather than interacting with the target molecule. Thus, these non-binding interactions will result in a certain degree of background signal, which can be mathematically removed. If too much signal is obtained, salts or other modifiers can be added directly to the assay plate until the desired specificity is obtained (Nichols et al., (1998) Anal. Biochem. 257:112-119).

[0706] VIII. General Synthesis

[0707] Compounds can be prepared using the methods disclosed herein and their conventional modifications, which will be apparent in view of the methods disclosed herein and well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of the exemplary compounds described herein can be accomplished as described in the following examples. If available, reagents can be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0708] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that unless otherwise specified, other process conditions can also be used when typical or preferred process conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) are given. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0709] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent unwanted reactions of certain functional groups. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, P.G.M., Greene, T.W., & Greene, T.W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience and the references cited herein.

[0710] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolvents, etc.

[0711] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts or obvious modifications thereof, such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0712] It will also be recognized that in each scheme, the addition of any substituent can result in the formation of many isomeric products (including but not limited to enantiomers or one or more diastereomers), any or all of which can be separated and purified using conventional techniques. When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials can be employed, as is conventional in the art or as described in the examples.

[0713] The compounds of the present disclosure can be synthesized according to the schemes and examples described below. The examples can be varied by substituting other materials having similar structures for the starting materials to produce the corresponding products. The structure of the desired product will generally make clear to those skilled in the art the starting materials required.

[0714] General Scheme 1

[0715]

[0716] Step 1: Compound (i) can be converted to compound (ii) by applying a peptide coupling reagent such as PyBroP (by way of example) under suitable reaction conditions (which can be in the presence of a tertiary amine such as triethylamine). The reaction can be carried out in a suitable solvent, which can be an aprotic solvent such as THF, but can vary depending on the starting material or intermediate compound. The variables E1, E2, A, G, R1, and R2 in General Scheme 1 are as defined in the present disclosure. The variable X in General Scheme 1 is a suitable leaving group such as Br or Cl.

[0717] Step 2: Compound (ii) can be converted to compound I by a cross-coupling reaction, such as a palladium-catalyzed Suzuki coupling with an organoborate such as to arrive at compound I, by way of example. The variable G can be further modified one or more times by the techniques described in the present disclosure or by techniques known in the art.

[0718] General Scheme 2

[0719]

[0720] Step 1': Compound (iv) can be converted to compound (v) by applying a peptide coupling reagent such as PyBroP (by way of example) in the presence of a tertiary amine such as triethylamine. The reaction can be carried out in an aprotic solvent such as THF. The variables E1, E2, A, R1, and R2 in General Scheme 1 are as defined in the present disclosure. The variable G' can be a BOC-protected G group or another precursor, which can be modified one or more times by the techniques described in the present disclosure or by techniques known in the art. G' can also be the same as the variable G described in the present disclosure, in which case there is no Step 2' to modify G'.

[0721] Step 2': Compound (v) can be converted to compound I by one or more techniques described in the present disclosure or known in the art. Such one or more techniques can include (by way of example) BOC deprotection, a peptide coupling reaction with HATU, amide formation with HOBt, or nucleophilic substitution.

[0722] Synthesis of Intermediate A

[0723] Intermediate A

[0724]

[0725] Step 1. 1-Amino-3-bromo-1H-pyrrole-2-carboxylic acid methyl ester

[0726]

[0727] A solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (25 g, 122.53 mmol) in DMF (200 mL) and THF (1000 mL) was treated with NaH (60% in mineral oil, 6.37 g, 159.25 mmol) at 0 °C for 1 h, then O-(2,4-dinitrophenyl)hydroxylamine (29.28 g, 147.04 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (500 ml) at 0 °C. The resulting mixture was diluted with water (1 L) and extracted with ethyl acetate (1.5 L x 2). The combined organic layers were washed with brine (1.5 L x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 20% ethyl acetate in hexane) to afford methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (22 g, 81.97%). LCMS (ESI-MS) m / z = 219.0 [M+H] +

[0728] Step 2. 5-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

[0729]

[0730] To a stirred solution of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (22 g, 100.43 mmol) in iPrOH (150 mL) was added formamidine acetate (20.91 g, 200.87 mmol). The mixture was stirred at 80 °C overnight. The resulting mixture was diluted with water (300 ml). The precipitated solid was collected by filtration and washed with water (100 ml x 3) and petroleum ether (200 ml) to afford 5-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (13.2 g crude). LCMS (ESI-MS) m / z = 214.0 [M+H] + 。

[0731] Step 3. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine

[0732]

[0733] A solution of 5-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (13.2 g, 61.97 mmol), 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (14.87 g, 61.97 mmol), PyBrop (43.31 g, 92.95 mmol) and Et3N (18.81 g, 185.91 mmol) in THF (300 mL) was stirred at 80 °C overnight. The resulting mixture was purified by silica gel column chromatography (0 - 80% ethyl acetate in hexane) to afford the title compound N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, Intermediate A (12 g, 27.33%). LCMS (ESI-MS) m / z = 436.0 [M+H] + 。

[0734] In the following synthetic examples, where pure stereoisomers are separated by chiral resolution, all pure stereoisomers of these compounds are eluted as separate fractions as described herein. The 1 1H NMR and MS data for each eluted pure stereoisomer are obtained to verify that all pure stereoisomers of such compounds are separated. The absolute stereochemistry of each separated fraction is not determined.

[0735] In other synthetic examples, conventional HPLC is used to separate endo-exo products or diastereoisomers to obtain fractions of each racemate. The 1 1H NMR and MS data for each eluted endo-exo product and diastereoisomer are obtained to verify that all endo-exo products or diastereoisomers of such compounds are separated. The absolute stereochemistry of each separated fraction is not determined.

[0736] All compounds in Table 1 are found to effectively inhibit one or more of HER2-YVMA, HER2 WT and EGFR WT.

[0737] The following example numbers correspond to the compound numbers in Table 1.

[0738] Example 1

[0739] EXAMPLE1

[0740]

[0741] Step 1. (E)-tert-butyl 3-(2-(phenylsulfonyl)vinyl)azetidine-1-carboxylate

[0742]

[0743] Under a nitrogen atmosphere at -20 °C, a solution of lithium bis(trimethylsilyl)amide (1 M solution in THF, 189 mL, 189 mmol) was added dropwise to a solution of phenyl methanesulfonate (16.7 g, 107 mmol) in anhydrous tetrahydrofuran (160 mL), and the reaction was allowed to stir at -20 °C for 30 minutes. Trimethylchlorosilane (12.6 mL, 99.2 mmol) was added to the reaction mixture and stirred for an additional 15 minutes. A solution of tert-butyl 3-formylazetidine-1-carboxylate (19.8 g, 106.9 mmol) in anhydrous tetrahydrofuran (200 mL) was added dropwise to the reaction mixture and allowed to stir at -20 °C for an additional 3 hours. This operation was repeated twice. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 L) and extracted with ethyl acetate (2 x 1 L). The combined organic matter was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate, 15%) to give tert-butyl (E)-3-(2-(phenylsulfonyl)vinyl)azetidine-1-carboxylate (52 g, 47.6%). LCMS (ESI-MS) m / z = 324.1 [M+H] + 。

[0744] Step 2. Ethyl 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate

[0745]

[0746] Under a nitrogen atmosphere at 0 °C, potassium 2-methyl-2-propanolate (11.0 g, 98.2 mmol) was added to a mixture of ethyl 2-isocyanoacetate (8.4 g, 37.1 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred for 10 minutes. Then, (E)-tert-butyl 3-(2-(phenylsulfonyl)vinyl)azetidine-1-carboxylate (20 g, 61.8 mmol) in THF (100 mL) was added to the mixture and stirred at 25 °C for a period of one hour. This operation was repeated twice. The reaction was quenched by adding saturated aqueous ammonium chloride (500 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10%) to give ethyl 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate (27 g, 42.2%). LCMS (ESI-MS) m / z = 295.2 [M+H] + 。

[0747] Step 3. Ethyl 1-amino-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate

[0748]

[0749] Add MTBE (1 L) and ammonium chloride (30 g, 0.565 mol) to a flask. Cool the reaction to -20 °C. Then add concentrated aqueous ammonium hydroxide (80 mL) to the reaction and subsequently slowly add commercial grade sodium hypochlorite solution (750 mL). After the addition, stir the reaction at -20 °C for an additional 30 minutes. Separate the MTBE layer, wash it with brine and dry over anhydrous sodium sulfate. Add ethyl 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate (27 g, 91.8 mmol) and dry DMF (300 mL) under nitrogen in a separate flask. Cool the reaction to 0 °C and add sodium hydroxide (7.3 g, 183.6 mmol) to the reaction in portions. Stir the reaction at 0 °C for an additional 1 hour and then cool it to -20 °C. At this point, slowly add the previously prepared MTBE solution of chloramine to the reaction and stir the mixture at -20 °C for 1 hour. Quench the reaction with saturated sodium thiosulfate solution. Separate the organic layer of the reaction, wash it with water and brine, dry over sodium sulfate, filter and concentrate to afford ethyl 1-amino-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate (21 g, 60.3%). LCMS (ESI-MS) m / z = 310.2 [M+H] + 。

[0750] Step 4. tert-Butyl 3-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate

[0751]

[0752] Add formamidine acetate (7.06 g, 67.8 mmol) to a mixture of ethyl 1-amino-3-[1-(tert-butoxycarbonyl)azetidin-3-yl]pyrrole-2-carboxylate (4 g, 13.5 mmol) in iPrOH (15 mL). Then stir the reaction mixture at 80 °C for 12 hours. Concentrate the reaction mixture in vacuo and purify it by silica gel column chromatography, eluting with PE / EA (37%) and concentrate to afford tert-Butyl 3-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (15 g, 76.1%). LCMS (ESI-MS) m / z = 291.1 [M+H] + 。

[0753] Step 5.3 - tert-Butyl 1-azetidinecarboxylate (4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)

[0754]

[0755] Bromotris(pyrrolidin-1-yl)phosphonium; hexafluoro-λ5-phosphanuide (2.41 g, 5.16 mmol) was added to a mixture of tert-butyl 1-azetidinecarboxylate (1 g, 3.44 mmol), 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (830 mg, 3.44 mmol), and triethylamine (1.1 g, 10.33 mmol) in THF (30 mL). The reaction mixture was then stirred at 80 °C overnight. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford the crude product and then purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:6) to afford 1.2 g of the crude product (containing 40% of the SM). The crude material was then repurified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min; detector, UV 254 nm and concentrated to afford tert-butyl 1-azetidinecarboxylate (4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl) (553 mg, 31.25%). LCMS (ESI-MS) m / z = 513.2 [M+H] + 。

[0756] Step 6. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0757]

[0758] A solution of TFA (1 mL) and tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (300 mg, 0.58 mmol) in DCM (2 mL) was stirred at 25 °C for 1 h. The resulting mixture was concentrated under vacuum to afford crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (250 mg). LCMS (ESI-MS) m / z = 413.2 [M+H] + 。

[0759] Step 7. (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0760]

[0761] A solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (250 mg, 0.61 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (94 mg, 0.72 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (277 mg, 0.72 mmol) and N,N-diisopropylethylamine (237 mg, 1.81 mmol) in DMF (5 mL) was stirred overnight at room temperature. The resulting mixture was purified by reverse phase flash with the following conditions (5 mmol / L NH4HCO3, flow rate: 50 mL / min, 30%) to afford (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 1 (138 mg, 42.9%). LCMS (ESI-MS) m / z = 524.1 [M+H] + 。

[0762] Example 3

[0763]

[0764] 1-(3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)prop-2-en-1-one

[0765] A solution of acryloyl chloride (19.3 mg, 0.21 mmol) in DCM (1 mL) was added dropwise to a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.19 mmol) and Et3N (98.1 mg, 0.97 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes, quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with methanol in dichloromethane from 0% to 10% to afford the crude product. The crude product was re-purified by Prep-HPLC with mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 20% B to 50% B to afford the desired product 1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)prop-2-en-1-one, Example 3 (13.3 mg, 9.8% yield). LCMS (ESI-MS) m / z = 467.3 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.94 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 7.68 (s, 1H), 7.29 - 7.17 (m, 2H), 7.12 (s, 1H), 7.09 - 7.02 (m, 1H), 6.99 (s, 2H), 6.81 (s, 1H), 6.47 - 6.32 (m, 1H), 6.13 (d, J = 16.4 Hz, 1H), 5.77 - 5.63 (m, 1H), 4.70 (s, 2H), 4.42 (s, 1H), 4.29 (s, 1H), 4.10 - 3.99 (m, 1H), 2.18 (s, 3H).

[0766] Example 6

[0767]

[0768] Step 1.4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0769]

[0770] Under a nitrogen atmosphere, a mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.45 mmol), piperazine-1-carboxylic acid tert-butyl ester (93.92 mg, 0.50 mmol), Pd2(dba)3 (41.98 mg, 0.05 mmol), BINAP (57.09 mg, 0.09 mmol) and t-BuONa (88.11 mg, 0.91 mmol) in dioxane (4 mL) was stirred at 100 °C for 72 h. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, 25 g, eluting with ethyl acetate in 0% to 80% petroleum ether at a flow rate of 20 mL / min), the desired fractions were combined and concentrated in vacuo to give the desired product 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 69%). LCMS (ESI-MS) m / z = 542.3 [M+H] + 。

[0771] Step 2. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0772]

[0773] A mixture of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperazine-1-carboxylate (200 mg, 0.37 mmol) and TFA (3 mL, 39.99 mmol) in DCM (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford the crude product. The crude product was purified by column chromatography (silica gel, 25 g, eluting with methanol in dichloromethane from 0% to 10%, flow rate 20 mL / min), the desired fractions were combined and concentrated under vacuum to afford N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (210 mg crude). LCMS (ESI-MS) m / z = 442.2 [M+H] + 。

[0774] Step 3. 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperazin-1-yl)prop-2-en-1-one

[0775]

[0776] A mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (210 mg, 0.47 mmol), acryloyl chloride (43.05 mg, 0.47 mmol) and Et3N (144.40 mg, 1.41 mmol) in DCM (2 mL) was stirred at 0 °C for 5 min. The reaction mixture was purified by column chromatography (silica gel, 25 g, eluting with ethyl acetate in petroleum ether from 0% to 80%, 20 mL / min). The fractions with the desired mass signal were combined and concentrated under vacuum to afford the desired product 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperazin-1-yl)prop-2-en-1-one, Example 6 (27.5 mg, 11.62%). LCMS (ESI-MS) m / z = 496.2 [M+H] + 。

[0777] Example 7

[0778]

[0779] Step 1. tert-Butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0780]

[0781] Under a nitrogen atmosphere, a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.46 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (141.75 mg, 0.46 mmol), Pd(dppf)Cl2 (37.34 mg, 0.05 mmol) and K2CO3 (126.71 mg, 0.92 mmol) in dioxane (4 mL) and H2O (1.2 mL) was stirred at 100 °C for 2 hours. The resulting mixture was concentrated in vacuo to afford a crude product. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate 1:10) to give tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, purity = 96.8%). LCMS (ESI-MS) m / z = 539.2 [M+H] + 。

[0782] Step 2. tert-Butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate

[0783] Under a hydrogen atmosphere, a solution of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.37 mmol) and Pd / C (395.16 mg, 3.71 mmol) in MeOH was stirred at room temperature overnight. The mixture was filtered off and the filtrate was concentrated in vacuo to afford a crude product. The crude product was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 541.3 [M+H]+ .

[0784] Step 3. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0785]

[0786] A solution of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate (140 mg, 0.26 mmol) in TFA (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to afford the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 441.2 [M+H] + .

[0787] Step 4. 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)prop-2-en-1-one

[0788]

[0789] A solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (70 mg, 0.16 mmol), acryloyl chloride (14.38 mg, 0.16 mmol) and Et3N (32.16 mg, 0.32 mmol) in DCM (2 mL) was stirred at 0 °C for 5 min. The resulting mixture was purified by Prep-TLC (ethyl acetate) to afford 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)prop-2-en-1-one, Example 7 (24.6 mg, 30.55%). LCMS (ESI-MS) m / z = 495.2 [M+H] + .

[0790] Example 8

[0791]

[0792] Step 1. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

[0793]

[0794] Under a nitrogen atmosphere, a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1 g, 2.29 mmol), tert-butyl 1,4-diazepane-1-carboxylate (918.15 mg, 4.58 mmol), PEPPSI (223.21 mg, 0.23 mmol) and Cs2CO3 (1493.65 mg, 4.58 mmol) in dioxane (10 mL) was stirred at 100 °C for 7 days. The resulting mixture was concentrated in vacuo to afford the crude product. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate 1:2) to give 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (500 mg crude). LCMS (ESI-MS) m / z = 556.3 [M+H] + 。

[0795] Step 2. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(2-aminoethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0796]

[0797] A solution of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,4-diazepane-1-carboxylate (500 mg, 0.90 mmol) and TFA (5 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford the crude product. The crude product was purified by Prep-TLC (dichloromethane / methanol 10:1) to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(2-aminoethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. LCMS (ESI-MS) m / z = 456.2 [M+H] + 。

[0798] Step 3. 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,4-diazepan-1-yl)prop-2-en-1-one

[0799]

[0800] A solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(2-aminoethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.44 mmol), acryloyl chloride (40.44 mg, 0.45 mmol) and NaHCO3 (110.65 mg, 1.32 mmol) in THF (1 mL) and H2O (1 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The crude product was purified by Prep-TLC (dichloromethane / methanol 10:1) to give 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,4-diazepan-1-yl)prop-2-en-1-one, Example 8 (31.5 mg, 13.85%). LCMS (ESI-MS) m / z = 510.1 [M+H] + 。

[0801] Example 9

[0802]

[0803] Step 1. 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine -1-tert-butyl carboxylate

[0804]

[0805] A solution of tert-butyl 4-oxoazepane-1-carboxylate (2 g, 9.37 mmol) in THF (20 mL) was treated with LiHMDS (10.3 mL, 10.31 mmol) at -78 °C for 1 h under a nitrogen atmosphere, and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (3.69 g, 10.31 mmol) was added dropwise at -78 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water (100 mL) at 0 °C and extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (9:1) to afford 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine -1-tert-butyl carboxylate (1.5 g, 46.32%). LCMS (ESI-MS) m / z = 346.1 [M+H] + 。

[0806] Step 2. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine -1-tert-butyl carboxylate

[0807]

[0808] To 4-(trifluoromethanesulfonyloxy)-2,3,6,7-tetrahydroazepine A solution of tert-butyl 1-formate (1.4 g, 4.05 mmol) in dioxane (20 mL) was added to 4,4,5,5-tetramethyl-2-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.46 g, 6.08 mmol), KOAc (1.19 g, 12.16 mmol) and Pd(dppf)Cl2 (0.30 g, 0.40 mmol). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction mixture was filtered off and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (9:1) to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine -1-carboxylic acid tert-butyl ester (1.1 g, 83.94%). LCMS (ESI-MS) m / z = 324.2 [M+H] + .

[0809] Step 3. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,3,6,7-tetrahydro-1H-azepine -1-carboxylic acid tert-butyl ester

[0810]

[0811] To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine A solution of tert-butyl 1-formate (200 mg, 0.61 mmol) in a mixture of dioxane (1 mL) and water (0.1 mL) was added to 5-bromo-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (134.97 mg, 0.30 mmol), K2CO3 (86.14 mg, 0.61 mmol) and Pd(dppf)Cl2 (22.64 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered off and the filtrate was concentrated in vacuo to afford a crude product. The crude product was purified by silica gel column chromatography, eluting with PE / EA (2:1) to afford tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,3,6,7-tetrahydro-1H-azepine -1-formate (110 mg, 32.18%). LCMS (ESI-MS) m / z = 553.3 [M+H] + .

[0812] Step 4. tert-Butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepane-1-carboxylate

[0813]

[0814] 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,3,6,7-tetrahydro-1H-azepine was hydrogenated at room temperature under a hydrogen atmosphere A mixture of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepane-1-carboxylate (110 mg, 0.199 mmol) in MeOH (3 mL) was stirred for 24 h. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 100% gradient, and concentrated under reduced pressure to afford tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepane-1-carboxylate (80 mg, 72.46%). LCMS (ESI-MS) m / z = 555.3 [M+H] + 。

[0815] Step 5. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azepan-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0816]

[0817] To a solution of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepane-1-carboxylate (70 mg, 0.126 mmol) in dichloromethane (3 mL) was added TFA (1 mL) for 1 h under a nitrogen atmosphere at room temperature. The resulting mixture was concentrated under reduced pressure to afford N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azepan-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine as a pale yellow solid. LCMS (ESI-MS) m / z = 455.2 [M+H] + 。

[0818] Step 6. 1-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepan-1-yl)prop-2-en-1-one

[0819]

[0820] To a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azepan-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.13 mmol) and Et3N (40.07 mg, 0.39 mmol) in DCM (2 mL) was added acryloyl chloride (11.95 mg, 0.13 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 min. The resulting mixture was concentrated and purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to give the crude product, which was then purified by reverse phase flash with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min, 60% B) to give 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azepan-1-yl)prop-2-en-1-one (3.0 mg, 4.44%). LCMS (ESI-MS) m / z = 510.2 [M+H] + 。

[0821] Example 10

[0822]

[0823] Step 1. tert-Butyl (E)-3-(3-(dimethylamino)acryloyl)azetidine-1-carboxylate

[0824]

[0825] A solution of tert-butyl 3-acetylazetidine-1-carboxylate (2 g, 10.03 mmol) in DMF-DMA (15 mL) was stirred at 110 °C overnight. The resulting mixture was concentrated in vacuo to give tert-butyl 3-[(2E)-3-(dimethylamino)prop-2-enoyl]azetidine-1-carboxylate (2.3 g, crude). LCMS (ESI-MS) m / z = 255.2 [M+H] + 。

[0826] Step 2. tert-Butyl 3-(1H-pyrazol-3-yl)azetidine-1-carboxylate

[0827]

[0828] A solution of tert-butyl 3-[(2E)-3-(dimethylamino)prop-2-enoyl]azetidine-1-carboxylate (2.1 g, 8.25 mmol) in hydrazine hydrate (20 mL) was stirred at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate in 0 - 40% hexane) to afford the title compound tert-butyl 3-(1H-pyrazol-3-yl)azetidine-1-carboxylate (1.5 g, 66.92%). LCMS (ESI-MS) m / z = 447.3 [2M+H] + 。

[0829] Step 3. tert-Butyl 3-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-3-yl)azetidine-1-carboxylate

[0830]

[0831] Under a nitrogen atmosphere, (1R,2R)-cyclohexane-1,2-diamine (153.43 mg, 1.34 mmol), potassium phosphate (380.27 mg, 1.79 mmol), and copper(I) iodide (85.30 mg, 0.44 mmol) were added to a stirred mixture of tert-butyl 3-(1H-pyrazol-3-yl)azetidine-1-carboxylate (200 mg, 0.89 mmol) and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (781.59 mg, 0.89 mmol) in toluene (3 mL). The resulting mixture was stirred at 100 °C overnight. The reaction mixture was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in 0 - 40% hexane) to afford the title compound tert-butyl 3-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-3-yl)azetidine-1-carboxylate (80 mg, 15.43%). LCMS (ESI-MS) m / z = 579.3 [M+H] + 。

[0832] Step 4. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(azetidin-3-yl)-1H-pyrazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0833]

[0834] To a stirred solution of tert-butyl 3-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-3-yl)azetidine-1-carboxylate (80 mg, 0.13 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 0.5 h and concentrated in vacuo to afford N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(azetidin-3-yl)-1H-pyrazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg crude). LCMS (ESI-MS) m / z = 479.2 [M+H] + 。

[0835] Step 5. 1-(3-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-3-yl)azetidin-1-yl)prop-2-en-1-one

[0836]

[0837] A stirred mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(azetidin-3-yl)-1H-pyrazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg crude) and Et3N (67.67 mg, 0.66 mmol) in dichloromethane (2 mL) was added dropwise acryloyl chloride (15.13 mg, 0.16 mmol) at 0 °C and stirred for 3 minutes. The reaction mixture was purified by Prep-TLC to give the crude product. The crude product (60 mg) was purified by Prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 58% B in 7 min, 58% B) to give 1-(3-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-pyrazol-3-yl)azetidin-1-yl)prop-2-en-1-one, Example 10 (11.2 mg, 12.57%). LCMS (ESI-MS) m / z = 533.1 [M+H] + .

[0838] Example 16

[0839]

[0840] Step 1. tert-Butyl 6-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0841]

[0842] Under a nitrogen atmosphere, a mixture of Cs2CO3 (298.7 mg, 0.91 mmol) and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.45 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.50 mmol), and PEPPSI (38.51 mg, 0.05 mmol) in dioxane (2 mL) was stirred at 100 °C for 72 h. The reaction mixture was filtered off and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, 25 g, eluted with ethyl acetate in petroleum ether from 0% to 40%, flow rate 100 mL / min), the desired fractions were combined and concentrated in vacuo to afford tert-butyl 6-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 41.73%). LCMS (ESI-MS) m / z = 554.3 [M+H] + 。

[0843] Step 2. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]hept-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0844]

[0845] A mixture of tert-butyl 6-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 0.27 mmol) and TFA (0.3 mL) in DCM (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford the crude product N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]hept-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg crude). LCMS (ESI-MS) m / z = 454.2 [M+H] + 。

[0846] Step 3.1 - (6-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0847]

[0848] A mixture of N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]hept-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.22 mmol), acryloyl chloride (19.96 mg, 0.22 mmol) and Et3N (66.94 mg, 0.65 mmol) in DCM (2 mL) was stirred at 0 °C for 5 minutes. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (ethyl acetate:petroleum ether = 1:1), and the fractions with the desired mass signals were dissolved in dichloromethane / methanol (10:1, 50 mL) and filtered. The filtrate was concentrated under vacuum to afford the desired product 1-(6-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-en-1-one, Example 16 (20.3 mg, 16.73%). LCMS (ESI-MS) m / z = 508.2 [M+H] + .

[0849] Example 20

[0850]

[0851] 2-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carbonyl)acrylic acid

[0852] Add 2-(trifluoromethyl)acrylic acid (18.9 mg, 1.5 Eq, 135 μmol) and HATU (51.4 mg, 1.5 Eq, 135 μmol) to a 1-dram vial equipped with a Teflon-coated stir bar. Then cap the vial and place it in an N2 glove box. Open the vial and add DMF (1.4 mL). Then recap the vial, remove it from the glove box, add DIPEA (81.6 mg, 110 μL, 7 Eq, 631 μmol) via syringe, and stir the reaction mixture at rt. After 30 minutes, add N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (TfOH salt, 50.0 mg, 1 Eq, 90.2 μmol in 1.0 mL DMF) via syringe and stir the reaction mixture at rt. After 30 minutes, filter the reaction mixture and purify it by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford Example 20 (3.99 mg, 6.78% yield). LCMS (ESI) [[M+H]] + = 539.2.

[0853] Example 21

[0854]

[0855] (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0856] To a 20 mL scintillation vial with a Teflon-coated stir bar was added N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (TFA salt, 50.0 mg, 1 Eq, 90.2 μmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (22.4 mg, 1.5 Eq, 135 μmol), and HATU (51.4 mg, 1.5 Eq, 135 μmol). The vial was then capped with a rubber septum, evacuated, and refilled with N2 (3x). Then DMF (3.0 mL) and diisopropylethylamine (46.6 mg, 62.3 μL, 4 Eq, 361 μmol) were added via syringe and the reaction was stirred overnight at rt. The resulting mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford the title compound, Example 21 (2.0 mg, 3.3% yield. LCMS (ESI) [M+H] + = 552.3.

[0857] Example 24

[0858]

[0859] (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one

[0860] To a 20 mL scintillation vial with a Teflon-coated stir bar was added N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (TFA salt, 50.0 mg, 1 Eq, 90.2 μmol), (E)-4-(4-methylpiperazin-1-yl)but-2-enoic acid hydrochloride (29.8 mg, 1.5 Eq, 135 μmol), and HATU (51.4 mg, 1.5 Eq, 135 μmol). The vial was then capped with a rubber septum, evacuated, and refilled with N2 (3x). Then DMF (3.0 mL) and diisopropylethylamine (46.6 mg, 62.3 μL, 4 Eq, 361 μmol) were added via syringe and the reaction was stirred overnight at rt. The resulting mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford Example 24 (1.8 mg, 2.8% yield). LCMS (ESI) [M+H]+ = 607.3。

[0861] Example 25

[0862]

[0863] (R,E)-1-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

[0864] To a 1-dram vial with a Teflon-coated stir bar was added (R,E)-3-(1-methylpyrrolidin-2-yl)acrylic acid hydrochloride (25.9 mg, 1.5 Eq, 135 μmol) and HATU (51.4 mg, 1.5 Eq, 135 μmol). The vial was then capped and placed in an N2 glove box, and the vial was opened and DMF (1.4 mL) was added. The vial was then recapped and removed from the glove box and DIPEA (81.6 mg, 110 μL, 7 Eq, 631 μmol) was added via septum. The reaction mixture was stirred at rt for 30 minutes. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (TFA salt, 50.0 mg, 1 Eq, 90.2 μmol in 1.0 mL DMF) was added via syringe. After 30 minutes the reaction mixture was filtered and then purified by preparative reverse phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford Example 25 (22.8 mg, 36.6% yield). LCMS (ESI) [M+H] + = 578.3。

[0865] Example 26

[0866]

[0867] 1-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridin-1(2H)-yl)-2-fluoroprop-2-en-1-one

[0868] Add tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 1 Eq, 92.8 μmol) and dichloromethane (0.5 mL) to a 1-dram vial equipped with a stir bar. Then add trifluoroacetic acid (106 mg, 70.7 μL, 10 Eq, 928 μmol) slowly and cap the vial and stir at rt. After complete consumption of the starting material via LCMS, concentrate the reaction and use without further purification. Reconstitute the crude residue in dichloromethane (1.0 mL) and add to a premixed solution of HATU (52.9 mg, 1.5 Eq, 139 μmol), 2-fluoroacrylic acid (12.5 mg, 1.5 Eq, 139 μmol), and DIPEA (48.0 mg, 64.7 μL, 4 Eq, 371 μmol) in dichloromethane (1.5 mL) and stir at rt. After 16 h, filter the reaction and concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography (0 - 10% methanol in dichloromethane) to afford Example 26 (4.2 mg, 8.9% yield). LCMS (ESI) + = 511.2.

[0869] Example 27

[0870]

[0871] 2-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidine-1-carbonyl)acrylonitrile

[0872] To a 1-dram vial with a Teflon-coated stir bar was added N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (TFA salt, 50.0 mg, 1 Eq, 90.2 μmol), dicyclohexylamine salt of 2-cyanoacrylic acid (75.3 mg, 3 Eq, 270 μmol), and HATU (171 mg, 5 Eq, 451 μmol). The vial was then capped and placed in an N2 glove box, and the vial was opened and DMF (1.4 mL) was added. The vial was recapped and removed from the glove box and DIPEA (117 mg, 157 μL, 10 Eq, 902 μmol) was added through the septum. After 30 minutes the reaction mixture was filtered and then purified by preparative reverse phase HPLC (acetonitrile / water gradient with 0.1% TFA) to afford Example 27 (10.0 mg, 18.4% yield). LCMS (ESI) [[M+H]] + = 603.3.

[0873] Example 42

[0874]

[0875] Step 1. (E)-4-(4-Methoxypiperidin-1-yl)but-2-enoic acid

[0876]

[0877] To a stirred mixture of (E)-4-bromobut-2-enoic acid (50 mg, 0.30 mmol) and 4-methoxypiperidine HCl (51 mg, 0.33 mmol) in DMF (1 mL) was added diisopropylethylamine (0.12 g, 0.91 mmol), and the reaction was stirred overnight at RT. The reaction mixture was used as is in the following step.

[0878] Step 2. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0879]

[0880] In RT, TFA (3 mL) was added to tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (438 mg, 855 μmol), and the mixture was stirred for 10 min. The resulting mixture was concentrated under vacuum to afford the crude product. The crude product was diluted with ethyl acetate (2 x 20 mL) and washed with NaHCO3 (20 mL). The organic layer was dried over MgSO4 and concentrated to give N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, which was used crude in the next step. LCMS (ESI-MS) m / z = 413.2 [M+H] + .

[0881] Step 3. (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(4-methoxypiperidin-1-yl)but-2-en-1-one

[0882]

[0883] O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (93 mg, 0.29 mmol) and N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg, 97 μmol) were added to a crude mixture of (E)-4-(4-methoxypiperidin-1-yl)but-2-enoic acid (58 mg, 0.29 mmol) in DMF (1 mL) and diisopropylethylamine (from step 1). The reaction was stirred at room temperature for 30 min. The reaction mixture was filtered and purified by prep HPLC, eluting with 10 - 40% ACN / water / 0.1% TFA. The fractions were diluted with ethyl acetate (20 mL) and washed with saturated NaHCO3 (20 mL). The organic layer was filtered through MgSO4 and the solvent was evaporated to afford (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(4-methoxypiperidin-1-yl)but-2-en-1-one, Example 42 (17.3 mg, 29%). 1 H NMR (499 MHz, chloroform-d) δ = 8.50 (d, J = 7.4 Hz, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.63 (d, J = 2.7 Hz, 1H), 7.60 (dd, J = 2.6, 8.6 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.94 (td, J = 6.2, 15.3 Hz, 1H), 6.89 (dd, J = 2.7, 7.4 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.11 (br d, J = 15.3 Hz, 1H), 4.83 - 4.72 (m, 1H), 4.65 (br t, J = 8.5 Hz, 1H), 4.46 - 4.37 (m, 1H), 4.37 - 4.25 (m, 2H), 3.33 (s, 3H), 3.23 (br d, J = 3.3 Hz, 1H), 3.21 - 3.14 (m, 2H), 2.74 (br s, 2H), 2.34 - 2.19 (m, 5H), 1.90 (br d, J = 12.0 Hz, 2H), 1.63 (br d, J = 8.8 Hz, 2H). LCMS (ESI-MS) m / z = 594.3 [M + H] + 。

[0884] Example 50

[0885]

[0886] Step 1. 4-(4-Chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0887]

[0888] Add 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (100 mg, 430 μmol) to a reaction tube equipped with a stir bar. Cap and evacuate the tube and refill with N2 (3x). Add dry THF (4.0 mL) via syringe and cool the reaction mixture to -78 °C for 15 min. Then slowly add nBuLi (33.1 mg, 215 μL, 2.4 molar, 516 μmol) via syringe and stir the reaction for 30 min. Then add tert-butyl 4-oxopiperidine-1-carboxylate (103 mg, 516 μmol) in THF (1.0 mL) via syringe and stir the reaction mixture at -78 °C for 2 h. Then quench the reaction with saturated NaHCO3 and warm to rt. Then add water (10 mL) and extract the reaction mixture with DCM (3 x 10 mL). Wash the combined organic layers with brine, dry over MgSO4, and concentrate. Purification via column chromatography (EtOAc in 10 - 100% hexane) affords 4-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (77 mg, 51%), which is used in the next step without further purification. LCMS (ESI) [[M+H]] + = 352.1.

[0889] Step 2. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0890]

[0891] Add tert-butyl 4-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylate (656 mg, 1.86 mmol) and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (447 mg, 1.86 mmol) to a 40 mL scintillation vial equipped with a stir bar. Cap and evacuate the vial and refill with N2 (3x), then add dry isopropanol (12.0 mL) via syringe and stir the reaction mixture at rt. After 1 h, wash the reaction mixture with saturated NaHCO3 (10 mL) and extract with DCM (3 x 10 mL). Purification via column chromatography with EtOAc / EtOH (3:1 mixture) in 10 - 100% hexanes affords tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylate (766 mg, 58%). LCMS (ESI) [M+H] + = 557.3.

[0892] Step 3. 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)piperidin-4-ol

[0893]

[0894] Add tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylate (100 mg, 180 μmol) and TFA (246 mg, 166 μL, 2.16 mmol) to a 1-dram vial equipped with a stir bar. Stir the reaction mixture at rt for 1.5 h then concentrate in vacuo. The crude product is used in the next step without any further purification. LCMS (ESI) [M+H] + = 456.2.

[0895] Step 4. (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0896]

[0897] Add the crude product from the previous step, DMF (2.5 mL), diisopropylethylamine (139 mg, 188 μL, 1.08 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (32.7 mg, 198 μmol), and HATU (102 mg, 269 μmol) to a 2-dram vial with a stir bar, and then stir the reaction mixture at rt. After 45 min, purify the reaction mixture directly via prepHPLC with 10 - 50% ACN in 0.1% TFA in water. Combine the fractions containing the desired product mass, neutralize with saturated aqueous NaHCO3 (10 mL), and extract with DCM (4 x 15 mL). Wash the combined organic layers with brine, dry over MgSO4, and concentrate to afford (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 50 (59.13 mg, 57%). 1 H NMR (499 MHz, chloroform-d) δ ppm 11.22 (s, 1H) 8.47 (d, J = 7.4 Hz, 1H) 8.06 (s, 1H) 7.99 (s, 1H) 7.79 (d, J = 2.5 Hz, 1H) 7.72 (dd, J = 8.6, 2.6 Hz, 1H) 7.48 (d, J = 2.7 Hz, 1H) 7.07 (d, J = 8.8 Hz, 1H) 6.91 (dd, J = 7.5, 2.6 Hz, 1H) 6.67 - 6.81 (m, 2H) 6.43 - 6.53 (m, 2H) 5.36 (br s, 1H) 4.57 (br d, J = 11.8 Hz, 1H) 3.92 (br d, J = 12.0 Hz, 1H) 3.67 (br t, J = 12.5 Hz, 1H) 3.23 (br t, J = 12.2 Hz, 1H) 3.10 (br d, J = 6.0 Hz, 2H) 2.27 (s, 6H) 2.22 (s, 3H) 1.89 - 2.19 (m, 4H).

[0898] Example 51

[0899]

[0900] Step 1. 1-Dibenzyl-3-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol

[0901]

[0902] 5-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (865.0 mg, 3.721 mmol) was added to a reaction tube equipped with a stir bar. The tube was capped and evacuated and refilled with N2 (3x). Dry THF (18.0 mL) was added via syringe and the reaction mixture was cooled to -78 °C for 10 min. Then n-BuLi (309.9 mg, 2.015 mL, 2.4 molar, 4.837 mmol) was slowly added via syringe and the reaction was stirred for 30 min. Then 1-dibenzylazetidin-3-one (1.104 g, 4.651 mmol) in THF (6.0 mL) was added via syringe and the reaction mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated NaHCO3 and warmed to rt. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered, and concentrated. Purification by column chromatography (EtOAc in 10 - 100% hexanes) afforded 1-dibenzyl-3-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol (456 mg, 31.4%). 1 H NMR (499 MHz, chloroform-d) δ 8.19 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.42 (br d, J = 7.4 Hz, 6H), 7.27 - 7.30 (m, 4H), 7.17 - 7.24 (m, 3H), 7.01 (d, J = 2.5 Hz, 2H), 4.46 (s, 1H), 3.79 (br d, J = 7.9 Hz, 2H), 3.58 (br d, J = 7.9 Hz, 2H). LCMS (ESI) [M+H] + = 391.1.

[0903] Step 2. 3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-dibenzylazetidin-3-ol

[0904]

[0905] Add 1-diphenylmethyl-3-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol (50.0 mg, 128 μmol) and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (32.3 mg, 134 μmol) to a 2-dram vial equipped with a stir bar. Cap and evacuate the vial and refill with N2 (3x), then add dry isopropanol (2.0 mL) via syringe and heat the reaction mixture to 50 °C. After 1 h, remove the reaction from heating, dilute with saturated NaHCO3 (20 mL) and extract with DCM (3 x 20 mL). Purification via column chromatography with EtOAc / EtOH (3:1 mixture) in 10 - 100% hexanes affords 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-diphenylmethylazetidin-3-ol (69.9 mg, 91.9%). 1 HNMR (499 MHz, chloroform-d) δ 10.14 (br s, 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.60 - 7.69 (m, 3H), 7.55 (d, J = 2.7 Hz, 1H), 7.39 - 7.51 (m, 5H), 7.29 (br t, J = 7.4 Hz, 4H), 7.21 (br d, J = 7.1 Hz, 3H), 6.96 - 7.10 (m, 2H), 6.85 (dd, J = 7.4, 2.7 Hz, 2H), 6.80 - 6.83 (m, 1H), 6.68 - 6.80 (m, 2H), 4.49 (br s, 2H), 3.68 (br s, 3H), 3.48 - 3.61 (m, 3H), 2.19 (s, 4H), 1.96 - 2.14 (m, 2H). LCMS (ESI) [M+H] + = 595.2.

[0906] Step 3. 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol

[0907]

[0908] Add 3-(5-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1-benzhydrylazetidin-3-ol (70 mg, 0.12 mmol), ammonium formate (0.22 g, 3.5 mmol), and palladium(II) hydroxide (83 mg, 20% Wt, 0.12 mmol) to a 1-dram vial equipped with a stir bar. Cap the vial, then evacuate and refill with N2 (3x). Then add anhydrous MeOH (5 mL) via septum and then heat the reaction vial to 40 °C with stirring at 1600 rpm. After 3 h, cool the reaction mixture to rt, neutralize with saturated aqueous NaHCO3 (20 mL), and extract with DCM (3 x 15 mL). Then wash the organic layer with brine, dry over MgSO4, and concentrate. The crude product is used in the next step without further purification. LCMS (ESI) [M+H] + = 429.2.

[0909] Step 4. (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-hydroxyazetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0910]

[0911] Add O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (57 mg, 0.18 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (29 mg, 0.18 mmol), DMF (2.0 mL), and diisopropylethylamine (61 mg, 0.47 mmol) to the crude residue from the previous step (Step 3). Then stir the reaction mixture at rt. After 1 h, purify the reaction mixture directly by prep HPLC 10 - 100% ACN in 0.1% TFA in water. Combine the collected fractions, neutralize with saturated aqueous NaHCO3 (10 mL), and extract with DCM (3 x 10 mL). Then wash the organic layer with brine, dry over MgSO4, and concentrate to afford (E)-1-(3-(5-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-hydroxyazetidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 51 (1.89 mg, 2.7% yield over 2 steps).1 1H NMR (499 MHz, chloroform-d) δ ppm 10.63 (s, 1H) 8.48 (d, J = 7.4 Hz, 1H) 8.13 (s, 1H) 8.02 (s, 1H) 7.78 - 7.82 (m, 1H) 7.70 - 7.74 (m, 1H) 7.52 - 7.57 (m, 1H) 7.08 (d, J = 8.8 Hz, 1H) 6.83 - 6.92 (m, 2H) 6.75 - 6.80 (m, 1H) 6.67 (d, J = 3.0 Hz, 1H) 6.19 - 6.27 (m, 1H) 4.52 - 4.66 (m, 3H) 4.40 (br d, J = 11.0 Hz, 1H) 3.26 (br d, J = 5.5 Hz, 2H) 3.08 (s, 1H) 2.29 - 2.38 (m, 6H) 2.19 - 2.25 (m, 3H).

[0912] Example 52

[0913]

[0914] Step 1. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester

[0915]

[0916] To a 1-dram vial equipped with a stir bar was added 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (153 mg, 275 μmol) and DCM (1.0 mL). The vial was capped and cooled to -78 °C, then DAST (266 mg, 218 μL, 1.65 mmol) was added slowly. The reaction mixture was stirred at -78 °C and allowed to warm slowly to rt overnight. The reaction was quenched with MeOH (1.0 mL) and stirred at rt for 1 h. Purification by column chromatography (MeOH in 0 - 15% DCM) afforded 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (24 mg, 15%). 11H NMR (499 MHz, methanol-d4) δ 8.72 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.6, 2.6 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 7.5, 2.6 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.01 (br d, J = 12.9 Hz, 2H), 3.17 - 3.40 (m, 5H), 2.30 (br d, J = 13.7 Hz, 2H), 2.23 (s, 3H), 1.94 - 2.03 (m, 2H), 1.47 (s, 9H). LCMS (ESI) [M+H] + = 570.3.

[0917] Step 2. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(4-methoxypiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0918]

[0919] To a 1-dram vial equipped with a stir bar was added tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylate (20 mg, 36 μmol) and TFA (41 mg, 28 μL, 0.36 mmol). The reaction mixture was stirred at rt for 20 min. The reaction mixture was then concentrated in vacuo and used directly in the next step without any further purification. LCMS (ESI) [M+H] + = 470.2.

[0920] Step 3. (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-methoxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0921]

[0922] Add N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(4-methoxypiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (30.0 mg, 63.8 μmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (21.1 mg, 128 μmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (40.9 mg, 128 μmol) to a 1-dram vial equipped with a stir bar. Then add DMF (2 mL), followed by diisopropylethylamine (33.0 mg, 44.4 μL, 255 μmol) and stir the reaction mixture at rt. After 1 h, purify the reaction mixture directly by prepHPLC 10 - 100% ACN in 0.1% TFA in water. Combine the fractions containing the desired product mass and neutralize with saturated aqueous NaHCO3 (7 mL) and extract with DCM (3 x 10 mL). Wash the combined organic fractions with brine, dry over anhydrous MgSO4, and concentrate to afford (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-methoxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 52 (4.27 mg, 11.0%). 1 H NMR (499 MHz, chloroform-d) δ ppm 10.54 (s, 1H) 8.49 (d, J = 7.4 Hz, 1H) 8.22 (s, 1H) 8.04 (s, 1H) 7.66 - 7.74 (m, 2H) 7.54 - 7.59 (m, 1H) 7.09 (d, J = 8.8 Hz, 1H) 6.89 (dd, J = 7.4, 2.7 Hz, 1H) 6.78 - 6.86 (m, 2H) 6.56 (d, J = 2.7 Hz, 1H) 4.51 - 4.72 (m, 2H) 3.94 - 4.16 (m, 2H) 3.36 - 3.75 (m, 4H) 3.29 (s, 3H) 3.16 - 3.25 (m, 1H) 2.41 - 2.78 (m, 6H) 2.32 - 2.40 (m, 2H) 2.25 (s, 3H). LCMS (ESI) [M+H] + = 582.3.

[0923] Example 72

[0924]

[0925] Step 1. tert-Butyl (1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrrolidin-3-yl)(methyl)carbamate

[0926]

[0927] A solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 229 μmol), tert-butyl methyl(pyrrolidin-3-yl)carbamate (138 mg, 688 μmol), potassium phosphate (146 mg, 688 μmol), L-proline (10.6 mg, 91.7 μmol) and copper(I) iodide (8.73 mg, 45.8 μmol) in DMSO (2 mL) was stirred at 90 °C overnight. The crude product was purified by reverse-phase flash chromatography. The fractions were lyophilized to afford tert-Butyl (1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrrolidin-3-yl)(methyl)carbamate (92 mg, 69%). LCMS (ESI-MS) m / z = 556.3 [M+H] + 。

[0928] Step 2. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0929]

[0930] The mixture of tert-butyl (1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrrolidin-3-yl)(methyl)carbamate (95 mg crude) in DCM (4 mL) and TFA (2 mL) was stirred at room temperature for 90 min and concentrated under vacuum. The crude product was diluted with DCM (10 mL) and washed with NaHCO3 (5 mL). The mixture was filtered through a phase separation column, and the solvent was evaporated to afford the crude product N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, crude). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 456.2 [M+H] + 。

[0931] Step 3. N-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrrolidin-3-yl)-N-methylacrylamide

[0932]

[0933] A solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (25 mg, 55 μmol), acrylic acid (5.9 mg, 82 μmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (26 mg, 82 μmol) and diisopropylethylamine (21 mg, 0.16 mmol) in DMF (1.5 mL) was stirred at room temperature for two hours. The crude product was purified by reverse-phase flash chromatography. The fractions were combined, diluted with ethyl acetate (20 mL), and washed with saturated NaHCO3 (10 mL). The organic layer was dried over MgSO4, and the solvent was evaporated to afford N-(1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrrolidin-3-yl)-N-methylacrylamide, Example 72 (9 mg, 30%). 11H NMR (499 MHz, DMSO-d6) δ = 9.67 - 9.57 (m, 1H), 8.93 (d, J = 7.4 Hz, 1H), 8.40 - 8.35 (m, 1H), 7.99 - 7.95 (m, 1H), 7.82 - 7.74 (m, 2H), 7.67 (d, J = 2.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.04 - 6.99 (m, 1H), 6.87 (br s, 1H), 6.81 - 6.66 (m, 2H), 6.16 - 6.04 (m, 1H), 5.72 - 5.63 (m, 1H), 5.36 - 5.19 (m, 1H), 3.30 - 3.23 (m, 2H), 3.22 - 3.04 (m, 4H), 3.02 - 2.94 (m, 1H), 2.19 (s, 3H), 2.15 - 2.02 (m, 2H). LCMS (ESI-MS) m / z = 510.3 [M+H] + 。

[0934] Example 86

[0935]

[0936] Step 1. Methyl (E)-3-bromo-1-((2-cyanoethylidene)amino)-1H-pyrrole-2-carboxylate

[0937]

[0938] At room temperature, 3,3-diethoxypropionitrile (3.92 g, 27.39 mmol) and TsOH (1.18 g, 6.84 mmol) were added to a stirred solution of methyl 1-amino-3-bromopyrrole-2-carboxylate (3 g, 13.69 mmol) in THF (60 mL). The resulting mixture was stirred at 80 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel column with ethyl acetate / petroleum ether = 1:1 to afford the desired product methyl (E)-3-bromo-1-((2-cyanoethylidene)amino)-1H-pyrrole-2-carboxylate (2 g, 32.1% yield). LCMS (ESI-MS) m / z = 270.0 [M+H] + 。

[0939] Step 2. 5-Bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile

[0940]

[0941] To a solution of (E)-3-bromo-1-((2-cyanoethylidene)amino)-1H-pyrrole-2-carboxylic acid methyl ester (2 g, 7.40 mmol) in DCE (20 mL) was added 1,8-diazabicycloundec-7-ene (1.13 g, 7.40 mmol). The resulting mixture was stirred at 85 °C for 18 h and concentrated in vacuo to afford the crude product. The residue was purified by silica gel column with ethyl acetate / petroleum ether = 2:1 to give the desired product 5-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile (1 g, 53.2% yield). LCMS (ESI-MS) m / z = 238.0 [M+H] + 。

[0942] Step 3. 4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile

[0943]

[0944] To a solution of 5-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile (900 mg, 3.78 mmol) in THF (20 mL) was added 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (908 mg, 3.78 mmol), Et3N (1.47 g, 11.34 mmol) and PyBrop (2.64 g, 5.67 mmol). The resulting mixture was stirred at 80 °C for 16 h and concentrated in vacuo to afford the crude product. The residue was purified by silica gel column with ethyl acetate / petroleum ether = 2:1 to give the desired product 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (800 mg, 45.9% yield). LCMS (ESI-MS) m / z = 460.0 [M+H] + 。

[0945] Step 4. tert-Butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanopyrrolo-[1,2-b]pyridazin-5-yl)azetidine-1-carboxylate

[0946]

[0947] Under a nitrogen atmosphere, 4,4'-di-tert-butyl-2,2'-bipyridine (29 mg, 0.11 mmol) and NiCl2 .A mixture of dme (33 mg, 0.11 mmol) in DCE (1 mL) was heated to 60 °C for 10 minutes. The solution was allowed to cool to room temperature (Solution 1). Under a nitrogen atmosphere, Ir[dF(CF3)ppy]2(dtbpy)PF6 (122 mg, 0.11 mmol) was added to a mixture of 4-((4-([1,2,4]-triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (616.6 mg, 2.0 mmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (297 mg, 1.19 mmol) and Na2CO3 (230 mg, 2.17 mmol) in DCE (10 mL), and then Solution 1 was added via syringe. The resulting mixture was maintained under nitrogen, stirred at room temperature and irradiated with a blue LED (450 nm) in a Penn Photo reactor m2 for 5 hours. The reaction mixture was purified by Prep-TLC with DCM / MeOH = 10:1 to give tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanopyrrolo-[1,2-b]pyridazin-5-yl)azetidine-1-carboxylate (500 mg crude), and the crude product was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 537.2 [M+H] + .

[0948] Step 5. 4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(azetidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

[0949]

[0950] A mixture of tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanopyrrolo-[1,2-b]pyridazin-5-yl)azetidine-1-carboxylate (500 mg crude) and TFA (1.6 mL) in DCM (10 mL) was stirred at room temperature for 1 hour and concentrated under vacuum to give the crude product 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(azetidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (150 mg crude). LCMS (ESI-MS) m / z = 437.2 [M+H] + .

[0951] Step 6. (E)-4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

[0952]

[0953] Diisopropylethylamine (148.05 mg, 1.14 mmol) was added to a mixture of 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanopyrrolo[1,2-b]pyridazin-5-yl)azetidine-1-carboxylate (100 mg, 0.22 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (29.59 mg, 0.22 mmol) and HATU (130.67 mg, 0.34 mmol) in DMF (3 mL). The resulting mixture was stirred at 25 °C for 1 h and concentrated in vacuo to afford the crude product. The residue was purified by preparative HPLC using the following conditions: column, C18 silica; mobile phase, ACN (0.1% FA) in water, 10% to 60% gradient over 10 min; to afford the crude desired product (E)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile, Example 86 (11.8 mg, 9% yield). LCMS (ESI-MS) m / z = 548.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 7.5 Hz, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 7.60 - 7.55 (m, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.83 - 6.80 (m, 1H), 6.62 (d, J = 2.6 Hz, 1H), 6.35 (s, 1H), 6.16 (d, J = 15.5 Hz, 1H), 4.14 - 4.10 (m, 1H), 3.85 - 3.80 (m, 2H), 3.68 - 3.65 (m, 2H), 3.35 (d, J = 6.3 Hz, 2H), 2.49 (s, 4H), 2.47 - 2.45 (m, 2H), 2.29 (s, 3H).

[0954] Example 87

[0955]

[0956] Step 1. (E)-(4-(3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo-[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-oxobut-2-en-1-yl)carbamic acid tert-butyl ester

[0957]

[0958] A mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (320 mg, 0.77 mmol), (E)-4-((tert-butoxycarbonyl)amino)but-2-enoic acid (186 mg, 0.92 mmol), HATU (350 mg, 0.92 mmol) and diisopropylethylamine (298 mg, 2.31 mmol) in DMF (30 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and the resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography (MeOH in 0 - 3% DCM) to afford the desired product (E)-(4-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo-[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-oxobut-2-en-1-yl)carbamic acid tert-butyl ester (260 mg, 56.7% yield). LCMS (ESI-MS) m / z = 596.3 [M+H] + 。

[0959] Step 2. (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-aminobut-2-en-1-one

[0960]

[0961] To a stirred solution of tert-butyl (E)-(4-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-oxobut-2-en-1-yl)carbamate (260 mg, 0.44 mmol) in DCM (10 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated to afford the crude product. The crude product was purified by Prep-HPLC with mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeOH to give the desired product (E)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-aminobut-2-en-1-one, Example 87 (34.5 mg, 15.8% yield). LCMS (ESI-MS) m / z = 496.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.70 - 7.52 (m, 3H), 7.15 - 6.99 (m, 3H), 6.95 - 6.79 (m, 2H), 6.73 (d, J = 2.9 Hz, 1H), 6.13 (d, J = 15.1 Hz, 1H), 4.85 - 4.62 (m, 2H), 4.48 - 4.27 (m, 3H), 3.54 (dd, J = 4.9, 2.0 Hz, 2H), 2.25 (s, 3H), 1.70 - 1.68 (m, 2H).

[0962] Example 88

[0963]

[0964] Step 1. 5-Bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one

[0965]

[0966] A mixture of imidazo[5,1-f][1,2,4]triazin-4(3H)-one (5 g, 36.73 mmol) and NBS (6.54 g, 36.73 mmol) in DMF (250 mL) was stirred at 0 °C for 1 h. The reaction was quenched at 0 °C by the addition of saturated aqueous sodium bicarbonate (500 mL). The reaction mixture was diluted with water (2000 mL), and the resulting solution was extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product 5-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (3.5 g crude), which was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 215.0 [M+H] + 。

[0967] Step 2. tert-Butyl 4-(4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0968]

[0969] A mixture of 5-bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (2 g, 9.30 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.88 g, 9.30 mmol), K2CO3 (2.57 g, 18.60 mmol), and Pd(dppf)Cl2 (754 mg, 0.93 mmol) in dioxane (20 mL) and water (6 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The crude reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography, eluting with ethyl acetate in 0% to 30% petroleum ether to afford the desired product tert-butyl 4-(4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 50.6% yield). LCMS (ESI-MS) m / z = 318.1 [M+H] + 。

[0970] Step 3. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0971]

[0972] DIEA (1.43 g, 14.18 mmol) was added to a stirred mixture of 4-(4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.5 g, 4.72 mmol), 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (1.14 g, 4.72 mmol) and PyBrop (3.31 g, 7.09 mmol) in THF (30 mL). The resulting mixture was stirred at 80 °C overnight, diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2 g crude). The crude product was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 540.2 [M+H] + 。

[0973] Step 4. 4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[0974]

[0975] Under a nitrogen atmosphere, Pd / C (3.94 g, 37.06 mmol) was added to a solution of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 3.70 mmol) in MeOH (20 mL). The resulting mixture was degassed, then charged with atmospheric hydrogen and stirred at room temperature for 2 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (4 x 100 mL). The combined filtrates were concentrated under reduced pressure to afford the crude product tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate (300 mg of crude product), which was used directly in the next step without further purification. LCMS (ESI-MS) m / z = 542.2 [M+H] + 。

[0976] Step 5. N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4-amine

[0977]

[0978] TFA (1 mL) was added to a stirred mixture of tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)piperidine-1-carboxylate (300 mg, 0.55 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo to afford the crude product. The residue was purified by column chromatography, eluting with 0% to 10% MeOH in DCM to afford the desired product N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (150 mg, 61.3% yield). LCMS (ESI-MS) m / z = 442.2 [M+H] + 。

[0979] Step 6. (E)-1-(4-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0980]

[0981] Diisopropylethylamine (131.74 mg, 1.02 mmol) was added to a stirred mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (150 mg, 0.34 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (65.82 mg, 0.51 mmol), and HATU (193.78 mg, 0.51 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature overnight, diluted with water (20 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography, eluting with MeOH in 0% to 10% DCM to afford the desired product (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)imidazo[5,1-f][1,2,4]triazin-5-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 88 (6.6 mg, 3% yield). LCMS (ESI-MS) m / z = 553.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.96 - 8.91 (m, 1H), 8.51 (s, 1H), 8.42 - 8.35 (m, 1H), 8.16 - 7.99 (m, 1H), 7.65 - 7.57 (m, 1H), 7.57 - 7.46 (m, 1H), 7.28 - 7.21 (m, 1H), 7.18 - 7.06 (m, 1H), 7.01 - 6.99 (m, 1H), 6.87 - 6.77 (m, 1H), 6.69 - 6.57 (m, 2H), 4.58 - 4.43 (m, 1H), 4.20 - 4.06 (m, 1H), 3.49 (s, 1H), 3.09 - 3.03 (m, 2H), 2.24 - 2.16 (m, 9H), 1.95 - 1.83 (m, 2H), 1.81 - 1.65 (m, 2H), 1.06 - 0.97 (m, 1H).

[0982] Example 89

[0983]

[0984] (E)-2-(3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile

[0985] Diisopropylethylamine (321 mg, 2.48 mmol) was added to a solution of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (256 mg, 0.62 mmol), (E)-2-cyano-4,4-dimethylpent-2-enoic acid (114 mg, 0.75 mmol), and HATU (472 mg, 1.24 mmol) in DMF (8 mL). The resulting mixture was stirred at room temperature for 5 h, diluted with water (40 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 0% to 10% MeOH in DCM to afford the desired product (E)-2-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, Example 89 (45.3 mg, 13.3% yield). LCMS (ESI-MS) m / z = 548.3 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 8.55 - 8.48 (m, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.67 - 7.50 (m, 4H), 7.14 - 7.07 (m, 1H), 6.94 - 6.84 (m, 3H), 6.79 - 6.74 (m, 1H), 5.14 - 5.05 (m, 1H), 4.77 - 4.64 (m, 2H), 4.45 - 4.33 (m, 2H), 2.25 (s, 3H), 1.32 (s, 9H).

[0986] Example 90

[0987]

[0988] Step 1. 3-Chloro-5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine

[0989]

[0990] To a solution of 3-(trifluoromethyl)phenol (4.2 g, 25.91 mmol) in THF (80 mL) at 0 °C under a nitrogen atmosphere was added NaH (60% in mineral oil, 1.12 g, 46.6 mmol), and the resulting mixture was stirred for 1 hour. Then 2,3-dichloro-5-nitropyridine (5 g, 25.9 mmol) was added to the mixture, and then the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched by the addition of water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford the crude product. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate = 5:1 to afford 3-chloro-5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine (7.91 g crude). LCMS (ESI-MS) m / z = 319.0 [M+H] + 。

[0991] Step 2. 5-Chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine

[0992]

[0993] At room temperature, iron powder (7.01 g, 125.53 mmol) was added to a mixture of 3-chloro-5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine (8 g, 25.11 mmol) and CaCl2 (1.39 g, 12.53 mmol) in EtOH (223 mL) and water (40 mL). Then the resulting mixture was stirred at 80 °C overnight, filtered, and the filtrate was diluted with water (3 x 100 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate = 1:1 to afford 5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine (4.8 g, 52% yield). LCMS (ESI-MS) m / z = 289.0 [M+H] + 。

[0994] Step 3. 3-(4-((5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylic acid tert-butyl ester

[0995]

[0996] Et3N (562.67 mg, 5.55 mmol) was added to a mixture of 5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine (535 mg, 1.85 mmol), tert-butyl 3-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (538.10 mg, 1.85 mmol) and PyBrop (1.30 g, 2.78 mmol) in THF (10 mL). The resulting mixture was stirred overnight at room temperature and concentrated in vacuo to afford a crude product. The residue was purified by preparative HPLC, ACN in water (10 mmol / L NH4HCO3), 10% to 50% to give tert-butyl 3-(4-((5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (550 mg, 20% yield). LCMS (ESI-MS) m / z = 561.2 [M+H] + 。

[0997] Step 4. 5-(Azetidin-3-yl)-N-(5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0998]

[0999] TFA (2 mL) was added to a solution of tert-butyl 3-(4-((5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (550 mg, 0.98 mmol) in DCM (6 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated in vacuo to afford a crude product. The residue was purified by Prep-TLC with petroleum ether / ethyl acetate = 1:1 to give the desired product 5-(azetidin-3-yl)-N-(5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (278 mg, 61.5% yield). LCMS (ESI-MS) m / z = 461.1 [M+H] + 。

[1000] Step 5. (E)-1-(3-(4-((5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[1001]

[1002] Diisopropylethylamine (389.8 mg, 3.01 mmol) was added to a mixture of 5-(azetidin-3-yl)-N-(5-chloro-6-(3-(trifluoromethyl)phenoxy)azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (278 mg, 0.60 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (93.50 mg, 0.72 mmol) and HATU (344.06 mg, 0.90 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo to afford a crude product. The residue was purified by preparative HPLC with mobile phase A: water (0.1% FA) and mobile phase B: ACN to give (E)-1-(3-(4-((5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one, Example 90 (14.9 mg, 4.31% yield). LCMS (ESI-MS) m / z = 572.3 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.51 - 8.50 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.93 (s, 1H), 7.76 - 7.68 (m, 2H), 7.68 - 7.62 (m, 2H), 7.56 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.58 - 6.55 (m, 1H), 6.26 (d, J = 15.4 Hz, 1H), 4.20 (dd, J = 12.4, 4.9 Hz, 1H), 3.89 (dd, J = 12.6, 5.2 Hz, 3H), 3.61 - 3.45 (m, 2H), 2.76 (d, J = 4.1 Hz, 6H).

[1003] Example 91

[1004]

[1005] (E)-1-(3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]-triazin-5-yl)azetidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one

[1006] Example 91 was prepared using a procedure similar to that in the preparation of Example 94.

[1007] Example 92

[1008]

[1009] Step 1. (Z)-2-(3-Ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1010]

[1011] To a cold solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (5 g, 20.6 mmol) in THF (50 mL) was added dropwise n-BuLi (2.5 M in hexanes, 9.91 mL, 24.7 mmol). The resulting mixture was stirred at -78 °C for 30 min, followed by the addition of tert-butyl 2-formylpyrrolidine-1-carboxylate (4.11 g, 20.6 mmol). The resulting solution was stirred at -78 °C for an additional 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl at -78 °C and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the crude product (Z)-2-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, crude). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 288.1 [M+H] + 。

[1012] Step 2. Ethyl (Z)-2-fluoro-3-(pyrrolidin-2-yl)acrylate

[1013]

[1014] To a solution of tert-butyl (Z)-2-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (5 g, 17.4 mmol) in DCM (50 mL) was added TFA (10 mL). The resulting solution was stirred at room temperature for 3 h and concentrated in vacuo to afford the crude product ethyl (Z)-2-fluoro-3-(pyrrolidin-2-yl)acrylate (4 g). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 188.2 [M+H] + .

[1015] Step 3. Ethyl (Z)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylate

[1016]

[1017] To a solution of ethyl (Z)-2-fluoro-3-(pyrrolidin-2-yl)acrylate (2 g, 10.7 mmol) in methanol (40 mL) was added formaldehyde (1.28 g, 42.7 mmol) and NaBH3CN (1.01 g, 16.0 mmol). The resulting mixture was stirred at room temperature for 16 h, quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford ethyl (Z)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylate ((1 g, 27.7% yield). LCMS (ESI-MS) m / z = 201.9 [M+H] + .

[1018] Step 4. (Z)-2-Fluoro-3-(1-methylpyrrolidin-2-yl)acrylic acid

[1019]

[1020] Lithium hydroxide (335.6 mg, 14.0 mmol) was added to a stirred mixture of ethyl (2Z)-2-fluoro-3-(1-methylpyrrolidin-2-yl)prop-2-enoate (940 mg, 4.67 mmol) in methanol (10 mL) and water (3 mL). The resulting mixture was stirred at room temperature for 3 h and concentrated to afford (2Z)-2-fluoro-3-(1-methylpyrrolidin-2-yl)prop-2-enoic acid (crude) without neutralization. LCMS (ESI-MS) m / z = 174.1 [M+H] + .

[1021] Step 5. (Z)-1-(3-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-1-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

[1022]

[1023] A mixture of (2Z)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylic acid (200 mg, crude, 1.16 mmol), N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-m...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein: A is N or CH; E 1 is N or C(CN); E 2 is C(R 4 ) or N; R 1 is an alkyl group, a haloalkyl group or a halogen; R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -O-heteroaryl-alkylene-aryl, -NH-alkyl, -NH-aryl or -NH-heteroaryl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl moieties is optionally substituted with 1-4 J 1 groups; or R 1 and R 2 forms, together with the carbon atom to which it is attached, a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the saturated or unsaturated carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 J 1 groups; G is -L 1 -R 3 , L 1a -R 3a or -W-X-Y; L 1 is a bond, -C(O)-, -S(O)2-, -N(R c )-, alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein the alkylene, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is each optionally substituted with 1-4 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring; L 1a is -C0-C6 alkylene -C(O)N(H)-, -C0-C6 alkylene -S(O)2N(H)-; R 3 is a 4- to 9-membered heterocycle containing at least one nitrogen ring atom, wherein R 3 is optionally substituted with 1 to 4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted with -L 2 -R; or R 3 is a 7- to 11-membered spiro group containing at least one nitrogen ring atom, wherein the 7- to 11-membered spiro group containing at least one nitrogen ring atom is optionally substituted with 1 to 4 J 3 groups, and wherein one nitrogen atom of the 7- to 11-membered spiro group is substituted with -L 2 -R; R 3a is an optionally C1-C6 alkylene-NR substituted by 1-4 J 2 groups a R b ; W is a bond, -C(O)- or -S(O)2-; X is aryl, heteroaryl, heterocycloalkyl or cycloalkyl, each of which is optionally substituted by 1-4 J 2 groups; Y is -C0-C4 alkylene-N(R d ))-L 2 -R, a -C(O)-4-7 membered heterocycloalkyl containing at least one nitrogen atom and substituted with 1-2 oxo groups, -4-7 membered heterocycloalkyl-L 2 R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4-ethyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the C0-C4 alkylene moiety is optionally substituted with 1-4 groups independently selected from halogen, cycloalkyl, alkoxyalkoxyalkyl or hydroxy; R 4 is H, halogen, alkyl or -O-alkyl; L 2 is -SO2- or -C(O)-; R is vinyl optionally substituted with 1 - 3 Q groups, ethynyl optionally substituted with Q, C1 - C4 alkylene - NR a R b , -CH2 - CN or a haloalkyl in which one halogen of the haloalkyl is on the carbon atom adjacent to L 2 and the haloalkyl, Each Q is independently selected from halogen, haloalkyl, alkyl, alkene, alkyne, -C1-C6 alkylene-NR a R b , -C1-C6 alkylene-OR c , cyano, hydroxyalkyl, -C0-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-alkyl, alkoxyalkyl, -C0-C4 alkylene-cycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-cycloalkenyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spirocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-heterocycloalkyl and -C0-C4 alkylene-heterocycloalkenyl optionally substituted with 1-3 J 4 groups; 4 ​ or -L 2 -R is -C=N-OH; Each J 1 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy and alkoxyalkyl; Each J 2 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; Each J 3 is attached to a carbon atom and is independently selected from halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy and alkoxyalkyl, or two of said optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optional 1-4 J 3 groups are on different ring carbons and together form a 1-3 carbon bridge; Each J 4 is independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group; R a and R b each independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and -C0-C3 alkylene-alkynyl optionally substituted by alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; and R c selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, alkyl, alkoxy and alkoxyalkyl; and R d Selected from H, alkyl, and haloalkyl.

2. The compound according to claim 1, wherein: R 1 is a C1-C4 alkyl group, a C1-C4 haloalkyl group or a halogen; R 2 is -O-(5- to 10-membered) aryl, -O-(5- to 10-membered) heteroaryl, -O-(4- to 7-membered) cycloalkyl, -O-(4- to 7-membered) heterocycloalkyl, -O-(5- to 10-membered) heteroaryl-C1-C4 alkylene-phenyl, -NH-(5- to 10-membered) aryl or -NH--(5- to 10-membered) heteroaryl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties is optionally substituted with 1-3 J 1 groups; or R 1 and R 2 together with the carbon atom to which it is attached forms a ring selected from 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein each ring is optionally substituted by 1 to 3 J 1 groups; G is -L 1 -R 3 or -W - X - Y; L 1 is a bond, -C(O)-, -S(O)2-, -N(H)-, -N(C1-C6 alkyl)-, C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl or 4- to 7-membered cycloalkyl, wherein the C1-C3 alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are each optionally substituted with 1 to 3 J 2 groups, provided that when L 1 is CH2, L 1 is not attached to a carbon or nitrogen of a saturated ring; R 3 is a 4- to 7-membered heterocycle containing at least one nitrogen ring atom, wherein the 4- to 7-membered heterocycle containing at least one nitrogen ring atom is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of the 4- to 7-membered heterocycle is substituted by -L 2 -R; or R 3 is a 7- to 11-membered spiro group containing at least one nitrogen ring atom, wherein the 7- to 11-membered spiro group is optionally substituted by 1 to 4 J 3 groups, and wherein one nitrogen atom of R 3 is substituted by -L 2 -R; W is a bond, -C(O)- or -S(O)2-; X is a 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl or 5- to 7-membered cycloalkyl, wherein the 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered cycloalkyl are optionally substituted by 1 to 3 J 2 groups; Y is -C0-C4 alkylene-N(R d )-L 2 -R, -C(O)-4-6 membered heterocycloalkyl containing one nitrogen atom and substituted with 1-2 oxo groups, -4-7 membered heterocycloalkyl-L 2 R, -C0-C4 alkylene-1-yl-1H-pyrrole-2,5-dione, -C0-C4 alkylene-C(H)=C(O)-NH2, -C0-C4 alkylene-C(H)=C(H)-C(O)-O-alkyl, -C0-C4 alkylene-ethynylene-C(O)-O-alkyl, -C0-C4 alkylene-C(H)=C(H)-CN, -C0-C4 alkylene-N=C=S, -C0-C4-ethyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=N-N(H)Boc, -C0-C4 alkylene-C(O)-CH2-Br, -C0-C4 alkylene-CH2-Cl, -C0-C4 alkylene-oxiranyl, -C0-C4 alkylene-SH, -C0-C4 alkylene-F and -C0-C4 alkylene-C(H)=O, wherein the -C0-C4 alkylene moiety is optionally substituted by 1-4 groups independently selected from halogen, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl-C1-C6 alkoxy or hydroxy; R 4 is H, halogen, C0-C4 alkyl or -O-C0-C4 alkyl; L 2 is -SO2- or -C(O)-; R is vinyl optionally substituted with 1 - 3 Q groups, ethynyl optionally substituted with Q, C1 - C4 alkylene - NR a R b , -CH2 - CN or C1 - C6 haloalkyl, wherein one halogen of the C1 - C6 haloalkyl is on the carbon atom adjacent to L 2 ; Each Q is independently selected from halogen, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , cyano, C1-C6 hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-C1-C6 alkyl, -C1-C4 alkylene-C1-C6 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 ; or -L 2 -R is -C=N-OH; Each J 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy, and -C1-C6 alkyl-C1-C6 alkoxy; Each J 2 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy; Each J 3 is attached to a carbon atom of R 3 and is independently selected from halogen, -C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and -C1-C6 alkyl-C1-C6 alkoxy, or two of said optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optional 1-4 J 3 groups are on different ring carbons and together form a 1-3 carbon bridge; Each J 4 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -C1-C6 alkyl-C1-C6 alkoxy, oxo, and -C0-C4 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group; R a and R b each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, and C0-C3 alkylene-C2-C6 alkynyl optionally substituted by alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -C1-C6 alkoxy-C1-C6 alkyl; and R c selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl; and R d selected from H, C1-C6 alkyl, and C1-C6 haloalkyl.

3. The compound according to any one of claims 1 or 2, which has one of the following formulas: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds.

4. The compound according to claim 3, which has formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of formula (IIa) or (IIb).

5. The compound according to any one of claims 1 or 2, which has one of the following formulas: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of the above-mentioned compounds.

6. The compound according to any one of claims 1-5, wherein G is -L 1 -R 3 .

7. The compound according to any one of claims 1-5, wherein G is Wherein: L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, wherein C1-C2 alkylene, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl is each optionally substituted with 1-2 J 2 groups, provided that when L 1 is CH2, Z 1 is not CH2 or N; L 2 is -SO2- or -C(O)-; Z 1 is -N(H)-, -C(R 5 )- or a 4- to 7-membered spirocyclic group optionally containing 1 to 2 nitrogen atoms; R 5 is H, halogen, C1-C3 alkyl or CN; Z 2 and Z 3 each independently is a C1-C3 alkylene or a C2-C3 alkenylene, wherein the C1-C3 alkylene and the C2-C3 alkenylene are each optionally substituted with 1-4 J 3 groups; R is vinyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with a Q group, C1-C4 alkylene-NR a R b , -CH2-CN or C1-C4 haloalkyl, where one halogen of the C1-C4 haloalkyl is on the carbon atom adjacent to L 2 ; Each Q is independently selected from halogen, C1-C4 haloalkyl, C1-C4 alkyl, -C1-C4 alkylene-NR a R b , -C1-C4 alkylene-cyano, C1-C4 hydroxyalkyl, -C1-C4 alkylene-C(O)OH, -C1-C4 alkylene-C(O)O-C1-C4 alkyl, -C1-C3 alkylene-C1-C4 alkoxy, -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted by 1-3 J 4 groups, -C0-C4 alkylene-4-7 membered heterocycloalkyl and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted by 1-3 J 4 groups; 4 ​ Each J 2 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy; Each J 3 is independently selected from halogen, -C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy and -C1-C4 alkyl-C1-C4 alkoxy, or two of said optional 1-4 J 3 groups form an oxo group or a 3-6 membered spiro group, or two of said optional 1-4 J 3 groups are on different ring carbon atoms and together form a 1-3 carbon bridge; and Each J 4 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, -C1-C4 alkyl-C1-C4 alkoxy, oxo and -C0-C4 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C4 alkylene-NR a R b group.

8. The compound according to claim 7, wherein G is Wherein: Z 1 is -N(H)-, -C(R 5 )- or a 4- to 6-membered spirocyclic group optionally containing 1 to 2 nitrogen atoms; R 5 is H, halogen, C1-C3 alkyl or CN; Z 2 is a -C1-C3 alkylene or -C2-C3 alkenylene, each of which is optionally substituted by 1-2 J 3 groups; Z 3 is an optionally 1-2 J 3 group-substituted -C1-C2 alkylene group; R is vinyl optionally substituted with 1 - 3 Q groups, ethynyl optionally substituted with a Q group, C1 - C4 alkylene - NR a R b , -CH2-CN or C1 - C3 haloalkyl, where one halogen of the C1 - C3 haloalkyl is on the carbon atom adjacent to -C(O)-; Each Q is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C(O)OH, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C0-C3 alkylene-C1-C3 alkoxy, -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with 1-3 J 4 groups, -C0-C4 alkylene-7-11 membered spiroheterocycloalkyl optionally substituted with 1-3 J 4 groups, -C0-C3 alkylene-4-6 membered heterocycloalkyl and -C0-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups; 4 ​ Each J 2 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy; Each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy, or two of said optional J 3 groups are on different ring carbon atoms and together form a 1-2 carbon bridge and Each J 4 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C1-C3 alkyl-C1-C3 alkoxy, oxo and -C0-C3 alkylene-NR a R b , provided that the J 4 groups may include only up to two oxo groups and up to one -C0-C3 alkylene-NR a R b group.

9. A compound according to any one of claims 1 - 6, wherein R 3 is which contains R 3 said heterocycle containing at least one nitrogen ring atom is optionally substituted by 1-3 J 3 groups; and Each J 3 is independently selected from halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy and -C1-C3 alkyl-C1-C3 alkoxy.

10. The compound according to any one of claims 1-5, wherein G is -X-Y.

11. The compound according to claim 10, wherein X is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 J 2 groups and Y is -C0-C4 alkylene-N(H)-L 2 -R.

12. The compound according to any one of claims 1-9 or 11, wherein R is vinyl optionally substituted by 1-2 groups independently selected from the following: halogen, C1-C3 haloalkyl, C1-C3 alkyl, -C1-C3 alkylene-NR a R b , -C1-C3 alkylene-cyano, C1-C3 hydroxyalkyl, -C1-C3 alkylene-C(O)O-C1-C3 alkyl, -C1-C3 alkylene-C1-C3 alkoxy, -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted by 1-3 J 4 groups, -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted by 1-3 J 4 groups, -C1-C3 alkylene-4-6 membered heterocycloalkyl optionally substituted by 1-3 J 4 groups and -C1-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted by 1-3 J 4 groups.

13. The compound according to any one of claims 1-9 or 11, wherein R is wherein: Each Q 1 is independently selected from H, F, and Cl; and Q 2 Selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , -C0-C4 alkylene-4-7 membered heterocycloalkyl optionally substituted by 1-3 J 4 groups and -C0-C4 alkylene-4-7 membered heterocycloalkenyl optionally substituted by 1-3 J 4 groups.

14. A compound according to any one of claims 1-13, wherein R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl or -N(H)-heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl moiety is optionally substituted with 1-3 J 1 groups.

15. A compound according to any one of claims 1-14, wherein R 2 is -O-(5- to 10-membered) heteroaryl containing at least one nitrogen atom and optionally substituted by 1 or 2 J 1 groups.

16. The compound according to any one of claims 1-15, wherein R 2 is Each of which is optionally substituted by 1-2 J 1 groups.

17. A compound according to any one of claims 1-16, wherein R 2 is Each of which is optionally substituted by 1-2 J 1 groups, where: Each J 1 is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, -C0-C3 alkylene-N(H)R c , C1-C6 alkoxy and -C1-C6 alkyl-C1-C6 alkoxy; and R c selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C3-C7 cycloalkyl, 4-7 membered heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl groups are each optionally substituted with 1-3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkoxy-C1-C6 alkyl.

18. A compound according to any one of claims 1-17, wherein R 2 is 19. The compound according to claim 1, which has one of the following formulas: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein: Each Q 1 is independently selected from H, F, and Cl; and Q 2 independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups. Or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein each Q 1 is independently selected from H, F and Cl; and Q 2 independently selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

20. The compound according to claim 1, which has one of the following formulas: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein: Each Q 1 is independently selected from H, F, and Cl; and Q 2 selected from H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , -C0-C3 alkylene-4-7 membered heterocycloalkyl optionally substituted with 1-3 J 4 groups and -C0-C3 alkylene-4-7 membered heterocycloalkenyl optionally substituted with 1-3 J 4 groups.

21. A compound according to any one of claims 19 or 20, wherein at least one Q 2 is H.

22. The compound according to any one of claims 19 or 20, wherein one Q 2 is -C1-C3 alkylene-NR a R b .

23. The compound according to any one of claims 19 or 20, wherein one Q 2 is a C0-C3 alkylene-4-7 membered heterocycloalkyl group optionally substituted with 1-3 J 4 groups.

24. The compound according to claim 1, which is selected from Table 1, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound according to any one of claims 1-24 and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25, further comprising a second medicament.

27. A method for treating a subject suffering from a Her2-mediated disease or condition, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1-24 or a pharmaceutically acceptable salt, deuterated analogue, tautomer or stereoisomer thereof, or the pharmaceutical composition according to any one of claims 25-26.

28. The method according to claim 27, wherein the disease or condition is a cancer having a Her2 YVMA insertion mutation.

29. The method according to claim 27, wherein the disease or condition is a cancer selected from the following: lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric and esophageal cancer, and uterine serous endometrial carcinoma.

30. The method for treating a disease or condition according to any one of claims 27-29, wherein the disease or condition is non-small cell lung cancer.

31. The method according to any one of claims 27-30, further comprising administering one or more additional therapeutic agents.

32. The method according to claim 31, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, 1,7-heptanediol bis(alkylsulfonate), ifosfamide, iproplatin, ilofosine, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) antibiotics selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, tegafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and CTLA4 inhibitors; v) antibody-drug conjugates selected from ado-trastuzumab emtansine and deruxtecan; vi) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprorelin, megestrol acetate, raloxifene, tamoxifen, and toremifene; vii) taxanes selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; viii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; x) antiangiogenic agents selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, lenalidine, and thalidomide; xi) topoisomerase inhibitors selected from amsacrine, edotecarin, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiv) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xv) IDO inhibitors;(xvi) Chemotherapeutic agents selected from 3-AP (3-amino-2-formyl thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elisidepsin, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors, and aromatase inhibitors (anastrozole, letrozole, exemestane); (xvii) BRAF inhibitors; (xviii) Mek inhibitors; (xix) c-Kit mutant inhibitors; (xx) EGFR inhibitors; (xxi) epigenetic regulators; (xxii) other adenosine axis blockers selected from CD39, CD38, A2AR, and A2BR; or (xxiii) agonists of TNFA superfamily members; and (xxiv) anti-ErbB2 mAb.; 33. The method according to claim 32, wherein the one or more additional therapeutic agents are ado-trastuzumab emtansine or deruxtecan.

34. The method according to claim 32, wherein the one or more additional therapeutic agents are pembrolizumab or nivolumab.

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