Compounds and methods for modulating HER2

Abstract

Formula (I): [Formula 1] JPEG2025528766000491.jpg5672, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 , R 2 , A, E 1 , E 2 and G is as described in any of the embodiments described in this disclosure), compositions thereof, and uses thereof are disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 373,172, filed August 22, 2022, U.S. Provisional Patent Application No. 63 / 507,357, filed June 9, 2023, and U.S. Provisional Patent Application No. 63 / 399,989, filed August 22, 2022, which are incorporated by reference in their entireties.

[0002] Field The present disclosure relates to compounds useful for modulating Her2, compositions of such compounds, and uses of such compounds. [Background technology]

[0003] 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 referred to as EGFR), Her2, human epidermal growth factor receptor 3 (Her3), and human epidermal growth factor receptor 4 (Her4). The Her2 receptor is a 185-kDa transmembrane protein encoded by the Her2 (also known as erb-b2 receptor tyrosine kinase 2 [ERBB2]) gene. Her2 is typically expressed on the plasma membrane of epithelial cells in several organs, such as the lung, breast, and skin, as well as the gastrointestinal, reproductive, and urinary tracts. While Her2 is expressed at low levels in normal cells, Her2-positive cancer cells exhibit up to 40- to 100-fold increased protein overexpression along with an increased number of Her2 gene copies (gene amplification) and Her2 receptors. The increased abundance of cell surface Her2 receptors associated with Her2 overexpression increases receptor-receptor interactions, inducing persistent tyrosine phosphorylation of the kinase domain and therefore constant activation of the signaling pathway.

[0004] Tumors driven by Her2 mutations or overexpression of Her2 wild-type may benefit from tyrosine kinase inhibitors targeting Her2. HER2+ mutations in NSCLC primarily affect the tyrosine kinase domain of Her2 and a cluster within exon 20 of the ERBB2 gene. Approximately 4% of lung cancer patients are estimated to harbor activating mutations in Her2 exon 20. Clinically approved tyrosine kinase inhibitors targeting ERBB are ineffective in these patients due to limited efficacy by EGFR wild-type-mediated dose-limiting toxicities. Afatinib and other pan-ERBB blockers have shown limited efficacy in patients with HER2 exon 20-mutated NSCLC, primarily due to limitations in achieving effective doses. EGFR wild-type-mediated toxicity, in particular, limits effective dosing. Mutant Her2 exon 20 pan-ERBB inhibitors include alitinib, ibrutinib, neratinib, poziotinib, and pyrotinib, all of which are limited by EGFR wild-type-mediated toxicity.

[0005] Current irreversible Her2 tyrosine kinase inhibitors in clinical development include poziotinib and pyrotinib, both of which lack selectivity for Her2-mutated tumors versus EGFR and have adverse event profiles consistent with EGFR-related toxicity. Specifically, patients receiving poziotinib experienced a grade 3 rash, among other grade 3 adverse events, that was difficult to tolerate, leading to significant dose reductions. Additionally, patients receiving pyrotinib also experienced a variety of grade 3 adverse events, including an increase in bowel movements (more than seven times per day), which usually required hospitalization.

[0006] Furthermore, Her2 YVMA insertion mutations account for approximately 65% ​​of insertion mutations in NSCLC. To date, no tyrosine kinase has yet been approved for the treatment of non-small cell lung cancer with Her2 mutations.

[0007] Therefore, there is an unmet medical need for novel compounds targeting Her2, and there is an urgent need for novel Her2 inhibitors that are more potent than EGFR wild-type against wild-type Her2 and / or YVMA Her2 exon 20 insertion mutations to overcome EGFR wild-type-mediated dose-limiting toxicity. Summary of the Invention

[0008] The present disclosure provides novel compounds that modulate wild-type Her2 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 mutant Her2 by irreversibly rebinding to the tyrosine kinase domain. In another embodiment, the compounds of the present disclosure selectively inhibit wild-type Her2 and / or mutant Her2 over wild-type EGFR, and thus are less prone to EGFR-associated toxicity. In another embodiment, the compounds of the present disclosure selectively inhibit the YVMA Her2 exon 20 insertion mutation over wild-type EGFR, and thus are less prone to EGFR-associated toxicity.

[0009] One embodiment of the present disclosure relates to a novel compound described in any of the embodiments herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, which is capable of modulating Her2 (which for purposes of this disclosure is the same as HER2). Another embodiment of the present disclosure relates to a novel compound described in any of the embodiments herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, which is capable of modulating 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 described in any of the embodiments herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, which is capable of inhibiting wild-type Her2 and / or mutant Her2 (such as the Her2 YVMA insertion mutation) more selectively than wild-type EGFR.

[0010] Another embodiment of the present disclosure is a compound of formula (I):

[0011] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 , R 2 , A, E 1 , E 2 , and G are described in any of the embodiments (including any sub-embodiments thereof) in this disclosure.

[0012] Other embodiments and subembodiments of formula (I) are described further in this disclosure.

[0013] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to Formula (I) or according to any of the embodiments and subembodiments of Formula (I) described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, and a pharmaceutically acceptable carrier or excipient.

[0014] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to Formula (I) or according to any of the embodiments and subembodiments of Formula (I) described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, and another therapeutic agent.

[0015] Another embodiment of the present disclosure relates to a method for treating a subject having a disease or condition mediated at least in part by Her2 (e.g., a Her2 wild-type tumor, a Her2 mutant tumor comprising Her2 with a YVMA insertion mutation), the method comprising administering to the subject an effective amount of a compound according to Formula (I) or according to any embodiment of Formula (I) described in this disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds described in this disclosure.

[0016] Also provided herein is the use of a compound according to Formula (I), or according to any embodiment of Formula (I) described in this disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds described in this disclosure, in the treatment of a disease or condition mediated by Her2.

[0017] Additional embodiments are further described in the detailed description of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0018] I. Definition As used herein, the following definitions apply unless clearly indicated otherwise: It is noted herein that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0019] Unless a point of attachment is indicated, the chemical moieties listed in the definitions of the variables of formula (I) and all embodiments thereof of the present disclosure are to be read from left to right, with the right side being directly attached to the parent structure as defined. However, when a point of attachment (e.g., a dash "-") is indicated on the left side of the chemical moiety (e.g., -C1-C6 alkyl-N(R 6 )2), the left side of this chemical moiety is directly attached to the defined parent moiety.

[0020] When considering the general descriptions of compounds described herein for the purpose of constructing a compound, it is assumed that such construction will result in the creation of a stable structure; that is, one of skill in the art will recognize that, in theory, some constructs would not normally be considered stable compounds (i.e., sterically practical and / or synthetically feasible).

[0021] "Alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons). Representative alkyl groups include straight 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 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, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. For each of the definitions herein (e.g., alkyl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, etc.), when a prefix indicating the number of carbon atoms in the alkyl moiety is not included, the alkyl moiety or portion thereof will have 12 or fewer main chain carbon atoms, 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms. For example, C1-C6 alkyl refers to a straight or branched chain hydrocarbon having 1, 2, 3, 4, 5, or 6 carbon atoms, including, but not limited to, -CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C2 alkyl, C2 alkyl, C3 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C2-C3 alkyl, C2-C4 alkyl, C2-C5 alkyl, C2-C6 alkyl, C3-C4 alkyl, C3-C5 alkyl, C3-C6 alkyl, C4-C5 alkyl, C4-C6 alkyl, C5-C6 alkyl, and C6 alkyl. It is understood that substituents are attached to any available atom to produce a stable compound.

[0022] "Alkylene," alone or as part of another substituent, means a straight- or branched-chain saturated divalent hydrocarbon derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., C-C means 1 to 6 carbons, and C-C alkylene is intended to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, etc.). C-C alkylene includes methylene -CH-, ethylene -CHCH-, propylene -CHCHCH-, and isopropylene -CH(CH)CH-, -CHCH(CH)-, -CH-(CH)CH-, -CH-CH(CH)CH-, -CH-C(CH)-CH-CHCH(CH)-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with groups having no more than 10, no more than 8, or no more than 6 carbon atoms. When no prefix is ​​included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or portion thereof will have no more than 12 main chain carbon atoms, no more than 8 main chain carbon atoms, no more than 6 main chain carbon atoms, no more than 4 main chain carbon atoms, no more than 3 main chain carbon atoms, no more than 2 main chain carbon atoms, or 1 carbon atom.

[0023] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group, where alkyl is as defined herein. For example, "C1-C6 alkoxy" refers to an -O-C1-C6 alkyl group, where alkyl is as defined herein. It is understood that substituents on an alkoxy will be attached to any available atom to produce a stable compound, but the alkoxy substituents are such that no O, S, or N (except when N is a heteroaryl ring atom) is attached to the alkyl carbon attached to the alkoxy O. Furthermore, when alkoxy is listed as a substituent on another moiety, the alkoxy oxygen is not attached to a carbon atom attached to an O, S, or N (except when N is a heteroaryl ring atom) of the other moiety, nor to an alkene or alkyne carbon of the other moiety.

[0024] "Amino" or "amine" refers to the group NH2.

[0025] "Aryl," alone or as part of another substituent, refers to a monocyclic, bicyclic, or polycyclic polyunsaturated aromatic hydrocarbon radical containing 6 to 14 ring carbon atoms, which may be one ring or multiple rings (up to three rings) fused or covalently linked together, unless otherwise specified. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl rings are fused with 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.

[0026] "Cycloalkyl" or "Carbocycle" or "Carbocyclic," alone or as part of another substituent, refers to a saturated or partially unsaturated non-aromatic monocyclic ring, bridged ring, spiro ring, fused ring, or cubane, such as cyclopropyl, cyclopentyl, cyclohexyl, etc., having the number of carbon atoms indicated in the prefix, or, if not specified, 3 to 6, 4 to 6, and 5 to 6 ring members per ring, in which one or two ring carbon atoms may be optionally replaced by a carbonyl. Furthermore, the term cycloalkyl is intended to encompass ring systems fused to an aromatic ring (e.g., an aryl or heteroaryl one), 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-C cycloalkyl and 3-6-membered cycloalkyl both refer to 3 to 6 ring carbon atoms). The term "cycloalkenyl" refers to a cycloalkyl having at least one unit of unsaturation. Substituents on a cycloalkyl or cycloalkenyl group may form a quaternary center at the point of attachment of the cycloalkyl or cycloalkenyl group.

[0027] "Halogen" or "halo" refers to all halogens, ie, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

[0028] "Heteroatom" is intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0029] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical containing 5 to 9 ring atoms (also referred to in this disclosure as a 5- to 9-membered heteroaryl), including monocyclic aromatic ring radicals containing 5 or 6 ring atoms (also referred to in this disclosure as a 5- to 6-membered heteroaryl) containing one or more, 14, 13, or 12 heteroatoms independently selected from the group consisting of O, S, and N. All aromatic rings or ring systems containing at least one heteroatom are heteroaryl, regardless of the point of attachment (i.e., through either one of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring 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 pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, phthalazinyl, benzotriazinyl, Examples of heteroaryls include, but are not limited to, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl, pteridinyl, thiadiazolyl, triazolopyridinyl, imidazotriazinyl, and pyrrolotriazinyl. "Nitrogen-containing heteroaryl nitrogen" refers to a heteroaryl in which at least one of the ring heteroatoms is N.

[0030] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, both of which are defined herein.

[0031] The terms "heterocycle" or "heterocyclic ring" are interchangeable and include heterocycloalkyl rings, heterocycloalkenyl rings, and heteroaryl rings as defined herein. Heterocycles can be saturated, unsaturated, or aromatic rings containing one or more heteroatoms. Exemplary heteroatoms include N, O, P, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. Bicyclic heterocycles include all combinations of saturated, unsaturated, and aromatic bicyclic rings, where valences permit.

[0032] The term "spirocycle" or "spirocyclic group" refers to a group having two or more rings, where the two rings are joined together by one atom. Spirocyclic groups can include carbocyclic and heterocyclic rings. In some embodiments, spirocyclic groups can include 6 to 12 members between the two or more rings. In some embodiments, spirocyclic groups can include 6 to 12 atoms (i.e., C 6-12spirocyclic cycloalkyl and 6-12 membered spirocyclic heterocycloalkyl). In some embodiments, the spirocyclic group can contain 7 to 11 atoms (i.e., 7-11 membered spirocyclic cycloalkyl and 7-11 membered spirocyclic heterocycloalkyl). 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]undecanyl, spiro[6,3]decanyl, spiro[6,5]dodecanyl, azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, diazaspiro[3.3]heptanyl, diazaspiro[3.4]octane, azaspiro[3.5]nonanyl, oxaspiro[3.5]nonanyl, thiaspiro[3.5]nonanyl, azaspiro[4.5]decanyl, and diazaspiro[5.5]undecanyl. The term "spiro group" may also be used herein to describe a cyclic substituent that is connected to another cyclic substituent such that a spiro ring is formed.

[0033] The term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group containing one to five heteroatoms selected from N, O, S (including S(O) and S(O)), or P (including phosphine oxide), where the nitrogen, sulfur, and phosphorus atoms are optionally oxidized, the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, with one or two C atoms optionally present as carbonyl. Heterocycloalkyl groups can have one or more carbon-carbon or carbon-heteroatom double bonds in the ring, provided that their presence does not render the ring aromatic. Furthermore, the term heterocycloalkyl is intended to encompass any ring or ring system containing at least one heteroatom that is not heteroaryl, regardless of the point of attachment to the rest of the moiety. Heterocycloalkyl groups include those having rings with formally charge-separated aromatic resonance structures, such as N-methylpyridonyl. Heterocycloalkyls can be substituted with one or two oxo groups and can include sulfone and sulfoxide derivatives. A heterocycloalkyl can be a monocyclic, bridged, fused bicyclic, or fused bicyclic ring system of 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, in which 1 to 5 ring atoms are heteroatoms selected from -N=, -N-, -O-, -S-, -S(O)-, or -S(O)2-, and in addition, 1 or 2 ring atoms are optionally replaced by a -C(O)- group. For example, a 4-9-membered heterocycloalkyl is a heterocycloalkyl containing 4 to 9 ring members with at least one heteroatom. A heterocycloalkyl can also be a heterocyclic alkyl ring fused with 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. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or a heteroatom."Heterocycloalkenyl" refers to a heterocycloalkyl having at least one unit of unsaturation. A heterocycloalkyl or heterocycloalkenyl substituent can form a quaternary center at the point of attachment of the heterocycloalkyl or heterocycloalkenyl group.

[0034] The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group. Examples include, but are not limited to, azetidinylmethyl, morpholinomethyl, and the like.

[0035] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl, as defined herein, substituted with one or more halogen atoms.

[0036] -C1-C4 alkylene-NR a R b " is attached to a parent moiety and represents NR a R b refers to -C1-C4 alkylene- substituted with

[0037] The term "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl, as defined herein, substituted with one or more hydroxy groups, as defined herein.

[0038] The term "-C0-C4 alkylene-C3-C7 cycloalkyl" refers to a -C0-C4 alkylene- bonded to a parent moiety and substituted with a C3-C7 cycloalkyl group, as defined herein.

[0039] The term "oxo" refers to C(=O) or (O). In some embodiments, the two possible points of attachment on the carbon form an oxo group.

[0040] "Hydroxyl" or "hydroxy" refers to the group OH. The terms "hydroxyalkyl" or "hydroxyalkylene" refer to an alkyl or alkylene group, as defined herein, that is substituted with one to five hydroxy groups, respectively.

[0041] The term "substituent" refers to an atom or group of atoms substituted in place of a hydrogen atom of a parent molecule. Non-limiting examples of substituents in the present disclosure include J, which may be monovalent or divalent substituents. 4 Monovalent substituents are attached to the parent moiety by replacing one hydrogen atom of the parent moiety with a single bond. The hydrogen atom replaced by the monovalent substituent may be an available hydrogen atom from a carbon atom or nitrogen atom of the parent moiety. Divalent substituents are attached to the parent moiety by replacing two available hydrogen atoms of the parent moiety with a double bond. It is understood that the substituents described in this disclosure cannot be attached to the parent moiety in a way that results in an unstable molecule.

[0042] "Optional substituent" or "optionally substituted," as used throughout this disclosure, means that substitution may or may not occur on a compound, and that the description includes both substituted and unsubstituted cases. For example, "1 to 3 J 1 The phrase "optionally substituted with a J group" is intended to 1 It means that a group may not necessarily be present. In this disclosure, it is assumed that optional substitutions on compounds occur in a manner that results in stable compounds.

[0043] As used herein with respect to compounds of the present disclosure, the term "synthesize," and like terms, means chemical synthesis from one or more precursor materials.

[0044] As used herein, the term "composition" refers to a formulation suitable for therapeutic administration to an intended animal subject, containing at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0045] The term "pharmaceutically acceptable" indicates that the indicated material does not possess properties that would cause a reasonably prudent physician to avoid administering the material to a patient, taking into account the disease or disorder to be treated and the corresponding route of administration. For example, it is generally required that such a material be essentially sterile, e.g., for injection.

[0046] "Pharmaceutically acceptable salt" refers to a salt acceptable for administration to a patient, such as a mammal (e.g., a salt having acceptable mammalian safety for a given dosing regimen). Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, bis-, tris-, tetrakis-, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by modifying the physical properties of the compound without preventing it from exerting a physiological effect. Useful modifications of physical properties include lowering the melting point to facilitate oral mucosal administration and increasing solubility to facilitate the administration of higher drug concentrations. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the specific substituents found on the compounds described herein.

[0047] 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 or aqueous alcoholic solution containing an appropriate acid, and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting a free base and a free acid in an organic solvent.

[0048] When a compound of the present disclosure contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound, neat or in a suitable inert solvent, with a sufficient amount of a desired base (i.e., a primary, secondary, tertiary, quaternary, or cyclic amine, alkali metal hydroxide, alkaline earth metal hydroxide, etc.). The desired acid can be, for example, a pyranosidyl acid (such as glucuronic acid or galacturonic acid), an α-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. In some embodiments, the salts are prepared from pharmaceutically acceptable acids, such as acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphoric acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic 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, Acids may be derived from sulfuric acid, sulfamic acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embonic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylaminosulfonic acid, quinic acid, alginic acid, hydroxybutyric acid, galactaric acid, and galacturonic acid, among others.

[0049] Also included are salts of amino acids, such as arginic acid, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., 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 functionalities that allow the compounds to be converted into either base or acid addition salts.

[0050] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.

[0051] Pharmaceutically acceptable salts of various compounds may be present as complexes. Examples of complexes include 8-chlorotheophylline complex (e.g., dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex, similar to dramamine), and various cyclodextrin inclusion complexes.

[0052] The term "deuterated," when used alone or as part of a group, refers to a substituted deuterium atom. The term "deuterated analog," when used alone or as part of a group, refers to a substituted deuterium atom in place of hydrogen. The deuterated analogs of the present disclosure can be fully or partially deuterium-substituted derivatives. In some embodiments, the deuterium-substituted derivatives of the present disclosure retain a fully or partially deuterium-substituted alkyl, aryl, or heteroaryl group.

[0053] The present disclosure also encompasses isotopically labeled compounds of the present disclosure, which are identical to those listed herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from that usually found in nature.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed 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, for example: 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 Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position may also be substituted with deuterium (D) or tritium ( 3 It is understood that hydrogen has the isotopic composition of its natural abundance or its isotopes, such as H. Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. Tritiated isotopes (i.e. 3 H), carbon-14 isotopes (i.e. 14 C), and fluorine-18 isotopes ( 18 F) are useful for their ease of preparation and detectability. 2Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability and, therefore, may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent following procedures similar to those described in the schemes and examples hereinafter.

[0054] "Prodrug" means any compound that releases an active parent drug according to Formula (I) in vivo when the prodrug is administered to a subject. Prodrugs of compounds of Formula (I) are prepared by modifying functional groups present in the compounds of Formula (I) such that the modifications can be cleaved in vivo to release the parent compound, either by conventional techniques or in vivo. Prodrugs may transition from the prodrug form to the active form in a single step, or may have one or more intermediate forms that may be active or inactive themselves. Some prodrugs are enzymatically activated to yield the active compound, or the active compound after further chemical reaction. Prodrugs include compounds of Formula (I) in which a hydroxyl group, amino group, carboxyl group, or sulfhydryl group in a compound of Formula (I) is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl group, amino group, or sulfhydryl group, respectively. 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) of the hydroxy functional group in the compound of Formula (I). Other examples of prodrugs include, but are not limited to, carbonates, ureides, solvates, or hydrates of the active compound. The preparation, selection, and use of prodrugs are discussed in "Prodrugs as Novel Delivery Systems" by T. Higuchi and V. Stella, Vol. 14 of the ACS Symposium Series; "Design of Prodrugs" edited by H. Bundgaard, Elsevier, 1985; and 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.

[0055] As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or less active than the corresponding active drug compound, contain one or more protecting groups, and are converted to an active form by metabolism or solvolysis. Both the active drug form and the released metabolites must have acceptably low toxicity. Typically, the formation of an active drug compound involves one of the following types of metabolic processes or reactions: (1) Oxidation Reactions: Oxidation reactions are exemplified without limitation to reactions such as oxidation of alcohol, carbonyl, and acidic functionalities, 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- and S-dealkylation, oxidative deamination, and other oxidation reactions. (2) Reduction Reactions: Reduction reactions are illustrated without limitation to reactions such as reduction of carbonyl functionality, reduction of alcohol functionality and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions. (3) Reactions with no change in oxidation state: Reactions with no change in oxidation state are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, dehydration reactions resulting in new atomic bonds, hydrolytic dehalogenation, elimination of hydrogen halide molecules, and other such reactions.

[0056] Carrier prodrugs are drug compounds that contain a transport moiety, for example, to improve uptake and / or local delivery to the site of action. Desirably, in such carrier prodrugs, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and the release transport moiety are acceptably non-toxic. For prodrugs in which the transport moiety is intended to enhance uptake, the release of the transport moiety must typically be rapid. In other cases, it is desirable to utilize a moiety that slows release, for example, certain polymers such as cyclodextrins or other moieties (see, for example, U.S. Patent Application Publication No. 2004 / 0077595 by Cheng et al., incorporated herein by reference). Such carrier prodrugs are often advantageous for orally administered drugs. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and side effects, and / or improved pharmaceutical properties (e.g., stability, water solubility, reduced undesirable organoleptic or physiochemical properties). For example, lipophilicity can be increased by esterification of a hydroxyl group with a lipophilic carboxylic acid or of a carboxylic acid group with an alcohol, e.g., an aliphatic alcohol.

[0057] The term "carrier" is also intended to include microspheres, liposomes, micelles, nanoparticles (natural nanocarriers, e.g., exosomes), etc. It is known that exosomes can be very effective drug carriers, and there are various methods by which drugs can be loaded into exosomes, including the techniques described in J Control Release. 2015 December 10;219:396-405, the contents of which are incorporated by reference in their entirety.

[0058] Metabolites, e.g., active metabolites, overlap with the above-mentioned prodrugs, e.g., bioprecursor prodrugs. Thus, such metabolites are compounds that are further metabolized into pharmacologically active compounds or derivatives thereof resulting from metabolic processes in the subject's body. Among these, active metabolites are such pharmacologically active derivative compounds. In prodrugs, the prodrug compounds are generally inactive or less active than the metabolites. In active metabolites, the parent compound may be either an active compound or an inactive prodrug.

[0059] Prodrugs and active metabolites can be identified by using conventional techniques known in the art.See, for example, Bertolini et al., 1997 J.Med.Chem., 40:2011-2016; Shan et al., 1997 J Pharm Sci 86(7):756-757; Bagshawe et al., 1995 Drug Dev.Res., 34:220-230.

[0060] "Tautomer" refers to a compound produced by the shifting of a proton from one atom of a molecule to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992). Tautomer also refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples include keto-enol tautomers such as acetone / propen-2-ol and imine-enamine tautomers, ring-chain tautomers such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, and tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom structure, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Tautomerism ("tautomerism") can occur when a compound contains, for example, a keto or oxime group, or an aromatic moiety. The compounds described herein may have one or more tautomers and thus include various isomers. One skilled in the art will recognize that other tautomeric ring atom structures are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0061] "Isomers" have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers."

[0062] "Stereoisomer" and "stereoisomers" refer to compounds that exist in various stereoisomeric forms, for example, if they have one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are termed "diastereomers," while those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, an atom such as a carbon bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the rules of Cahn and Prelog R and S sequencing or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." As another example, stereoisomers include geometric isomers, such as cis- or trans-oriented substituents on adjacent carbons of a double bond. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 6th ed., J. March, John Wiley and Sons, New York, 2007), and differ in the chirality of one or more stereocenters.

[0063] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means bringing a particular molecule, complex, cell, tissue, organism, or other particular material into close proximity such that possible binding interactions and / or chemical reactions can occur between the compound and the other particular material.

[0064] "Assaying" refers to the creation of experimental conditions and the collection of data regarding a particular outcome from subjecting specific experimental conditions to such conditions. For example, enzymes can be assayed based on their ability to act on a detectable substrate. Compounds can be assayed based on their ability to bind to a particular target molecule or molecules.

[0065] As used herein, the terms "ligand" and "modulator" are used equally to refer to compounds that alter (i.e., increase or decrease) the activity of a target biomolecule, e.g., an enzyme such as those described herein. Generally, a ligand or modulator is a small molecule, where "small molecule" refers to a compound with 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 that has better pharmacological and / or pharmacokinetic properties than a reference compound, where "better" can be defined by one of skill in the art with respect to a particular biological system or therapeutic application.

[0066] The term "binds," with respect to the interaction between a target and a candidate binding compound, indicates that the candidate binding compound associates with the target to a statistically significant extent compared to association with proteins 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, a binding compound has a dissociation constant (K) 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. D ) interacts with a specific target. The term "selective" indicates that a compound binds more tightly than a reference compound or than the same compound under reference conditions, i.e., with a lower dissociation constant. Certain compounds of the present disclosure inhibit wild-type Her2 and / or mutant Her more selectively than wild-type EGFR, thereby reducing EGFR dose-limiting toxicity.

[0067] In some embodiments, the higher affinity of one or more compounds in Table 1 is at least 1.5, 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times higher affinity. Certain compounds of the present disclosure selectively inhibit wild-type Her2 and / or mutant Her over wild-type EGFR, thereby reducing EGFR dose-limiting toxicity.

[0068] Terms such as "modulate" and "modulation" refer to the ability of a compound to increase or decrease the function and / or expression of a target, such as interaction with Her2 (including mutant forms thereof); such function may include transcriptional regulatory activity and / or binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes direct or indirect inhibition, antagonism, partial antagonism, activation, agonism, or partial agonism of a function or characteristic associated with Her2, and / or direct or indirect up- or down-regulation of Her2 expression. In another embodiment, modulation is direct. An inhibitor or antagonist is a compound that, for example, binds to, partially or completely blocks stimulation, reduces, prevents, inhibits, delays activation, inactivates, desensitizes, or down-regulates signal transduction. An activator or agonist is a compound that, for example, binds to, stimulates, increases, opens, activates, promotes, or enhances activation, or activates, sensitizes, or up-regulates signal transduction. In another example, a compound that modulates Her2 can do so by irreversibly binding or covalently binding to Her2 tyrosine kinase, or by inhibiting Her2 by reversibly binding or covalently binding to Her2 tyrosine kinase.

[0069] As used herein, the terms "treat," "treating," "therapy," "therapies," and the like refer to administering a material, e.g., any one or more compounds described herein, in an amount effective to inhibit Her2, including wild-type Her2 and mutant Her2, such as Her2 with a YVMA insertion mutation. In other embodiments of the present disclosure, these terms apply to administering a compound of the present disclosure to a subject having a disease state associated with overexpression of Her2 and / or amplification of HER2. In other embodiments, the terms "treat," "treating," "therapy," "therapies," and the like refer to administering a material, e.g., any one or more compounds described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or disorder, i.e., an indication, and / or prolong the survival of the subject being treated. In other embodiments of the present disclosure, these terms apply to administering a compound of the present disclosure to a subject having a disease state associated with overexpression of Her2 and / or amplification of HER2.

[0070] As used herein, the terms "prevent," "preventing," "prevention," and grammatical variations thereof, refer to partially or completely delaying or eliminating the onset or recurrence of a disease, disorder, or condition, and / or one or more of its attendant symptoms, preventing a subject from acquiring or re-acquiring a disease or condition, or a method of reducing a subject's risk of acquiring or re-acquiring a disease or condition or one or more of its attendant symptoms.

[0071] As used herein, terms such as "subject" and "animal subject" refer to living organisms, including, but not limited to, humans and non-human vertebrates, e.g., any mammal, such as humans, other primates, athletic animals, and commercial animals such as cows, horses, sheep, or pigs, rodents, or pets such as dogs and cats.

[0072] A "unit dosage form" refers to a composition intended for single administration to treat a subject suffering from a disease or condition. Each unit dosage form typically contains each of the active ingredients of the present disclosure as well as pharmaceutically acceptable excipients. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions, or suspensions. Treatment of a disease or illness may require regular administration of a unit dosage form, for example, one unit dosage form two or more times a day, one with each meal, one every four hours or other intervals, or only once a day. The phrase "oral unit dosage form" refers to a unit dosage form designed to be ingested.

[0073] The term "administering" refers to oral administration, suppository administration, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a slow-release device, such as a mini-osmotic pump. Administration can be by any route, including parenteral and oral mucosa (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery forms include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0074] In this context, the terms "therapeutically effective" or "effective amount" refer to a compound or material, or an amount of a compound or material, when administered, that is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of the disease, disorder, or condition being treated and / or 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, as well as the age and weight of the mammal being treated. In general, good results in a subject have been shown to be obtained with a daily administration of about 0.1 to about 10 g per kg of the subject's body weight. In some embodiments, the daily dose ranges from about 0.10 to 10.0 mg per kg of body weight, about 1.0 to 3.0 mg per kg of body weight, about 3 to 10 mg per kg of body weight, about 3 to 150 mg per kg of body weight, about 3 to 100 mg per kg of body weight, about 10 to 100 mg per kg of body weight, about 10 to 150 mg per kg of body weight, or about 150 to 1000 mg per kg of body weight. The dosage may conveniently be administered in divided doses, for example, up to four times daily, or in sustained release form.

[0075] As used herein, the term "Her2-mediated disease or condition" (which is intended to mean "Her2-mediated disease or condition," as well as "wild-type Her2 and / or mutant Her2-mediated disease or condition") refers to a disease or condition in which the biological function of Her2 influences the progression and / or course of the disease or condition and / or modulation of Her2 interactions alters the progression, course, and / or symptoms. Her2-mediated diseases or conditions include those in which disrupted Her2 interactions (e.g., by inhibiting Her2 with a YVMA insertion mutation) provide a therapeutic benefit, e.g., treatment with a Her2 inhibitor, including a compound described herein, provides a therapeutic benefit to a subject suffering from or at risk of the disease or condition. Her2-mediated diseases or conditions are intended to include cancers or tumors with loss of function mutations in Her2 or cancers in which there is activation of Her2. In other embodiments of the present disclosure, the Her2-mediated disease or condition is associated with overexpression of Her2 and / or amplification of Her2. Her2-mediated diseases or conditions are also intended to include various human cancers, including lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastroesophageal cancer, serous endometrial cancer, as well as all associated co-morbidities such as pulmonary disease, hypertension, hypercholesterolemia, heart disease, kidney dysfunction, thyroid disorders, obesity, depression, anxiety, osteoporosis, liver disorders, autoimmune diseases, dementia, Alzheimer's disease, and the like.

[0076] Also, in the context of a compound that binds to a biomolecular target, the term "higher specificity" refers to a compound that binds to a specific target to a greater extent than another biomolecule, or a biomolecule that may be present under the 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, for example, in the case of Her2 or Her2+ mutations. In certain embodiments, the higher specificity is at least 2, 3, 4, 5, 8, 10, 20, 50, 100, 200, 400, 500, or 1000 times higher specificity.

[0077] As used herein with respect to a binding compound or ligand, the term "specific for Her2" (intended to include wild-type Her2, mutant Her2, or both wild-type and mutant Her2), and terms of similar import, means that a particular compound binds to Her2 to a statistically greater extent than to other targets that may be present in a particular sample, such as wild-type EGFR. Additionally, when a biological activity other than binding is indicated, the term "specific for Her2" indicates that the biological effect of a particular compound is greater than that associated with binding to Her2 than to other enzymes, e.g., inhibition of enzymatic activity.

[0078] The term "first-line cancer treatment" refers to a treatment administered to a subject as an initial regimen to reduce the number of cancer cells. First-line treatment is also referred to as induction therapy, primary therapy, and primary treatment. First-line treatment can be administered in combination with one or more drugs. A summary of the currently accepted approach to first-line treatment for a particular disease can be found in the NCI guidelines for that disease.

[0079] "Second-line cancer treatment" refers to a cancer treatment administered to a subject who does not respond to first-line treatment, i.e., who has been given frequent first-line treatments, or whose cancer has recurred after a period of remission. In certain embodiments, the second-line treatment that can be administered includes a repeat of an initial successful cancer treatment, which can be any of the treatments listed under "first-line cancer treatment." A summary of the currently accepted approach to second-line treatment for a particular disease is provided in the NCI guidelines for that disease.

[0080] The term "refractory" refers to a subject that does not respond to or otherwise exhibits resistance to a cancer treatment or therapy. The cancer treatment may be a first-line, second-line, or any subsequent treatment. In certain embodiments, refractory refers to a state in which a subject does not achieve complete remission after two induction attempts. A subject may be refractory due to the inherent resistance of cancer cells to a particular treatment, or due to acquired resistance that develops during the course of a particular treatment.

[0081] Additionally, the abbreviations used herein have the following meanings:

[0082] [Table 1-1]

[0083] [Table 1-2]

[0084] II. Compounds Embodiment 1 of the present disclosure relates to a compound of formula (I):

[0085] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or halogen; R 2is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -O-heteroaryl-alkylene-aryl, -NH-alkyl, -NH-aryl, or -NH-heteroaryl, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains from 1 to 4 J 1 optionally substituted with a group, Or R 1 and R 2 form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and the saturated or unsaturated carbocyclic or heterocyclic ring is a ring having 1 to 4 J 1 optionally substituted with a group, G is -L 1 -R 3 , L 1a -R 3a , or -WXY, L 1 is a bond, -C(O)-, -S(O)2-, -N(R c )-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, each of which contains 1 to 4 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom 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, and R 3 is 1 to 4 J 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, Or R 3is a 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 7- to 11-membered spirocyclic ring is optionally substituted with -L 2 -R is substituted, R 3a is 1 to 4 J 2 C1-C6 alkylene optionally substituted with a -NR group a R b and W is a bond, —C(O)—, or —S(O)—; X is 1 to 4 J 2 aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with a group; 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 to 2 oxo groups, -4 to 7-membered heterocycloalkyl-L 2 R, -C0-C4 alkylen-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(e theyny), -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=NN(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; the C0-C4 alkylene portion is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxy, alkoxyalkyl, or hydroxy; R 4 is H, halo, alkyl, or -O-alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C1-C4 alkylene-NR a R b , —CH—CN, or haloalkyl, and one halogen in the haloalkyl is L 2 on the carbon atom adjacent to Q is independently a halogen, a haloalkyl, an alkyl, or a -C1-C6 alkylene-NR a R b , cyano, hydroxyalkyl, -C1-C6 alkylene-C(O)OH, -C1-C6 alkylene-C(O)O-alkyl, alkoxyalkyl, 1 to 3 J 4 -C0-C4 alkylene-cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-cycloalkenyl optionally substituted with a group, 1 to 3 J 4 a —C0-C4 alkylene-7 to 11-membered spirocyclic group optionally substituted with a group, 1 to 3 J 4 a —C0-C4 alkylene-7 to 11-membered spirocyclic group optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl; J 2are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; J 3 are each bonded to a carbon atom and are independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, or two of the optional one to four J groups form an oxo group or a 3- to 6-membered spiro group, or two of the optional one to four J groups form an oxo group or a 3- to 6-membered spiro group, 3 two of the groups are on different ring carbons and are linked to form a 1-3 carbon bridge; J 4 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and -C0-C4 alkylene-NR a R b and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C0-C3 alkylene-alkynyl optionally substituted with alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R c is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl, alkoxy, and alkoxyalkyl; R d is selected from the group consisting of H, alkyl, and haloalkyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0086] Embodiment 1(a) of the present disclosure is directed to a compound in which G is -L 1 -R 3 The present invention relates to a compound according to embodiment 1, wherein

[0087] Embodiment 1(b) of the present disclosure is directed to a compound in which G is -L 1a -R 3a In another embodiment of embodiment 1(b), L 1a is C0-C3 alkylene-C(O)N(H)-. In another embodiment of embodiment 1(b), R 3 is -C1-C4 alkylene-NR a R b and R a and R b are each independently selected from the group consisting of C-C alkyl, C-C haloalkyl, and C-C hydroxyalkyl. In another aspect of embodiment 1(b), R 3 is -C1-C3 alkylene-NR a R b and R a and R b are each C1-C3 alkyl.

[0088] Embodiment 1(c) of the present disclosure relates to compounds according to embodiment 1, wherein G is -WXY.

[0089] Embodiment 2 of the present disclosure is R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen; R 2is -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, and each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties is selected from 1 to 3 J 1 optionally substituted with a group, Or R 1 and R 2 are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each ring containing 1-3 J 1 optionally substituted with a group, G, -L 1 -R 3 , or -WXY, 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, and each of 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 is preferably 1 to 3 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom, and the 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 4- to 7-membered heterocycle is optionally substituted with -L 2 -R is substituted, Or R 3is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic group is 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, W is a bond, —C(O)—, or —S(O)—; X is a 5- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 5- to 7-membered heterocycloalkyl, or a 5- to 7-membered cycloalkyl, and the 10-membered aryl, the 5- to 10-membered heteroaryl, the 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered cycloalkyl are optionally joined by 1 to 3 J 2 optionally substituted with a group, Y is -C0-C4 alkylene-N(R d )-L 2 -R, -C(O)-4 to 6-membered heterocycloalkyl containing at least one nitrogen atom and substituted with 1 to 2 oxo groups, -4 to 7-membered heterocycloalkyl-L 2 R, -C0-C4 alkylen-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( -C-C alkylene-C(O)-CH-Br, -C-C alkylene-CH-Cl, -C-C alkylene-oxiranyl, -C-C alkylene-SH, -C-C alkylene-F, and -C-C alkylene-C(H)=O, wherein the -C-C alkylene portion is optionally substituted with one to four groups independently selected from the group consisting of halogen, C-C cycloalkyl, C-C alkoxy, -C-C alkyl-C-C alkoxy, or hydroxy; R 4is H, halo, C0-C4 alkyl, or —O—C0-C4 alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C1-C4 alkylene-NR a R b , —CH—CN, or C1-C6 haloalkyl, and one halogen of the C1-C6 haloalkyl is L 2 on the carbon atom adjacent to 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, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-7-11 membered spirocyclic heterocycloalkyl optionally substituted with a group, 1-3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently 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; J 2are each independently selected from the group consisting of halogen, C-C alkyl, C-C haloalkyl, hydroxy, C-C hydroxyalkyl, C-C alkoxy, and —C-C alkyl-C-C alkoxy; J 3 are R 3 and are independently selected from the group consisting of 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 optional one to four J3 groups form an oxo group or a 3-6 membered spiro group, or two of the optional one to four J3 groups form an oxo group or a 3-6 membered spiro group, 3 two of the groups are on different ring carbons and are linked to form a 1-3 carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, and C-C alkylene-C-C alkynyl optionally substituted with alkyl, C-C haloalkyl, C-C hydroxyalkyl, or —C-C alkoxyC-C alkyl; R cis selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl; R d is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0090] Embodiment 3 of the present disclosure relates to a compound of the formula:

[0091] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of the foregoing compounds. Another aspect of Embodiment 3 of the present disclosure relates to a compound of any one of Embodiments 1 or 2 having any one of Formulas (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0092] Embodiment 4 of the present disclosure relates to a compound according to embodiment 3, having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of formula (IIa) or (IIb).

[0093] Embodiment 4(a) of the present disclosure relates to a compound according to embodiment 4 having formula (IIa):

[0094] Embodiment 4(a) of the present disclosure relates to a compound according to embodiment 4 having formula (IIb):

[0095] Embodiment 5 of the present disclosure relates to a compound of the formula:

[0096] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of the foregoing compounds. Another aspect of embodiment 5 of the present disclosure relates to a compound of any one of embodiments 1 or 2 having any one of formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0097] 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, having formula (IIIa):

[0098] 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, having formula (IIIb):

[0099] 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, having formula (IIIc):

[0100] 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, having formula (IIId):

[0101] 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, having formula (IIIe):

[0102] 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, having formula (IIIf):

[0103] Embodiment 6 of the present disclosure is directed to a compound in which G is -L 1 -R 3 Another aspect of 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 any one of embodiments 1, 2, 3, 4, or 5, wherein

[0104] In a seventh embodiment of the present disclosure, G is

[0105] [ka] where: L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl, and each of C1-C2 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered cycloalkyl is selected from the group consisting of 1 to 2 J 2 optionally substituted with a group, provided that L 1 When is CH2, Z 1 is assumed to be neither CH2 nor N, L 2 is -SO2- or -C(O)-, Z 1 -N(H)-, -C(R 5 )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 and Z 3 are each independently —C1-C3 alkylene or —C2-C3 alkenylene, wherein each —C1-C3 alkylene and —C2-C3 alkenylene is optionally substituted with 1 to 4 J3 groups; R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q groups, C1-C4 alkylene-NR a R b , —CH2—CN, or C1-C4 haloalkyl, and one halogen in the C1-C4 haloalkyl is L 2 on the carbon atom adjacent to 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, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-7-11 membered spirocyclic heterocycloalkyl optionally substituted with a group, 1-3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; J 2are each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy; J 3 are each independently selected from the group consisting of 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 one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, or two of the optional one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, 3 two of the groups are on different ring carbon atoms and are linked to form a 1-3 carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b

[0023] Another aspect of 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, provided that G may only contain a group.

[0106] [ka] where: L 1is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl, and each of C1-C2 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered cycloalkyl is selected from the group consisting of 1 to 2 J 2 optionally substituted with a group, provided that L 1 When is CH2, Z 1 is assumed to be neither CH2 nor N, L 2 is -SO2- or -C(O)-, Z 1 -N(H)-, -C(R 5 )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 and Z 3 are each independently —C1-C3 alkylene or —C2-C3 alkenylene, wherein each —C1-C3 alkylene and —C2-C3 alkenylene is optionally substituted with 1 to 4 J3 groups; R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q groups, —CH—CN, or C-C haloalkyl, wherein one halogen of the C-C haloalkyl is selected from L 2 on the carbon atom adjacent to 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, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 1 to 3 J 4-C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy; J 3 are each independently selected from the group consisting of 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 one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, or two of the optional one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, 3 two of the groups are on different ring carbon atoms and are linked to form a 1-3 carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b Any one of embodiments 1, 2, 3, 4, 5, or 6, provided that the R may only contain groups.

[0107] In an eighth embodiment of the present disclosure, G is

[0108] [ka] where: Z 1 -N(H)-, -C(R 5 )- or a 4- to 6-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 Each has 1-2 J 3 -C1-C3 alkylene or -C2-C3 alkenylene optionally substituted with a group; Z 3 is 1 to 2 J 3 is a -C1-C2 alkylene optionally substituted with a group; R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C1-C4 alkylene-NR a R b , —CH—CN, or C1-C3 haloalkyl, wherein one halogen atom 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, 1 to 3 J 4 -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-7-11 membered spirocyclic heterocycloalkyl optionally substituted with a group, 1-3 J 4 -C0-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4-C0-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy, or the optional J 3 two of the groups are on different ring carbon atoms and are linked to form a one to two carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C3 alkylene-NR a R b The present invention relates to compounds according to embodiment 7, provided that the R, R, and R groups may be present.

[0109] Embodiment 9 of the present disclosure is R 3 but

[0110] [ka]

[0111] [ka] where R 3 The heterocycle containing at least one nitrogen ring atom of 3optionally substituted with a group, J 3 and n is independently selected from the group consisting of halogen, -C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy.

[0112] Another aspect of embodiment 9 is R 3 but

[0113] [ka]

[0114] [ka] where R 3 The heterocycle containing at least one nitrogen ring atom of 3 optionally substituted with a group, J 3 with respect to a compound of any one of embodiments 1-6, wherein each independently is selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy.

[0115] Embodiment 9(a) of the present disclosure provides R 3 but

[0116] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0117] Embodiment 9(b) of the present disclosure is R 3 but

[0118] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0119] Embodiment 9(c) of the present disclosure provides R 3 but

[0120] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0121] Embodiment 9(d) of the present disclosure provides R 3 but

[0122] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0123] Embodiment 9(e) of the present disclosure provides R 3 but

[0124] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0125] Embodiment 9(f) of the present disclosure provides R 3 but

[0126] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0127] Embodiment 9(g) of the present disclosure is directed to R 3 but

[0128] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0129] Embodiment 9(h) of the present disclosure provides R 3 but

[0130] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0131] Embodiment 9(i) of the present disclosure is directed to R 3 but

[0132] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0133] Embodiment 9(j) of the present disclosure provides a compound comprising R 3 but

[0134] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0135] Embodiment 9(k) of the present disclosure provides R 3 but

[0136] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0137] Embodiment 9(l) of the present disclosure is directed to R 3 but

[0138] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0139] Embodiment 9(m) of the present disclosure provides a compound comprising R 3but

[0140] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0141] Embodiment 9(n) of the present disclosure is directed to R 3 but

[0142] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0143] Embodiment 9(o) of the present disclosure is directed to R 3 but

[0144] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0145] Embodiment 9(p) of the present disclosure is 3 but

[0146] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0147] Embodiment 9(q) of the present disclosure is R 3 but

[0148] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0149] Embodiment 9(s) of the present disclosure is 3 but

[0150] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0151] Embodiment 9(t) of the present disclosure is 3 but

[0152] [ka] Embodiment 10 relates to a compound according to embodiment 9, wherein

[0153] Embodiment 10 of the present disclosure relates to compounds according to any one of embodiments 1 to 5, wherein G is -XY.

[0154] An eleventh embodiment of the present disclosure is a group in which X is 1 to 3 J 2 and Y is a 5-10 membered heteroaryl optionally substituted with a -C0-C4 alkylene-N(H)-L 2 11. The compound of claim 10, wherein R is —R.

[0155] Embodiment 12 of the present disclosure is a compound in which R is selected from the group consisting of 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, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 49(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 the aryl group is ethenyl optionally substituted with 1 to 2 groups independently selected from the group consisting of -C1-C3 alkylene-4 to 6 membered heterocycloalkenyl optionally substituted with a group. Another aspect of embodiment 12 of the present disclosure is that R is selected from the group consisting of 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, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 and 12, -C1-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with a group: ethenyl optionally substituted with 1-2 groups independently selected from the group consisting of: -C1-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with a group.

[0156] A thirteenth embodiment of the present disclosure is a compound in which R is

[0157] [ka] where: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 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 the heterocycloalkenyl is selected from the group consisting of: -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0158] Another aspect of embodiment 13 of the present disclosure is R 3 but

[0159] [ka] where: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 12. The compound according to any one of embodiments 1 to 9 or 11, wherein the alkyl group is selected from the group consisting of: -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0160] Embodiment 13(a) of the present disclosure provides Q 2 is H.

[0161] Embodiment 13(b) of the present disclosure provides Q 2 is C1-C6 haloalkyl.

[0162] Embodiment 13(c) of the present disclosure provides Q 2 is C1-C6 alkyl.

[0163] Embodiment 13(d) of the present disclosure provides Q 2 -C1-C4 alkylene-NR a R b 14. The compound of embodiment 13, wherein

[0164] Embodiment 13(e) of the present disclosure provides Q 2 However, 1 to 3 J 4 14. The compound according to embodiment 13, wherein the aryl group is -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group.

[0165] Embodiment 13(f) of the present disclosure provides Q 2 However, 1 to 3 J 4 14. The compound according to embodiment 13, wherein the alkyl group is -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0166] A fourteenth embodiment of the present disclosure is R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J 1 14. The compound according to any one of embodiments 1 to 13, optionally substituted with a group.

[0167] A fifteenth embodiment of the present disclosure is R 2 contains at least one nitrogen atom and 1 to 2 J 1 15. The compound according to any one of embodiments 1 to 14, wherein the heteroaryl is -O-(5-10 membered)heteroaryl optionally substituted with a group.

[0168] A sixteenth embodiment of the present disclosure is R 2 However, each has 1-2 J 1 optionally substituted with a group,

[0169] [ka] 16. The compound according to any one of embodiments 1 to 15, wherein

[0170] Embodiment 17 of the present disclosure is R 2 However, each has 1-2 J 1 optionally substituted with a group,

[0171] [ka] where: J 1 are each independently 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; R c is selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1-3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl.

[0172] An eighteenth embodiment of the present disclosure is R 2 but

[0173] [ka] 18. The compound according to any one of embodiments 1 to 17, wherein:

[0174] Embodiment 19 of the present disclosure provides a compound of the formula:

[0175] [ka]

[0176] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene, -NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 Q is a —C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 are independently H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 The present invention relates to compounds according to embodiment 1, wherein the alkyl group is selected from the group consisting of: -C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0177] Embodiment 20 of the present disclosure relates to a compound of the formula:

[0178] [ka]

[0179] [ka]

[0180] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene, -NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 The present invention relates to compounds according to embodiment 1, wherein the alkyl group is selected from the group consisting of: -C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0181] Embodiment 21 of the present disclosure provides at least one Q 2 is H.

[0182] Embodiment 22 of the present disclosure is a single Q 2 -C1-C3 alkylene-NR a R b 21. The compound according to any one of embodiments 19 or 20, wherein

[0183] Embodiment 23 of the present disclosure is a single Q 2 However, 1 to 3 J 4 21. The compound according to any one of embodiments 19 or 20, wherein the heterocycloalkyl group is C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group.

[0184] Embodiment 24 of the present disclosure relates to a compound according to embodiment 1, selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0185] Another embodiment of the present disclosure relates to a compound according to any one of embodiments 1 to 24, wherein the compound is selected from Table 1.

[0186] Embodiments P1 to P14 Embodiment P1 of the present disclosure is a compound of formula (I):

[0187] [ka] a compound having or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or halogen; R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl, or -NH-heteroaryl, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains from 1 to 4 J 1 optionally substituted with a group, Or R 1 and R 2form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and the saturated or unsaturated carbocyclic or heterocyclic ring is a ring having 1 to 4 J 1 optionally substituted with a group, G is -L 1 -R 3 or XY, L 1 is a bond, -C(O)-, -S(O)2-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and each of the alkylene, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups contains 0 to 4 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4-8 membered heterocycle containing at least one nitrogen ring atom, and R 3 is 1 to 4 J 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 7- to 11-membered spirocyclic ring is optionally substituted with -L 2 -R is substituted, X is 1 to 4 J 2 aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with a group; Y is -C0-C4 alkylene-N(H)-L 2 -R, -C0-C4 alkylene-OC(O)-C(H)=CH2, -C0-C4 alkylene-OC(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -4- to 7-membered heterocycloalkyl-L 2R, -C0-C4 alkylen-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-etheyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=NN(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 portion is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxy, alkoxyalkyl, or hydroxy; R 4 is H, halo, alkyl, or -O-alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl, ethynyl, -CH2-CN, or haloalkyl, and one halogen of the haloalkyl is L 2 and ethenyl and ethynyl are 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, 0 to 3 J 4 -C0-C4 alkylene-cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-heterocycloalkenyl optionally substituted with groups; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl; J 2 are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; J 3 are each independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, and alkoxy, and alkoxyalkyl, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and -C0-C4 alkylene-NR a R b and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C0-C3 alkylene-alkynyl optionally substituted with alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R cis selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl, alkoxy, and alkoxyalkyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0188] Embodiment P2 of the present disclosure is R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen; R 2 is -O-(5-10 membered)aryl, -O-(5-10 membered)heteroaryl, -O-(4-7 membered)cycloalkyl, -O-(4-7 membered)heterocycloalkyl, -NH-(5-10 membered)aryl, or -NH--(5-10 membered)heteroaryl, and each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties contains 1 to 3 J 1 optionally substituted with a group, Or R 1 and R 2 are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each ring containing 1-3 J 1 optionally substituted with a group, G, -L 1 -R 3 or XY, L 1is 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, and each of 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 is preferably 0 to 3 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom, and the 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 4- to 7-membered heterocycle is optionally substituted with -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic group is 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, X is a 5- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 5- to 7-membered heterocycloalkyl, or a 5- to 7-membered cycloalkyl, and the 10-membered aryl, the 5- to 10-membered heteroaryl, the 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered cycloalkyl are optionally joined by 1 to 3 J 2 optionally substituted with a group, Y is -C0-C4 alkylene-N(H)-L 2 -R, -C0-C4 alkylene-OC(O)-C(H)=CH2, -C0-C4 alkylene-OC(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -4- to 7-membered heterocycloalkyl-L 2R, -C0-C4 alkylen-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-etheyny, -C0-C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene -C(H)=NN(H)Boc, -C-C alkylene-C(O)-CH-Br, -C-C alkylene-CH-Cl, -C-C alkylene-oxiranyl, -C-C alkylene-SH, -C-C alkylene-F, and -C-C alkylene-C(H)=O, wherein the -C-C alkylene portion is optionally substituted with 1 to 4 groups independently selected from halogen, C-C cycloalkyl, C-C alkoxy, -C-C alkyl-C-C alkoxy, or hydroxy; R 4 is H, halo, C0-C4 alkyl, or —O—C0-C4 alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl, ethynyl, -CH2-CN, or C1-C6 haloalkyl, and one halogen of the C1-C6 haloalkyl is selected from L 2 and the ethenyl and ethynyl are each 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, 0 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with a group, 0 to 3 J 4-C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently 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; J 2 are each independently selected from the group consisting of halogen, C-C alkyl, C-C haloalkyl, hydroxy, C-C hydroxyalkyl, C-C alkoxy, and —C-C alkyl-C-C alkoxy; J 2 are each independently selected from the group consisting of halogen, —C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and —C1-C6 alkyl-C1-C6 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R bare each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, and C-C alkylene-C-C alkynyl optionally substituted with alkyl, C-C haloalkyl, C-C hydroxyalkyl, or —C-C alkoxyC-C alkyl; R c is selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl.

[0189] Embodiment P3 of the present disclosure is a compound of the formula:

[0190] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the foregoing compounds.

[0191] Embodiment P4 of the present disclosure relates to compounds according to embodiment P3 having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of formula (IIa) or (IIb).

[0192] Embodiment P5 of the present disclosure is directed to a compound in which G is -L 1 -R 3 The present invention relates to a compound according to any one of embodiments P1 to P5, wherein:

[0193] Embodiment P6 of the present disclosure is R 3 but

[0194] [ka] where: L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl, and each of C1-C2 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered cycloalkyl may contain 0 to 2 J 2 optionally substituted with a group, provided that L 1 When is CH2, Z 1 is assumed to be neither CH2 nor N, L 2 is -SO2- or -C(O)-, Z 1 -N(H)-, -C(R 5 )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, and -C1-C3 alkylene and -2-C3 alkenylene each independently represent 1 to 4 J 3 optionally substituted with a group, R is ethenyl, ethynyl, -CH2-CN, or C1-C4 haloalkyl, and one halogen in the C1-C4 haloalkyl is L 2 and ethenyl and ethynyl are, respectively, 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, 0 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b The present invention relates to compounds according to any one of embodiments P1 to P5, provided that the R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -

[0195] Embodiment 8 of the present disclosure is R 3 but

[0196] [ka] where: Z 1 -N(H)-, -C(R 5 )- or a 4- to 6-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 Each has 1-2 J 3 -C1-C3 alkylene or -C2-C3 alkenylene optionally substituted with a group; Z 3 is 1 to 2 J 3 is a -C1-C2 alkylene optionally substituted with a group; R is ethenyl, ethynyl, -CH2-CN, or C1-C3 haloalkyl, one halogen of the C1-C3 haloalkyl being on the carbon atom adjacent to -C(O)-, and ethenyl and ethynyl are 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, 0 to 3 J 4 -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C0-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C3 alkylene-4 to 6 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C3 alkylene-NR a R b The present invention relates to compounds according to embodiment P6, provided that the R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -R 47 -R 48 -R 59 -R 50 -R 51 -R 52 -R 53 -R 54

[0197] Embodiment P8 of the present disclosure is an embodiment wherein R is 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, 0 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with a group, 0 to 3 J4 -C1-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 6

[0198] Embodiment P9 of the present disclosure relates to compounds according to any one of embodiments P1 to P4, wherein G is -XY.

[0199] In embodiment P10 of the present disclosure, X is 1 to 3 J 2 and Y is a 5-10 membered heteroaryl optionally substituted with a -C0-C4 alkylene-N(H)-L 2 -R.

[0200] Embodiment P11 of the present disclosure is 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J 1 The present invention relates to compounds according to any one of embodiments P1 to P10, optionally substituted with a group.

[0201] Embodiment P12 of the present disclosure is 2 contains at least one nitrogen atom and 1 to 2 J 1 The present invention relates to compounds according to any one of embodiments P1 to P11, wherein the heteroaryl is -O-(5-10 membered)heteroaryl optionally substituted with a group.

[0202] Embodiment P13 of the present disclosure is 2 However, each has 1-2 J 1 optionally substituted with a group,

[0203] [ka] The present invention relates to compounds according to any one of embodiments P1 to P12, wherein:

[0204] Embodiment P14 of the present disclosure is 2 but

[0205] [ka] The present invention relates to compounds according to any one of embodiments P1 to P13, wherein:

[0206] Embodiment 101 of the present disclosure relates to a compound of formula (I):

[0207] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or halogen; R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl, or -NH-heteroaryl, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains from 1 to 4 J 1 optionally substituted with a group, Or R 1 and R 2 form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and the saturated or unsaturated carbocyclic or heterocyclic ring is a ring having 1 to 4 J 1 optionally substituted with a group, G is -L 1-R 3 or XY, L 1 is a bond, -C(O)-, -S(O)2-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and each of the alkylene, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups contains 0 to 4 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4-8 membered heterocycle containing at least one nitrogen ring atom, and R 3 is 1 to 4 J 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 7- to 11-membered spirocyclic ring is optionally substituted with -L 2 -R is substituted, X is 1 to 4 J 2 aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with a group; Y is -C0-C4 alkylene-N(H)-L 2-R, -C0-C4 alkylene-OC(O)-C(H)=CH2, -C0-C4 alkylene-OC(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -C0-C4 alkylen-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-ethenyl (etheyny), —C0-C4 alkylene-ethynyl, —C0-C4 alkylene-CN, —C0-C4 alkylene-C(H)═NN(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 portion is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxy, alkoxyalkyl, or hydroxy; R 4 is H, alkyl, or -O-alkyl, L 2 is -SO2- or -C(O)-, R is ethenyl, ethynyl, -CH2-CN, or haloalkyl, and one halogen of the haloalkyl is L 2 and ethenyl and ethynyl are 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, 0 to 3 J 4 -C0-C4 alkylene-cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-cycloalkenyl optionally substituted with a group, 0 to 3 J 4-C0-C4 alkylene-heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-heterocycloalkenyl optionally substituted with groups; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl; J 2 are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; J 3 are each independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, and alkoxy, and alkoxyalkyl, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and -C0-C4 alkylene-NR a R b and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C0-C3 alkylene-alkynyl optionally substituted with alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R cis selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl, alkoxy, and alkoxyalkyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0208] An embodiment 102 of the present disclosure includes: R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen; R 2 is -O-(5-10 membered)aryl, -O-(5-10 membered)heteroaryl, -O-(4-7 membered)cycloalkyl, -O-(4-7 membered)heterocycloalkyl, -NH-(5-10 membered)aryl, or -NH--(5-10 membered)heteroaryl, and each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties contains 1 to 3 J 1 optionally substituted with a group, Or R 1 and R 2 are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each ring containing 1-3 J 1 optionally substituted with a group, G, -L 1 -R 3 , or XY, L 1is 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, and each of 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 is selected from the group consisting of 0 to 3 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom, and the 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 4- to 7-membered heterocycle is optionally substituted with -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic group is 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, X is a 5- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 5- to 7-membered heterocycloalkyl, or a 5- to 7-membered cycloalkyl, and the 10-membered aryl, the 5- to 10-membered heteroaryl, the 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered cycloalkyl are optionally joined by 1 to 3 J 2 optionally substituted with a group, Y is -C0-C4 alkylene-N(H)-L 2-R, -C0-C4 alkylene-OC(O)-C(H)=CH2, -C0-C4 alkylene-OC(O)-ethynyl, -C0-C4 alkylene-C(H)=C(CN)-C(O)-NH2, -C0-C4 alkylen-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-ethenyl, -C0- C alkylene-ethynyl, —C-C alkylene-CN, —C-C alkylene-C(H)═NN(H)Boc, —C-C alkylene-C(O)—CH—Br, —C-C alkylene-CH—Cl, —C-C alkylene-oxiranyl, —C-C alkylene-SH, —C-C alkylene-F, and —C-C alkylene-C(H)═O, wherein the —C-C alkylene portion is optionally substituted with one to four groups independently selected from the group consisting of halogen, C-C cycloalkyl, C-C alkoxy, —C-C alkyl-C-C alkoxy, or hydroxy; R 4 is H, C0-C4 alkyl, or —O—C0-C4 alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl, ethynyl, -CH2-CN, or C1-C6 haloalkyl, and one halogen of the C1-C6 haloalkyl is selected from L 2 and the ethenyl and ethynyl are each 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, 0 to 3 J 4-C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently 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; J 2 are each independently selected from the group consisting of halogen, C-C alkyl, C-C haloalkyl, hydroxy, C-C hydroxyalkyl, C-C alkoxy, and —C-C alkyl-C-C alkoxy; J 2 are each independently selected from the group consisting of halogen, —C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and —C1-C6 alkyl-C1-C6 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NRa R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, and C-C alkylene-C-C alkynyl optionally substituted with alkyl, C-C haloalkyl, C-C hydroxyalkyl, or —C-C alkoxyC-C alkyl; R c is selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl.

[0209] Embodiment 103 of the present disclosure provides a compound of the formula:

[0210] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the above compounds.

[0211] Embodiment 104 of the present disclosure relates to a compound according to embodiment 103 having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of formula (IIa) or (IIb).

[0212] An embodiment 105 of the present disclosure is a compound in which G is -L 1 -R 3 The compound according to any one of embodiments 101 to 105, wherein

[0213] The embodiment 106 of the present disclosure is R 3 but

[0214] [ka] where: L 1 is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl, and each of C1-C2 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered cycloalkyl may contain 0 to 2 J 2 optionally substituted with a group, provided that L 1 When is CH2, Z 1 is assumed to be neither CH2 nor N, L 2 is -SO2- or -C(O)-, Z 1 -N(H)-, -C(R 5 )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 and Z 3 are each independently -C1-C3 alkylene or -C2-C3 alkenylene, and -C1-C3 alkylene and -2-C3 alkenylene each independently represent 1 to 4 J 3 optionally substituted with a group, R is ethenyl, ethynyl, -CH2-CN, or C1-C4 haloalkyl, and one halogen in the C1-C4 haloalkyl is L 2and ethenyl and ethynyl are, respectively, 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, 0 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C4 haloalkyl, CN, C1-C4 alkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b The present invention relates to compounds according to any one of embodiments 101 to 105, provided that the compound may only contain a group.

[0215] Embodiment 107 of the present disclosure is 3 but

[0216] [ka] where: Z 1 -N(H)-, -C(R 5 )- or a 4- to 6-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 Each has 1-2 J 3 -C1-C3 alkylene or -C2-C3 alkenylene optionally substituted with a group; Z 3 is 1 to 2 J 3 is a -C1-C2 alkylene optionally substituted with a group; R is ethenyl, ethynyl, -CH2-CN, or C1-C3 haloalkyl, one halogen of the C1-C3 haloalkyl being on the carbon atom adjacent to -C(O)-, and ethenyl and ethynyl are 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, 0 to 3 J 4 -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with a group, 0 to 3 J 4-C0-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 optionally substituted with 1 to 3 groups independently selected from the group consisting of -C0-C3 alkylene-4 to 6 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy, with the proviso that J 3 is assumed to be bonded to carbon, J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C3 alkylene-NR a R b 107. The compounds according to embodiment 106, provided that they may only contain the group.

[0217] Embodiment 108 of the present disclosure is an alkyl group selected from the group consisting of 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, 0 to 3 J 4-C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 0 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with a group, 0 to 3 J 4 -C1-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 0 to 3 J 4 Embodiment 108 relates to compounds according to any one of embodiments 101-107, wherein the alkyl group is ethenyl optionally substituted with 1 to 2 groups independently selected from the group consisting of -C1-C3 alkylene-4 to 6 membered heterocycloalkenyl optionally substituted with groups.

[0218] Embodiment 109 of the present disclosure relates to compounds according to any one of embodiments 101 to 108, wherein G is -XY.

[0219] In an embodiment 110 of the present disclosure, X is 1 to 3 J 2 and Y is a 5-10 membered heteroaryl optionally substituted with a -C0-C4 alkylene-N(H)-L 2 -R.

[0220] The embodiment 111 of the present disclosure is R 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J 1 111. The compound according to any one of embodiments 101 to 110, optionally substituted with a group.

[0221] The embodiment 112 of the present disclosure is R 2 contains at least one nitrogen atom and 1 to 2 J 1 112. The compound according to any one of embodiments 101 to 111, wherein the heteroaryl is -O-(5-10 membered)heteroaryl optionally substituted with a group.

[0222] Embodiment 113 of the present disclosure is 2 However, each has 1-2 J 1 optionally substituted with a group,

[0223] [ka] 113. The compound according to any one of embodiments 101 to 112, wherein

[0224] The embodiment 114 of the present disclosure is R 2 but

[0225] [ka] The compound according to any one of embodiments 101 to 113, wherein

[0226] Embodiment 115 of the present disclosure relates to a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0227] Embodiment 116 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 115 and a pharmaceutically acceptable carrier.

[0228] Embodiment 117 of the present disclosure relates to a pharmaceutical composition according to embodiment 113, further comprising a second pharmaceutical agent.

[0229] Embodiment 118 of the present disclosure relates to a method of treating a subject having a disease or disorder mediated by Her2, comprising administering to the subject an effective amount of a compound described in any one of embodiments 1-15, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition described in any one of embodiments 16-17.

[0230] Embodiment 119 of the present disclosure relates to the method of embodiment 118, wherein the disease or condition is cancer with Her2 YVMA insertion mutation.

[0231] Embodiment 120 of the present disclosure relates to a method for treating a disease or condition according to embodiment 118, wherein the disease or condition is a cancer selected from the group consisting of 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 cancer.

[0232] Embodiment 121 of the present disclosure relates to a method for treating a disease or condition according to any one of embodiments 118 to 120, wherein the disease or condition is non-small cell lung cancer.

[0233] Embodiment 122 of the present disclosure relates to a method according to any one of embodiments 118-121, further comprising administering one or more additional therapeutic agents.

[0234] Embodiment 123 of the present disclosure is a method for treating rheumatoid arthritis, wherein the one or more additional therapeutic agents are selected from i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan. alkylating agents, ii) antibiotics selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin, iii) azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, and pemetrexed , an antimetabolite selected from raltitrexed, thioguanine, and trimetrexate; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA4 inhibitor; v) an antibody-drug conjugate selected from ado-trastuzumab emtansine and trastuzumab deruxtecan; vi) enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole; vii) a hormone or hormone antagonist selected from leuprolide, megestrol, raloxifene, tamoxifen, and toremifene; vii) a taxane selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; viii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine;and vinorelbine; x) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; xi) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin. xii) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiv) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; and xv) an IDO inhibitor. , xvi) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoganazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, and aromatase inhibitors (anastrozole, letrozole, exemestane), xvii) a BRAF inhibitor, xviii) a Mek inhibitor, xix) a c-Kit mutant inhibitor, xx) an EGFR inhibitor, xxi) an epigenetic modulator, xxii) other adenosine axis blockade agents selected from CD39, CD38, A2AR, and A2BR, or xxiii) an agonist of a TNFA superfamily member, and xxiv) an anti-ErbB2 mAb.

[0235] Embodiment 124 of the present disclosure relates to the method of embodiment 122, wherein the one or more additional therapeutic agents is ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0236] Embodiment 201 of the present disclosure relates to a compound of formula (I):

[0237] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or 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, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains from 1 to 4 J 1 optionally substituted with a group, Or R 1 and R 2 form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and the saturated or unsaturated carbocyclic or heterocyclic ring is a ring having 1 to 4 J 1 optionally substituted with a group, G is -L 1 -R 3 , or -WXY, L 1 is a bond, -C(O)-, -S(O)2-, -N(R c)-, alkylene, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, each of which contains 1 to 4 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4- to 9-membered heterocycle containing at least one nitrogen ring atom, and R 3 is 1 to 4 J 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 7- to 11-membered spirocyclic ring is optionally substituted with -L 2 -R is substituted, W is a bond, —C(O)—, or —S(O)—; X is 1 to 4 J 2 aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with a group; 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 by 1 to 2 oxo groups, -C0-C4 alkylen-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, -C -C4 alkylene-ethynyl, -C0-C4 alkylene-CN, -C0-C4 alkylene-C(H)=NN(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 portion is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxy, alkoxyalkyl, or hydroxy; R 4 is H, alkyl, or -O-alkyl, L 2 is -SO2- or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, —CH—CN, or haloalkyl, wherein one halogen of the haloalkyl is selected from L 2 on the carbon atom adjacent to Q is independently a halogen, a haloalkyl, an alkyl, an alkene, an alkyne, or a -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, 1 to 3 J 4 -C0-C4 alkylene-cycloalkyl optionally substituted with a group, 1 to 3 J 4-C0-C4 alkylene-cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-7-11 membered spirocyclic cycloalkyl or heterocycloalkyl optionally substituted with a group, 1-3 J 4 -C0-C4 alkylene-heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl; J 2 are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; J 3 are each bonded to a carbon atom and are independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, or two of the optional one to four J groups form an oxo group or a 3- to 6-membered spiro group, or two of the optional one to four J groups form an oxo group or a 3- to 6-membered spiro group, 3 two of the groups are on different ring carbons and are linked to form a 1-3 carbon bridge; J 4 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and -C0-C4 alkylene-NR a R b and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C0-C3 alkylene-alkynyl optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; R c is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl, alkoxy, and alkoxyalkyl; R d is selected from the group consisting of H, alkyl, and haloalkyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0238] The embodiment 202 of the present disclosure includes: R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen; 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, and each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties is selected from 1 to 3 J 1 optionally substituted with a group, Or R 1 and R 2are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each ring containing 1-3 J 1 optionally substituted with a group, G, -L 1 -R 3 , or -WXY, 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, and each of 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 is preferably selected from the group consisting of 1 to 3 J 2 optionally substituted with a group, provided that L 1 When is CH2, L 1 is not attached to a carbon or nitrogen atom of a saturated ring, R 3 is a 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom, and the 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom is 3 group, and one nitrogen atom of the 4- to 7-membered heterocycle is optionally substituted with -L 2 -R is substituted, Or R 3 is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, and the 7- to 11-membered spirocyclic group is 3 optionally substituted with R 3 One nitrogen atom of -L 2 -R is substituted, W is a 9a bond, —C(O)—, or —S(O)2—; X is a 5- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 5- to 7-membered heterocycloalkyl, or a 5- to 7-membered cycloalkyl, and the 10-membered aryl, the 5- to 10-membered heteroaryl, the 5- to 7-membered heterocycloalkyl, and the 5- to 7-membered cycloalkyl are optionally joined by 1 to 3 J 2 optionally substituted with a group, Y is -C0-C4 alkylene-N(R d )-L 2 -R, -C(O)-4 to 6-membered heterocycloalkyl containing at least one nitrogen atom and substituted by 1 to 2 oxo groups, -C0-C4 alkylen-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-etheyny, -C0-C4 alkylene-ethynyl , —C0-C4 alkylene-CN, —C0-C4 alkylene-C(H)═NN(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 portion is optionally substituted with one to four groups independently selected from the group consisting of halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, —C1-C6 alkyl-C1-C6 alkoxy, or hydroxy; R 4 is H, C0-C4 alkyl, or —O—C0-C4 alkyl; L 2 is -SO2- or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q groups, —CH—CN, or C-C haloalkyl, and one halogen of the C-C haloalkyl is selected from L 2 on the carbon atom adjacent to 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, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; Alternatively, -L 2 -R is -C=N-OH, J 1 are each independently 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; J 2 are each independently selected from the group consisting of halogen, C-C alkyl, C-C haloalkyl, hydroxy, C-C hydroxyalkyl, C-C alkoxy, and —C-C alkyl-C-C alkoxy; J 3 are R 3 and is independently selected from the group consisting of halogen, —C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and —C1-C6 alkyl-C1-C6 alkoxy, or optionally 1 to 4 J 3 two of the groups form an oxo group or a 3- to 6-membered spiro group, or optionally 1 to 4 J3 two of the groups are on different ring carbons and are linked to form a 1-3 carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b It is assumed that the aryl group can only contain aryl groups. R a and R b are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, and C-C alkylene-C-C alkynyl optionally substituted with alkyl, C-C haloalkyl, C-C hydroxyalkyl, or —C-C alkoxyC-C alkyl; R c is selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl; R d is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0239] An embodiment 203 of the present disclosure provides a compound of the formula:

[0240] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the above compounds.

[0241] Embodiment 204 of the present disclosure relates to a compound according to embodiment 203 having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of formula (IIa) or (IIb).

[0242] An embodiment 205 of the present disclosure provides a compound of the formula:

[0243] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the above compounds.

[0244] An embodiment 205 of the present disclosure is 1 -R 3 The compound according to any one of embodiments 201 to 204, wherein

[0245] An embodiment 207 of the present disclosure is

[0246] [ka] where: L 1is a bond, -C(O)-, -S(O)2-, C1-C3 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl, and each of C1-C2 alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered cycloalkyl is selected from the group consisting of 1 to 2 J 2 optionally substituted with a group, provided that L 1 When is CH2, Z 1 is assumed to be neither CH2 nor N, L 2 is -SO2- or -C(O)-, Z 1 -N(H)-, -C(R 5 )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 and Z 3 are each independently —C1-C3 alkylene or —C2-C3 alkenylene, wherein each —C1-C3 alkylene and —C2-C3 alkenylene is optionally substituted with 1 to 4 J3 groups; R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q groups, —CH—CN, or C-C haloalkyl, wherein one halogen of the C-C haloalkyl is selected from L 2 on the carbon atom adjacent to 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, 1 to 3 J 4 -C0-C4 alkylene-C3-C7 cycloalkyl optionally substituted with a group, 1 to 3 J 4-C0-C4 alkylene--C3-C7 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; J 2 are each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and —C1-C4 alkyl-C1-C4 alkoxy; J 3 are each independently selected from the group consisting of 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 one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, or two of the optional one to four J3 groups form an oxo group or a 3- to 6-membered spiro group, 3 two of the groups are on different ring carbon atoms and are linked to form a 1-3 carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C4 alkylene-NR a R b 207. The compound according to any one of embodiments 201 to 206, provided that the compound may only contain a group.

[0247] An embodiment 208 of the present disclosure is

[0248] [ka] where: Z 1 -N(H)-, -C(R 5 )- or a 4- to 6-membered spiro group optionally containing 1 to 2 nitrogen atoms, R 5 is H, halogen, C1-C3 alkyl, or CN; Z 2 Each has 1-2 J 3 -C1-C3 alkylene or -C2-C3 alkenylene optionally substituted with a group; Z 3 is 1 to 2 J 3 is a -C1-C2 alkylene optionally substituted with a group; R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, —CH—CN, or C-C haloalkyl, wherein one halogen of the C-C 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, 1 to 3 J 4 -C0-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C0-C3 alkylene--C3-C6 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C0-C3 alkylene-4 to 6 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 -C0-C3 alkylene-4-6 membered heterocycloalkenyl optionally substituted with a group; J 2are each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and -C1-C3 alkyl-C1-C3 alkoxy; J 3 are each independently selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy, or the optional J 3 two of the groups are on different ring carbon atoms and are linked to form a one to two carbon bridge; J 4 are each 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 and wherein J is selected from the group consisting of 4 The group may contain up to two oxo groups and up to one -C0-C3 alkylene-NR a R b 208. The compounds according to embodiment 207, provided that they may only contain the group.

[0249] The embodiment 209 of the present disclosure is 3 but

[0250] [ka]

[0251] [ka] where R 3 The heterocycle containing at least one nitrogen ring atom of 3 optionally substituted with a group, J 3relates to compounds according to any one of embodiments 201-206, wherein each independently is selected from the group consisting of halogen, —C1-C3 haloalkyl, CN, C1-C3 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and —C1-C3 alkyl-C1-C3 alkoxy.

[0252] Embodiment 210 of the present disclosure relates to a compound according to any one of embodiments 201-205, wherein G is -XY.

[0253] In an embodiment 211 of the present disclosure, X is 1 to 3 J 2 and Y is a 5-10 membered heteroaryl optionally substituted with a -C0-C4 alkylene-N(H)-L 2 211. The compound according to embodiment 210, wherein R is —R.

[0254] An embodiment 212 of the present disclosure is an alkyl group wherein R is 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, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-C3-C6 cycloalkenyl optionally substituted with a group, 1 to 3 J 4 -C1-C3 alkylene-4 to 6-membered heterocycloalkyl optionally substituted with a group, 1 to 3 J 4 and 212, optionally substituted with 1 to 2 groups independently selected from the group consisting of -C1-C3 alkylene-4 to 6 membered heterocycloalkenyl, optionally substituted with a group.

[0255] An embodiment 213 of the present disclosure is

[0256] [ka] where: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 are independently H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C4 alkylene-NR a R b , 1 to 3 J 4 -C0-C4 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 The present invention relates to compounds according to any one of embodiments 201 to 209, wherein the heterocycloalkenyl is selected from the group consisting of: -C0-C4 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0257] The embodiment 214 of the present disclosure is 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J 1 214. The compound according to any one of embodiments 201 to 213, optionally substituted with a group.

[0258] The embodiment 215 of the present disclosure is 2 contains at least one nitrogen atom and 1 to 2 J 1 The present invention relates to compounds according to any one of embodiments 201 to 214, wherein the heteroaryl is -O-(5-10 membered)heteroaryl optionally substituted with a group.

[0259] The embodiment 216 of the present disclosure is 2 However, each has 1-2 J 1 optionally substituted with a group,

[0260] [ka] 216. The compound according to any one of embodiments 201 to 215, wherein

[0261] The embodiment 217 of the present disclosure is 2 However, each has 1-2 J 1 optionally substituted with a group,

[0262] [ka] where: J 1 are each independently 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; R c is selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C-C cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and C-C alkoxy-C-C alkyl.

[0263] An embodiment 218 of the present disclosure is 2 but

[0264] [ka] 218. The compound according to any one of embodiments 201 to 217, wherein

[0265] An embodiment 219 of the present disclosure provides a compound of the formula:

[0266] [ka]

[0267] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene, -NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 Q is a —C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 are independently H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 202. The present invention relates to compounds according to embodiment 201, wherein the heterocycloalkenyl is selected from the group consisting of: -C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0268] An embodiment 220 of the present disclosure is a compound of the formula:

[0269] [ka]

[0270] [ka]

[0271] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 is H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene, -NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 Q is a —C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group; 1 are each independently selected from the group consisting of H, F, and Cl; Q 2 are independently H, C1-C6 haloalkyl, C1-C6 alkyl, -C1-C3 alkylene-NR a R b , 1 to 3 J 4 -C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group, and 1 to 3 J 4 202. The present invention relates to compounds according to embodiment 201, wherein the heterocycloalkenyl is selected from the group consisting of: -C0-C3 alkylene-4 to 7 membered heterocycloalkenyl optionally substituted with a group.

[0272] The embodiment 221 of the present disclosure is 2 is H.

[0273] The embodiment 222 of the present disclosure is 2 -C1-C3 alkylene-NR a R b221. The compound according to any one of embodiments 219 or 220, wherein

[0274] The embodiment 223 of the present disclosure is 2 However, 1 to 3 J 4 221. The compound according to any one of embodiments 219 or 220, wherein the heterocycloalkyl group is C0-C3 alkylene-4 to 7 membered heterocycloalkyl optionally substituted with a group.

[0275] Embodiment 224 of the present disclosure relates to a compound according to embodiment 201, selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0276] Embodiment 225 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of embodiments 201-224 and a pharmaceutically acceptable carrier.

[0277] Embodiment 226 of the present disclosure relates to a pharmaceutical composition according to embodiment 225, further comprising a second pharmaceutical agent.

[0278] Embodiment 227 of the present disclosure relates to a method of treating a subject having a disease or disorder mediated by Her2, 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 analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition according to any one of embodiments 225-226.

[0279] Embodiment 228 of the present disclosure relates to a method according to embodiment 227, wherein the disease or condition is cancer with a Her2 YVMA insertion mutation.

[0280] Embodiment 229 of the present disclosure relates to a method for treating a disease or condition described in embodiment 227, wherein the disease or condition is a cancer selected from the group consisting of 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 cancer.

[0281] Embodiment 230 of the present disclosure relates to a 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.

[0282] Embodiment 231 of the present disclosure relates to a method according to any one of embodiments 227-230, further comprising administering one or more additional therapeutic agents.

[0283] Embodiment 232 of the present disclosure is directed to a method for treating rheumatoid arthritis, wherein the one or more additional therapeutic agents are selected from i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan. alkylating agents, ii) antibiotics selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin, iii) azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, and pemetrexed , an antimetabolite selected from raltitrexed, thioguanine, and trimetrexate; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA4 inhibitor; v) an antibody-drug conjugate selected from ado-trastuzumab emtansine and trastuzumab deruxtecan; vi) enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole; vii) a hormone or hormone antagonist selected from leuprolide, megestrol, raloxifene, tamoxifen, and toremifene; vii) a taxane selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; viii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine;and vinorelbine; x) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; xi) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin. xii) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiv) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; and xv) an IDO inhibitor. , xvi) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoganazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt 232. The method of embodiment 231, wherein the chemotherapeutic agent is one or more of: a chemotherapeutic agent selected from an ErbB2 inhibitor, an Hsp90 inhibitor, a farnesyltransferase inhibitor, and an aromatase inhibitor (anastrozole, letrozole, exemestane); xvii) a BRAF inhibitor; xviii) a Mek inhibitor; xix) a c-Kit mutant inhibitor; xx) an EGFR inhibitor; xxi) an epigenetic modulator; xxii) other adenosine axis blockade agents selected from CD39, CD38, A2AR, and A2BR; or xxiii) an agonist of a TNFA superfamily member; and xxiv) an anti-ErbB2 mAb.

[0284] Embodiment 233 of the present disclosure relates to the method of embodiment 232, wherein the one or more additional therapeutic agents is ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0285] Embodiment 234 of the present disclosure relates to the method of embodiment 232, wherein the one or more additional therapeutic agents is pembrolizumab or nivolumab.

[0286] Embodiment 301 of the present disclosure is a compound of formula (I):

[0287] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or halogen; R 2 is -O-alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, -NH-alkyl, -NH-aryl, or -NH-heteroaryl, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains from 1 to 4 J 1 optionally substituted with a group, Or R 1 and R 2 form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and the saturated or unsaturated carbocyclic or heterocyclic ring is a ring having 1 to 4 J 1 optionally substituted with a group, G is -L 1 -R 3 and L 1is —C0-C6 alkylene-C(O)N(H)—, or —C0-C6 alkylene-S(O)2N(H)—, R 3 is 1 to 4 J 2 -C1-C6 alkylene optionally substituted with -NR group a R b and R 4 is H, alkyl, or -O-alkyl, J 1 are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C0-C4 alkylene-N(H)R c , alkoxy, and alkoxyalkyl; J 2 are each independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, and alkoxy, and alkoxyalkyl, with the proviso that J 3 is assumed to be bonded to carbon, R a and R b are each independently selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C0-C3 alkylene-alkynyl optionally substituted with alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

[0288] The embodiment 302 of the present disclosure includes: R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or halogen; R 2is -O-(5-10 membered)aryl, -O-(5-10 membered)heteroaryl, -O-(4-7 membered)cycloalkyl, -O-(4-7 membered)heterocycloalkyl, -NH-(5-10 membered)aryl, or -NH--(5-10 membered)heteroaryl, and each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl moieties contains 1 to 3 J 1 optionally substituted with a group, Or R 1 and R 2 are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each ring containing 1-3 J 1 optionally substituted with a group, L 1 is —C0-C3 alkylene-C(O)N(H)—, or —C0-C3 alkylene-S(O)2N(H)—; R 3 But 1-2 J 2 -C1-C4 alkylene optionally substituted with -NR group a R b and R 4 is H, C0-C4 alkyl, or —O—C0-C4 alkyl; J 1 are each independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, -C0-C4 alkylene-N(H)R c , C1-C6 alkoxy, and -C1-C6 alkoxy-C1-C6 alkyl; J 2 are each independently selected from the group consisting of halogen, —C1-C6 haloalkyl, CN, C1-C6 alkyl, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and —C1-C6 alkoxy-C1-C6 alkyl, with the proviso that J 3 is assumed to be bonded to carbon, R a and R bare each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, —C-C alkyl-C-C alkoxy, and C-C alkylene-C-C alkynyl optionally substituted with alkyl, C-C haloalkyl, C-C hydroxyalkyl, or —C-C alkoxyC-C alkyl.

[0289] An embodiment 303 of the present disclosure is a compound of the formula:

[0290] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue of any of the foregoing compounds.

[0291] Embodiment 304 of the present disclosure relates to a compound according to embodiment 303 having formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of formula (IIa) or (IIb).

[0292] The embodiment 305 of the present disclosure is L 1 is —C0-C3 alkylene-C(O)N(H)—.

[0293] The embodiment 306 of the present disclosure is 3 -C1-C4 alkylene-NR a R b and R a and R b are each independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0294] The embodiment 307 of the present disclosure is 3-C1-C3 alkylene-NR a R b and R a and R b and R are each C1-C3 alkyl.

[0295] The embodiment 308 of the present disclosure is 2 is -O-heteroaryl, -O-heterocycloalkyl, -NH-heteroaryl, or -N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J 1 The present invention relates to compounds according to any one of embodiments 301 to 307, optionally substituted with a group.

[0296] The embodiment 309 of the present disclosure is 2 contains at least one nitrogen atom and 1 to 2 J 1 The present invention relates to compounds according to any one of embodiments 301 to 308, wherein the R is -O-(5-10 membered)heteroaryl optionally substituted with a group.

[0297] The embodiment 310 of the present disclosure is 2 However, each has 1-2 J 1 optionally substituted with a group,

[0298] [ka] The compound according to any one of embodiments 301 to 309, wherein

[0299] The embodiment 311 of the present disclosure is 2 but

[0300] [ka] The compound according to any one of embodiments 301 to 310, wherein

[0301] Embodiment 312 of the present disclosure relates to a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0302] Embodiment 313 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of embodiments 301-312 and a pharmaceutically acceptable carrier.

[0303] Embodiment 314 of the present disclosure relates to a pharmaceutical composition according to embodiment 313, further comprising a second pharmaceutical agent.

[0304] Embodiment 315 of the present disclosure relates to a method of treating a subject having a disease or disorder mediated by Her2, 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 analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition according to any one of embodiments 313-314.

[0305] Embodiment 316 of the present disclosure relates to a method according to embodiment 315, wherein the disease or condition is cancer with a Her2 YVMA insertion mutation.

[0306] 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 group consisting of 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 cancer.

[0307] 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.

[0308] Embodiment 319 of the present disclosure relates to a method according to any one of embodiments 315-318, further comprising administering one or more additional therapeutic agents.

[0309] Embodiment 320 of the present disclosure is directed to a method for treating rheumatoid arthritis, wherein the one or more additional therapeutic agents are selected from i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan. alkylating agents, ii) antibiotics selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin, iii) azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, and pemetrexed , an antimetabolite selected from raltitrexed, thioguanine, and trimetrexate; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA4 inhibitor; v) an antibody-drug conjugate selected from ado-trastuzumab emtansine and trastuzumab deruxtecan; vi) enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole; vii) a hormone or hormone antagonist selected from leuprolide, megestrol, raloxifene, tamoxifen, and toremifene; vii) a taxane selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; viii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine;and vinorelbine; x) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; xi) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin. xii) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiv) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; and xv) an IDO inhibitor. , xvi) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoganazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt 320. The method of embodiment 319, wherein the chemotherapeutic agent is one or more of: a chemotherapeutic agent selected from an ErbB2 inhibitor, an Hsp90 inhibitor, a farnesyltransferase inhibitor, and an aromatase inhibitor (anastrozole, letrozole, exemestane); xvii) a BRAF inhibitor; xviii) a Mek inhibitor; xix) a c-Kit mutant inhibitor; xx) an EGFR inhibitor; xxi) an epigenetic modulator; xxii) other adenosine axis blockade agents selected from CD39, CD38, A2AR, and A2BR; or xxiii) an agonist of a TNFA superfamily member; and xxiv) an anti-ErbB2 mAb.

[0310] Embodiment 321 of the present disclosure relates to the method of embodiment 319, wherein the one or more additional therapeutic agents is ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0311] The compounds contemplated herein are described in terms of both general formulas and specific compounds. Furthermore, the compounds described herein may exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs (e.g., carboxylic acid esters), and active metabolites.

[0312] It is understood that some compounds may show tautomerism.In such cases, the formula provided herein clearly represents only one of possible tautomeric forms.Therefore, it should be understood that the formula provided herein is intended to represent all tautomeric forms of the compound represented, and is not limited to the specific tautomeric form that is simply depicted by the formula diagram.

[0313] Similarly, some compounds according to the present disclosure may exist as stereoisomers as defined herein. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present disclosure. Unless specified to the contrary, all such stereoisomeric formulas are included within the formulas provided herein. In some embodiments, chiral compounds of the present disclosure are in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“ee”) or diastereomeric excess (“de”)), or at least 85% (70% ee or de), 90% (80% ee or de), 95% (90% ee or de), 97.5% (95% ee or de), or 99% (98% ee or de). As is generally understood by those skilled in the art, an optically pure compound having one asymmetric center consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one asymmetric center is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in optically pure form.

[0314] For compounds where synthesis requires the addition of a single group at a double bond, specifically a carbon-carbon double bond, the addition can occur at either of the double-bonded atoms, and for such compounds, the present disclosure includes both such positional isomers.

[0315] In addition to the present formulas and compounds described herein, the present disclosure also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

[0316] Unless specified to the contrary, the specification of a compound herein includes pharmaceutically acceptable salts of such compound.

[0317] In some embodiments, the compounds of the present disclosure are complexed with an acid or base, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; acid addition salts such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochloride, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, and tosylate; 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 is promoted by mechanochemical methods such as spray drying, roller compaction, or microwave irradiation of the parent compound mixed with an acid or base. Such methods may also include the addition of ionic and / or nonionic polymer systems to further stabilize the amorphous nature of the complex, including, but not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (e.g., Eudragit® L100-55). Such amorphous complexes offer several advantages. For example, the reduced melting temperature relative to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Additionally, the friability of amorphous complexes improves compression for solid loading into capsule or tablet forms.

[0318] III. Formulation and Administration Embodiment 25 of the present disclosure relates to a pharmaceutical composition comprising a compound according to any one of the preceding embodiments and a pharmaceutically acceptable carrier.

[0319] Embodiment 26 of the present disclosure relates to the pharmaceutical composition of embodiment 25, further comprising a second pharmaceutical agent.

[0320] Suitable dosage forms depend in part on the intended use or route of administration, for example, oral, transdermal, oral mucosal, inhalation, or injection (parenteral). Such dosage forms must allow the compound to reach target cells. Other factors are well known in the art, including considerations such as toxicity and dosage forms that delay the compound or composition from taking effect. Techniques and formulations can generally be found in The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference).

[0321] The compounds of the present disclosure (i.e., any of the compounds described in embodiments 1-24, including any of the subembodiments thereof) can be formulated as pharmaceutically acceptable salts.

[0322] Carrier or additive can be used to produce the composition.Carrier or additive can be selected to facilitate the administration of compound.Examples of carrier include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, or various kinds of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol, and physiologically compatible solvent.Examples of physiologically compatible solvent include water for injection (WFI), saline solution, and sterilized solution of dextrose.

[0323] Compound can be administered by various routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, oral mucosal, rectal, transdermal or inhalation.In some embodiments, compound can be administered by oral administration.For oral administration, for example, compound can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations, for example, syrup, elixir and concentrated drops.

[0324] For inhalants, the compounds of the present disclosure can be formulated as dry powder or suitable solution, suspension or aerosol.Powder and solution can be formulated with suitable additives known in the art.For example, powder can contain suitable powder base such as lactose or starch, and solution can contain propylene glycol, sterilized water, ethanol, sodium chloride, and other additives such as acid, alkali, and buffer salt.Such solution or suspension can be administered by inhalation through spray, pump, atomizer or nebulizer. The compounds of the present disclosure may also be used in combination with other inhaled therapeutic agents, for example, corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta-agonists such as albuterol, salmeterol, and formoterol; anticholinergics such as ipratropium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides such as single- or double-stranded DNA, RNA, or siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.

[0325] Oral pharmaceutical preparations can be obtained, for example, by combining active compound with solid excipient, optionally pulverizing the resulting mixture, and then processing the granular mixture after adding suitable excipients as needed to obtain tablets or sugar-coated tablet cores.Suitable excipients are specifically fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone).If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt, such as sodium alginate, can be added.

[0326] Sugar-coated core is provided with suitable coating.For this purpose, concentrated sugar solution can be used, which can optionally contain, for example, gum-100-yridin, talc, polyvinylpyrrolidone, -100-yridin gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture.Dyes or pigments can be added to tablets or sugar-coated tablets to identify or characterize different combinations of active compound dosages.

[0327] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gel capsules") as well as soft, sealed capsules made of gelatin and plasticizers 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 soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol (PEG). In addition, stabilizers may be added.

[0328] Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal, and / or subcutaneous, may be used.For injection, the compound of the present disclosure is formulated in a sterile liquid solution, such as a physiologically compatible buffer or solution, such as Hanks' solution or Ringer's solution.In addition, the compound may be formulated in solid form and redissolved or suspended immediately before use.Lyophilized form may also be produced.

[0329] Administration can also be via oral mucosal, topical, transdermal, or inhalation routes. For oral mucosal, topical, or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives for oral mucosal administration. Additionally, detergents may be used to enhance penetration. Oral mucosal administration may be via, for example, nasal sprays or suppositories (rectal or vaginal). The topical preparations of the present disclosure may be formulated as oils, creams, lotions, ointments, etc., by selection of an appropriate carrier known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white liquid paraffin), branched-chain fats or oils, animal fats, and high molecular weight alcohols (C 12 or above). In another embodiment, the carrier is one in which the active ingredient is soluble. Optionally, emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents imparting color or fragrance. 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. Additionally, administration by transdermal means may include a transdermal patch or dressing, such as a bandage, impregnated with the active ingredient and, optionally, one or more carriers or excipients known in the art. For administration in the form of a transdermal delivery system, the dosage is continuous rather than intermittent throughout the administration regimen.

[0330] The amount of various compounds administered is determined based on the IC 50The dosage can be determined by 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 importance of these and other factors is well known to those skilled in the art. Generally, the dosage is about 0.01 to 50 mg per kg of the subject being treated, or 0.1 to 20 mg per kg. Multiple doses may also be used.

[0331] The compound of the present disclosure may also be used in combination with other therapeutic agents for treating the same disease.This combination includes administering the compound and one or more other therapeutic agents at different times, or administering the compound and one or more other therapeutic agents simultaneously.In some embodiments, the dosage of the compound of the present disclosure or one or more other therapeutic agents used in combination may be changed by methods well known to those skilled in the art, for example, by reducing the dosage compared to the compound or therapeutic agent used alone.

[0332] Combination is understood to include use in conjunction with other therapeutic agents, drugs, medical procedures, etc., where the other therapeutic agent or procedure may be administered at different times from the compound of the present disclosure (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours), or within an extended period of time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)), or simultaneously with the compound of the present disclosure. Combination also includes the use of a treatment or medical procedure administered once or infrequently, such as surgery, with a compound of the present disclosure administered within a short period of time or an extended period of time before or after the other treatment or procedure. In some embodiments, the present disclosure provides for the delivery of a compound of the present disclosure and one or more other therapeutic agents delivered by different routes of administration or the same route of administration. Combination for any route of administration includes the delivery of a compound of the present disclosure and one or more other drug therapies delivered together by the same route of administration, in any formulation, including formulations in which the two compounds are chemically linked so as to maintain therapeutic activity upon administration. In one aspect, the other drug therapies may be co-administered with one or more compounds of the present disclosure. Co-administration includes co-formulations or formulations of chemically linked compounds, or administration of two or more compounds in separate formulations within a short time (e.g., within 1 hour, 2 hours, 3 hours, or up to 24 hours) by the same or different routes. Co-administration of separate formulations includes co-administration via delivery via a single device, such as the same inhaler or syringe, or administration from separate devices within a short time of each other. Co-formulation of a compound of the present disclosure with one or more additional drug therapies delivered by the same route includes preparing the materials together for administration via a single device, including separate compounds combined in a single formulation, or compounds modified to retain biological activity while chemically linked. Such chemically linked compounds may remain substantially linked in vivo, or the linkage may be broken in vivo to separate the two active ingredients.

[0333] IV.How to use Indications and Regulation of Her2 Typical Her2-associated disorders Her2 overexpression has been reported in a variety of tumors, including lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastric cancer, and esophageal cancer, as well as uterine serous endometrial cancer [1]. Furthermore, comorbidities that may be associated with Her2-mediated tumors, such as stage IV WT NSCLC, include pulmonary disease, hypertension, hypercholesterolemia, heart disease, renal dysfunction, thyroid disorders, obesity, depression and anxiety, osteoporosis, liver disorders, autoimmune diseases, dementia, and Alzheimer's disease. It is contemplated that such comorbidities can also be treated with Her2 inhibitors, such as the compounds disclosed herein. The present methods and compounds are typically used to treat human subjects. However, they may also be used to treat similar or identical indications in other animal subjects.

[0334] References: 1.Iqbal N,Iqbal N.Human Epidermal Growth Factor Receptor 2(HER2)in cancers:Overexpression and therapeutic implications.Molecular Biology International.2014;852748:2014

[0335] In certain embodiments, the patient is 60 years or older and has relapsed after first-line cancer therapy. In certain embodiments, the patient is 18 years or older and has relapsed or is refractory to second-line cancer therapy. In certain embodiments, the patient is 60 years or older and is primarily refractory to first-line cancer therapy. In certain embodiments, the patient is 70 years or older and has not previously been treated. In certain embodiments, the patient is 70 years or older and is ineligible for and / or unlikely to benefit from cancer therapy.

[0336] 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.

[0337] In certain embodiments herein, a mammal having a disease or disorder is administered a compound of any one of embodiments 1-24 or subembodiments thereof, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 25-26, for at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 135, 150, 200, 250, 300, 350, 400, 1000, 1550, 1000, 1650, 1650, 1700, 1750, 1800, 1850, 1900, 2000, 2100, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 4000, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 64 Methods are provided for treating a disease or disorder mediated by Her2 by administering 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 of the compound, wherein the compound is administered into an empty stomach.

[0338] Embodiment 27 of the present disclosure relates to a method for treating a subject having a disease or condition mediated by Her2, comprising administering to the subject an effective amount of a compound of any one of embodiments 1-24 or subembodiments thereof, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 25-26.

[0339] Embodiment 28 of the present disclosure relates to the method of embodiment 27, wherein the disease or condition is cancer with a Her2 YVMA insertion mutation.

[0340] Embodiment 29 of the present disclosure relates to a method according to embodiment 27, wherein the disease or condition is a cancer selected from the group consisting of lung cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, bladder cancer, lung cancer, cervical cancer, head and neck cancer, gastroesophageal cancer, and uterine serous endometrial cancer.

[0341] Embodiment 30 of the present disclosure relates to a method according to any one of embodiments 27 to 29, wherein the disease or condition is non-small cell lung cancer.

[0342] V. Combination Therapy Her2 modulators may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. In one embodiment, the combination includes any one or more compounds described herein together with one or more compounds therapeutically effective for the same indication, where the compounds exert a synergistic effect for the indication. In one embodiment, the combination includes any one or more compounds described herein that are effective in treating cancer and one or more other compounds that are effective in treating the same cancer, where the compounds are synergistically effective in treating cancer.

[0343] Embodiment 31 of the present disclosure relates to the method of any one of embodiments 27-29, further comprising administering one or more additional therapeutic agents.

[0344] Embodiment 32 of the present disclosure is directed to a method for treating rheumatoid arthritis, wherein the one or more additional therapeutic agents are selected from i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan. alkylating agents, ii) antibiotics selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin, iii) azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, and pemetrexed , an antimetabolite selected from raltitrexed, thioguanine, and trimetrexate; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA4 inhibitor; v) an antibody-drug conjugate selected from ado-trastuzumab emtansine and trastuzumab deruxtecan; vi) enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole; vii) a hormone or hormone antagonist selected from leuprolide, megestrol, raloxifene, tamoxifen, and toremifene; vii) a taxane selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; viii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine;and vinorelbine; x) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; xi) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin. xii) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiv) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; and xv) an IDO inhibitor. , xvi) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoganazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt 32. The method of claim 31, wherein the therapeutic agent is one or more of: a chemotherapeutic agent selected from an ErbB2 inhibitor, an Hsp90 inhibitor, a farnesyltransferase inhibitor, and an aromatase inhibitor (anastrozole, letrozole, exemestane); xvii) a BRAF inhibitor; xviii) a Mek inhibitor; xix) a c-Kit mutant inhibitor; xx) an EGFR inhibitor; xxi) an epigenetic modulator; xxii) other adenosine axis blockade agents selected from CD39, CD38, A2AR, and A2BR; or xxiii) an agonist of a TNFA superfamily member; and xxiv) an anti-ErbB2 mAb.This is a key mechanism underlying the endocytosis and resulting efficacy of anti-Her2 antibody-drug conjugates (ADCs). Non-limiting examples of anti-HER2 ADCs include Kadcycla® (ado-trastuzumab emtansine) (T-DM1), which has been approved for patients with Her2-positive metastatic breast cancer and Her2-positive early-stage breast cancer. Another ADC is currently in phase 2 in pre-treatment Her-mutated 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. The irreversible Her2 kinase inhibitors of the present disclosure can enhance potential Her2 ubiquitination and internalization by disrupting the Her2:HSP90 chaperone interaction, leading to degradation of the Her2 receptor. Thus, the Her2 kinase inhibitors of the present disclosure can enhance the efficacy of these ADC drugs that require co-internalization of Her2 into lysosomes to release tumor cell-killing payloads.

[0345] Embodiment 33 of the present disclosure relates to the method of embodiment 32, wherein the one or more additional therapeutic agents is ado-trastuzumab emtansine or trastuzumab deruxtecan.

[0346] Embodiment 34 of the present disclosure relates to the method of embodiment 32, wherein the one or more additional therapeutic agents is pembrolizumab or nivolumab.

[0347] Embodiment 34 of the present disclosure relates to the method of embodiment 32, wherein the one or more additional therapeutic agents is pembrolizumab.

[0348] Non-limiting examples of PD-1 inhibitors that can be combined with the compounds of the present disclosure in the treatment methods of the present disclosure include pembrolizumab (KEYTRUDA®), nivolumab, and 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.

[0349] In another embodiment, a compound of the present disclosure is combined with docetaxel or gemcitabine in the treatment methods of the present disclosure.

[0350] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof by administering an effective amount of a composition comprising any one or more compounds described herein in combination with one or more other therapies or medical procedures effective in treating cancer, including suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, the one or more suitable anti-cancer therapies or medical procedures are selected from treatment with a chemotherapeutic agent (e.g., chemotherapy drug), radiation therapy (e.g., X-ray, gamma ray, or electron, proton, neutron, or alpha particle beam), hyperthermia (e.g., microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma 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, adenovector-encoded MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexatin lutetium), surgery, or bone marrow and stem cell transplantation.

[0351] VI. Kit In another aspect, the present disclosure provides a kit comprising one or more compounds described in any one of the compounds in any one of Embodiments 1-15, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition in any one of Embodiments 16-17. In some embodiments, the compound or composition may be packaged, for example, in a vial, bottle, or flask, or further packaged, for example, in a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition may be approved for administration to a mammal, for example, a human, for a Her2-mediated disease or disorder. The kits described herein may include instructions for use and / or other instructions indicating that the compound or composition is suitable for or approved for administration to a mammal, for example, a human, for a Her2-mediated disease or disorder. The compound or composition may be packaged in a unit dose or single dosage form, for example, a single-dose pill or capsule.

[0352] VII. Binding Assays The method of the present disclosure may include an assay capable of detecting the binding of a compound to a target molecule. Such binding is statistically significant, i.e., the assay signal represents binding to the target molecule, i.e., is distinguishable from background, and has a confidence level of at least 90%, or at least 95, 97, 98, 99% or more. In some embodiments, a control is used to distinguish target binding from non-specific binding. A wide variety of assays showing binding are known for different target types and can be used in the present disclosure.

[0353] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound is one that does not exceed the inhibitory concentration (IC) under standard conditions. 50 ) or effective concentration (EC 50 ) is greater than 1 μM. "Very low activity" is defined as an IC50 activity greater than 100 μM under standard conditions. 50 or EC50 "Extremely low activity" means an IC of more than 1 mM under standard conditions. 50 or EC 50 "Moderate activity" means an IC of 200 nM to 1 μM under standard conditions. 50 or EC 50 "Moderately high activity" means an IC of 1 nM to 200 nM. 50 or EC 50 "High activity" means an IC of less than 1 nM under standard conditions. 50 or EC 50 It means IC 50 or EC 50 is defined as the concentration of a compound at which 50% of the activity in the target molecule (e.g., enzyme or other protein) activity being measured is reduced or increased compared to the range of activity observed in the absence of the compound. Activity can be measured using methods known to those of skill in the art, for example, by measuring any detectable product or signal produced by the occurrence of an enzymatic reaction or other activity by the protein being measured.

[0354] "Background signal" with respect to binding assays refers to the signal recorded under standard conditions in a particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule. Those skilled in the art will recognize that accepted methods exist and are widely available for determining background signal.

[0355] "Standard deviation" means the square root of the variance. Variance is a measure of how spread out a distribution is. It is calculated as the mean 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:

[0356]

number

[0357] Measurement of enzyme and binding reactions during screening assays Techniques for measuring the progress of enzyme and binding reactions, for example in multicontainer carriers, are known in the art and include, but are not limited to: spectrophotometric and spectrofluorometric assays are well known in the art. An example of such an assay is the use of a colorimetric assay for the detection of peroxide, as described in Gordon, AJ and Ford, RA (1972) in The Chemist's Companion: A Handbook of Practical Data, Techniques, and References, John Wiley and Sons, NY, p. 437. 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 skilled in the art. For reviews, see Bashford et al. (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd., and Bell (1981) Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press.

[0358] In spectrofluorometric assays, an enzyme is exposed to a substrate that changes its intrinsic fluorescence when processed by a 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 Amplex® Red reagent (Molecular Probes, Eugene, OR). To measure sphingomyelinase activity using Amplex® Red, the following reactions occur: First, Smase hydrolyzes sphingomyelin to produce ceramide and phosphorylcholine. Next, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, choline is oxidized to betaine by choline oxidase. Finally, H2O2 reacts with Amplex® Red in the presence of horseradish peroxidase to produce the fluorescent product resorufin, from which a signal is detected using spectrofluorometric assays. Fluorescence polarization (FP) is based on the slowing down of a fluorophore's molar rotation upon binding to a larger molecule, such as a receptor protein, taking into account the polarized fluorescence emission caused by the bound ligand. FP is empirically determined by measuring the vertical and horizontal components of the fluorophore's emission after excitation with plane-polarized light. As the fluorophore's molar rotation decreases, the polarized emission increases. When bound to a larger molecule (i.e., a receptor), the fluorophore produces a larger polarized signal, and the fluorophore's molar rotation slows down. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Therefore, polarization of the "bound" signal depends on maintaining high-affinity binding.

[0359] FP is a homogeneous technique, and the reaction is very fast, requiring seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prepared, resulting in high reproducibility. These properties have demonstrated that FP is highly automatable and is often performed in a single incubation with a single, premixed tracer-receptor reagent. For a review, see Owicki et al. (1997), "Application of Fluorescence Polarization Assays in High-Throughput Screening," Genetic Engineering News, 17:27.

[0360] FP is particularly desirable because its readout is independent of emission intensity (Checovich, WJ et al. (1995) Nature 375:254-256; Dandliker, WB et al. (1981) Methods in Enzymology 74:3-28), and is therefore insensitive to the presence of colored compounds that quench the fluorescence emission. FP and FRET (see below) are well suited to identifying compounds that block the interaction of sphingolipid receptors with their ligands. See, for example, 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.

[0361] Sphingolipid-derived fluorophores that can be used in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin), N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin), and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine (BODIPY® FL C5-ceramide), respectively. U.S. Pat. No. 4,150,949 (Immunoassay for gentamicin) discloses fluorescently labeled gentamicin, including fluorescein isothiosemicarbanyl gentamicin. Additional fluorophores may be prepared using methods well known to those skilled in the art. Exemplary standard and polarized fluorescence readers include the POLARION® Fluorescence Polarization System (Tecan AG, Hombrechtikon, Switzerland). General multiwell plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multiwell plate spectrophotometer (both manufactured by Molecular Devices). Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. See, for example, Heim et al. (1996) Curr. Biol. 6:178-182 and Mitra et al. (1996) Gene. 173:13-17, and Selvin et al. (1995) Meth. Enzymol. 246:300-345. FRET detects energy transfer between two fluorescent substances in close proximity with known excitation and emission wavelengths.For example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are brought into close proximity, e.g., when the proteins specifically interact with a target molecule, resonance energy can be transferred from one excited molecule to another. As a result, the emission spectrum of the sample shifts, which can be measured by a fluorometer such as the fMAX multiwell fluorometer (Molecular Devices, Sunnyvale, Calif.).

[0362] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interactions with target molecules.SPA has been widely used and described in the pharmaceutical field (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.One commercially available system uses FLASHPLATE® scintillant-coated plates (NEN Life Science Products, Boston, MA).

[0363] Target molecules can be bound to scintillator plates by a variety of well-known means. Scintillant plates are available that are derivatized to bind fusion proteins, such as GST, His6, or Flag fusion proteins. If the target molecule is a protein complex or multimer, one protein or subunit can first attach to the plate, and then other components of the complex can be added later under binding conditions, resulting in a bound complex.

[0364] In a typical SPA assay, gene products in the expression pool are radiolabeled and added to 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. In either case, if the radiolabel is sufficiently close to the scintillant coating, a signal is generated that can be detected by a device such as the TOPCOUNT NXT® Microplate Scintillation Counter (Packard BioScience Co., Meriden Conn.). If the radiolabeled expression product binds to the target molecule, the radiolabel remains in close proximity to the scintillant long enough to generate a detectable signal.

[0365] In contrast, labeled proteins that do not bind to the target molecule, or that only briefly bind to it, do not remain in the vicinity of the scintillant long enough to generate a signal above background. Time spent in the vicinity of the scintillator due to random Brownian motion also does not result in a significant signal. Similarly, residual unincorporated radiolabel used during the expression process may be present but does not generate a significant signal because it does not interact with the target molecule and remains in solution. These non-bonded interactions therefore result in a certain level of background signal that can be mathematically removed. If too much signal is obtained, salt or other modifiers can be added directly to the assay plate until the desired specificity is achieved (Nichols et al. (1998) Anal. Biochem. 257:112-119).

[0366] VIII.Basic synthesis The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent from the methods disclosed herein and those well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. The synthesis of typical compounds described herein may be achieved as described in the following examples. Where available, reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0367] The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following basic methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0368] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein.

[0369] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds can be prepared as pure stereoisomers, i.e., individual enantiomers, diastereomers, or diastereomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise specified. Pure stereoisomers (and enriched mixtures) may be prepared, for example, using optically active materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be prepared, for example, using chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, etc.

[0370] 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 of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard references 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), or obvious modifications thereof.

[0371] It will also be understood that in each of the schemes, the addition of any substituent will result in the production of several isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which may be isolated and purified using conventional techniques. Where enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be utilized, as conventionally used in the art or as described in the Examples.

[0372] The compounds of the present disclosure may be synthesized according to the schemes and examples set forth below. These examples may be modified by replacing the starting materials with other materials of similar structure to yield the corresponding products. The structure of the desired product, as a whole, will make the necessary starting materials apparent to one skilled in the art.

[0373] [ka]

[0374] Step 1: Compound (i) can be converted to compound (ii) by applying a peptide reagent such as PyBroP (one example) under suitable reaction conditions, which can be in the presence of a tertiary amine such as triethylamine. This 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 Basic Scheme 1 are as defined in the present disclosure. The variable X in Basic Scheme 1 is a suitable leaving group, such as Br or Cl.

[0375] Step 2: To reach compound I, a cross-coupling reaction, e.g.,

[0376] [ka]

[0377] Compound (ii) can be converted to compound I by palladium-catalyzed Suzuki coupling with an organoborate such as: The variable G can be further modified one or more times by techniques described in this disclosure or known in the art.

[0378] [ka]

[0379] Step 1': Compound (iv) can be converted to compound (v) by applying a peptide coupling reagent such as PyBroP in the presence of a tertiary amine such as triethylamine. This reaction can be carried out in an aprotic solvent such as THF. Variables E1, E2, A, R1, and R2 in Basic Scheme 1 are as defined in this disclosure. Variable G' in Basic Scheme 1 can be a BOC-protected G group or another precursor that can be modified one or more times by techniques described in this disclosure or known in the art. G' can also be the same variable G as described in this disclosure, but there is no step 2' to modify variable G'.

[0380] Step 2': Compound (v) can be converted to compound I by one or more techniques described in this disclosure or known in the art. Such one or more techniques can include, by way of example, BOC deprotection, peptide coupling reaction with HATU, amide formation with HOBt, or nucleophilic substitution.

[0381] Synthesis of intermediate A Intermediate A

[0382] [ka]

[0383] Step 1. Methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate

[0384] [ka]

[0385] 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, followed by the addition of O-(2,4-dinitrophenyl)hydroxylamine (29.28 g, 147.04 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction was quenched at 0° C. by the addition of saturated aqueous ammonium chloride solution (500 mL). The resulting mixture was diluted with water (1 L) and extracted with ethyl acetate (2×1.5 L). The combined organic layers were washed with brine (2×1.5 L), 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 give methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (22 g, 81.97%). LCMS (ESI-MS) m / z = 219.0 [M+H] +

[0386] Step 2. 5-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

[0387] [ka]

[0388] 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 formimidamide 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 (3 x 100 mL) and petroleum ether (200 mL) to give 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] + .

[0389] 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

[0390] [ka]

[0391] 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 EtN (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 give 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] + .

[0392] In the following synthetic examples, pure stereoisomers were separated by chiral separation, and all pure stereoisomers of these compounds eluted in separate fractions as described herein. 1 H NMR and MS data were obtained to verify that all of the pure stereoisomers of these compounds were separated. The absolute stereochemistry of each of the separated fractions was not determined.

[0393] In other synthetic examples, the endo-exo products or diastereomers were separated using conventional HPLC to obtain fractions of each racemate. 1H NMR and MS data were acquired to verify that all endo-exo products of this compound were separated. The absolute stereochemistry of each separated fraction was not determined.

[0394] All compounds in Table 1 were found to dynamically inhibit one or more of HER2-YVMA, HER2 WT, and EGFR WT. [Example]

[0395] The numbers in the following examples correspond to the compound numbers in Table 1.

[0396] Example 1

[0397] [ka]

[0398] Step 1. Tert-butyl (E)-3-(2-(phenylsulfonyl)vinyl)azetidine-1-carboxylate

[0399] [ka]

[0400] To a solution of methanesulfonylbenzene (16.7 g, 107 mmol) in anhydrous tetrahydrofuran (160 mL) at −20° C. under a nitrogen atmosphere, lithium bis(trimethylsilyl)amide (1 M solution in THF, 189 mL, 189 mmol) was added dropwise, and the reaction was stirred at −20° C. for 30 minutes. Chlorotrimethylsilane (12.6 mL, 99.2 mmol) was added to the reaction mixture and stirred slowly 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 stirred at −20° C. for an additional 3 hours. This procedure was repeated twice. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 L) and extracted with ethyl acetate (2×1 L). The combined organics were 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] + .

[0401] Step 2. Ethyl 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate

[0402] [ka]

[0403] Potassium 2-methylpropan-2-olate (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) under a nitrogen atmosphere at 0° C. and stirred for 10 minutes. Then, tert-butyl (E)-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 1 hour. This procedure was repeated twice. The reaction was quenched at 0° C. by the addition of saturated aqueous ammonium chloride solution (500 mL). The resulting mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (3×500 mL) and 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] + .

[0404] Step 3. Ethyl 1-amino-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate

[0405] [ka]

[0406] To a flask was added MTBE (1 L) and ammonium chloride (30 g, 0.565 mol). The reaction was cooled to -20 °C. Concentrated aqueous ammonium hydroxide (80 mL) was then added to the reaction, followed by the slow addition of commercial grade sodium hypochlorite solution (750 mL). After the addition, the reaction was stirred at -20 °C for an additional 30 minutes. The MTBE layer was separated, washed with brine, and dried over anhydrous sodium sulfate. To a separate flask under nitrogen, ethyl 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrrole-2-carboxylate (27 g, 91.8 mmol) and dry DMF (300 mL) were added. The reaction was cooled to 0 °C, and sodium hydroxide (7.3 g, 183.6 mmol) was added portionwise to the reaction. The reaction was stirred at 0 °C for an additional 1 hour before being cooled to -20 °C. At this time, the previously prepared chloramine solution in MTBE was slowly added to the reaction, and the mixture was stirred at -20°C for 1 hour. The reaction was quenched with saturated sodium thiosulfate solution. The organic layer of the reaction was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 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] + .

[0407] Step 4. Tert-butyl 3-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate

[0408] [ka]

[0409] Methanimidamide acetate (7.06 g, 67.8 mmol) was added 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). The reaction mixture was then stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with PE / EA (37%) and concentrating to give 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] + .

[0410] Step 5. 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

[0411] [ka]

[0412] Bromotris(pyrrolidin-1-yl)phosphanium; hexafluoro-lambda 5-phosphanide (2.41 g, 5.16 mmol) was added to a mixture of tert-butyl 3-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidine-1-carboxylate (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 give the crude product, which was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:6) to give 1.2 g of crude product (containing 40% SM). The crude material was then purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm, and concentrated to give 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 (553 mg, 31.25%). LCMS (ESI-MS) m / z = 513.2 [M+H] + .

[0413] 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

[0414] [ka]

[0415] 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 in vacuo to give 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] + .

[0416] 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

[0417] [ka]

[0418] 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 hexafluorophospate (277 mg, 0.72 mmol), and N,N-diisopropylethylamine (237 mg, 1.81 mmol) in DMF (5 mL) was stirred at room temperature overnight. The resulting mixture was purified by reverse-phase flash under the following conditions (5 mmol / L NH4HCO3, flow rate: 50 mL / min, 30%) to give (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] + .

[0419] Example 3

[0420] [ka]

[0421] 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 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 EtN (98.1 mg, 0.97 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, 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 NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0% to 10% methanol in dichloromethane to give the crude product. The crude product was re-purified by preparative HPLC with mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 20% B to 50% B to give 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 H NMR(400MHz,DMSO-d6)δ(ppm)8.94(d,J=7.2Hz,1H),8.53(s,1H),8.39(s,1 H),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=16.4Hz,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).

[0422] Example 6

[0423] [ka]

[0424] 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)piperazine-1-carboxylate

[0425] [ka]

[0426] 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), tert-butyl piperazine-1-carboxylate (93.92 mg, 0.50 mmol), Pd(dba) (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 under a nitrogen atmosphere for 72 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, 25 g, 20 mL / min flow rate, eluting with 0% to 80% ethyl acetate in petroleum ether), and the desired fractions were combined and concentrated in vacuo to give the desired product 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, 69%). LCMS (ESI-MS) m / z = 542.3 [M+H] + .

[0427] 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

[0428] [ka]

[0429] 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 hour. The resulting mixture was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, 25 g, 20 mL / min flow rate, eluting with 0% to 10% methanol in dichloromethane), and the desired fractions were combined and concentrated in vacuo to give 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] + .

[0430] 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

[0431] [ka]

[0432] 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 EtN (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, 20 mL / min, eluted with ethyl acetate in petroleum ether from 0% to 80%). Fractions with the desired mass signal were combined and concentrated in vacuo to give 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] + .

[0433] Example 7

[0434] [ka]

[0435] 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

[0436] [ka]

[0437] 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)Cl (37.34 mg, 0.05 mmol), and KCO (126.71 mg, 0.92 mmol) in dioxane (4 mL) and HO (1.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate 1:10) to give tert-butyl 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] + .

[0438] 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 A solution of 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 overnight at room temperature under a nitrogen atmosphere. The mixture was filtered off and the filtrate was concentrated in vacuo to give the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI-MS) m / z=541.3 [M+H] + .

[0439] 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

[0440] [ka]

[0441] 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 give 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] + .

[0442] 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

[0443] [ka]

[0444] 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 EtN (32.16 mg, 0.32 mmol) in DCM (2 mL) was stirred at 0 °C for 5 min. The resulting mixture was purified by preparative TLC (ethyl acetate) 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)piperidin-1-yl)prop-2-en-1-one, Example 7 (24.6 mg, 30.55%). LCMS (ESI-MS) m / z=495.2 [M+H] + .

[0445] Example 8

[0446] [ka]

[0447] 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)-1,4-diazepane-1-carboxylate

[0448] [ka]

[0449] 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 CsCO (1493.65 mg, 4.58 mmol) in dioxane (10 mL) was stirred at 100 °C under a nitrogen atmosphere for 7 days. The resulting mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate 1:2) 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)-1,4-diazepane-1-carboxylate (500 mg crude). LCMS (ESI-MS) m / z=556.3 [M+H] + .

[0450] 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

[0451] [ka]

[0452] 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 hour. The resulting mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative 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] + .

[0453] 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

[0454] [ka]

[0455] 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 NaHCO (110.65 mg, 1.32 mmol) in THF (1 mL) and HO (1 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EA (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative 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] + .

[0456] Example 9

[0457] [ka]

[0458] Step 1. Tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate

[0459] [ka]

[0460] A solution of tert-butyl 4-oxazepane-1-carboxylate (2 g, 9.37 mmol) in THF (20 mL) was treated with LiHMDS (10.3 mL, 10.31 mmol) under a nitrogen atmosphere at −78° C. for 1 h, followed by the dropwise addition of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (3.69 g, 10.31 mmol) 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 (3×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography eluting with PE / EA (9:1) to give tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (1.5 g, 46.32%). LCMS (ESI-MS) m / z = 346.1 [M+H] + .

[0461] Step 2. Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate

[0462] [ka]

[0463] To a solution of tert-butyl 4-(trifluoromethanesulfonyloxy)-2,3,6,7-tetrahydroazepine-1-carboxylate (1.4 g, 4.05 mmol) in dioxane (20 mL) was added 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)Cl (0.30 g, 0.40 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography eluting with PE / EA (9:1) to give tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (1.1 g, 83.94%). LCMS (ESI-MS) m / z = 324.2 [M+H] + .

[0464] Step 3. 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-carboxylate

[0465] [ka]

[0466] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (200 mg, 0.61 mmol) in a mixture of dioxane (1 mL) and water (0.1 mL) was added 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), KCO (86.14 mg, 0.61 mmol), and Pd(dppf)Cl (22.64 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography eluting with PE / EA (2:1) 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)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (110 mg, 32.18%). LCMS (ESI-MS) m / z = 553.3 [M+H] + .

[0467] 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

[0468] [ka]

[0469] 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)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (110 mg, 0.199 mmol) in MeOH (3 mL) was stirred under a hydrogen atmosphere at room temperature for 24 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 100% gradient, and concentrated under reduced pressure 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)azepane-1-carboxylate (80 mg, 72.46%). LCMS (ESI-MS) m / z = 555.3 [M+H] + .

[0470] 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

[0471] [ka]

[0472] 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 methylene chloride (3 mL) was added TFA (1 mL) under a nitrogen atmosphere at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 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] + .

[0473] 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

[0474] [ka]

[0475] 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 EtN (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 preparative TLC (CHCl / MeOH 10:1) to give the crude product, which was subsequently purified by reverse-phase flash under the following conditions: (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO+0.1% NH.H0), 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] + .

[0476] Example 10

[0477] [ka]

[0478] Step 1. Tert-butyl (E)-3-(3-(dimethylamino)acryloyl)azetidine-1-carboxylate

[0479] [ka]

[0480] A solution of tert-butyl 3-acetylazetidine-1-carboxylate (2 g, 10.03 mmol) in DMF-DMA (15 mL) was stirred overnight at 110° C. 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] +

[0481] Step 2. Tert-butyl 3-(1H-pyrazol-3-yl)azetidine-1-carboxylate

[0482] [ka]

[0483] 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 in vacuo. The residue was purified by silica column chromatography (0-40% ethyl acetate in hexanes) to give 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] +

[0484] 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

[0485] [ka]

[0486] 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), (1R,2R)-cyclohexane-1,2-diamine (153.43 mg, 1.34 mmol), potassium phosphate (380.27 mg, 1.79 mmol), and copper iodide (85.30 mg, 0.44 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (0-40% ethyl acetate in hexane) to give 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] + .

[0487] 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

[0488] [ka]

[0489] 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 hours and concentrated in vacuo to give 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] + .

[0490] 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

[0491] [ka]

[0492] To 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 EtN (67.67 mg, 0.66 mmol) in dichloromethane (2 mL) was added acryloyl chloride (15.13 mg, 0.16 mmol) dropwise at 0° C. and stirred for 3 min. The reaction mixture was purified by preparative TLC to give the crude product. The crude product (60 mg) was purified by preparative HPLC using 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.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 58% B, 58% B in 7 min) 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, i.e., Example 10 (11.2 mg, 12.57%). LCMS (ESI-MS) m / z = 533.1[M+H] + .

[0493] Example 16

[0494] [ka]

[0495] 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

[0496] [ka]

[0497] A mixture of CsCO (298.7 mg, 0.91 mmol), 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 under a nitrogen atmosphere for 72 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, 25 g, 100 mL / min flow rate, eluting with 0% to 40% ethyl acetate in petroleum ether), and the desired fractions were combined and concentrated in vacuo to give 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] + .

[0498] Step 2. N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0499] [ka]

[0500] 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 hour. The mixture was concentrated in vacuo to give the crude product N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg crude). LCMS (ESI-MS) m / z = 454.2 [M+H] + .

[0501] 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]heptan-2-yl)prop-2-en-1-one

[0502] [ka]

[0503] A mixture of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2,6-diazaspiro[3.3]heptan-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 EtN (66.94 mg, 0.65 mmol) in DCM (2 mL) was stirred at 0 °C for 5 min. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate:petroleum ether = 1:1), and the fraction with the desired mass signal was dissolved in dichloromethane / methanol (10:1, 50 mL) and filtered. The filtrate was concentrated in vacuo to give 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]heptan-2-yl)prop-2-en-1-one, Example 16 (20.3 mg, 16.73%). LCMS (ESI-MS) m / z=508.2 [M+H] + .

[0504] Example 20

[0505] [ka]

[0506] 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 To a 1-dram vial containing a Teflon-coated stir bar was added 2-(trifluoromethyl)acrylic acid (18.9 mg, 1.5 Eq, 135 μmol) and HATU (51.4 mg, 1.5 Eq, 135 μmol). The vial was then sealed and placed in a N glovebox, and DMF (1.4 mL) was added. The vial was resealed and removed from the glovebox, and DIPEA (81.6 mg, 110 μL, 7 Eq, 631 μmol) was added via syringe, and the reaction mixture was stirred at room temperature. After 30 min, 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) was added via syringe, and the reaction mixture was stirred at room temperature. After 30 min, the reaction mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give Example 20 (3.99 mg, 6.78% yield). LCMS (ESI) [M+H] + =539.2.

[0507] Example 21

[0508] [ka]

[0509] (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 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), (£)-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 backfilled with N (three times). DMF (3.0 mL) and diisopropylethylamine (46.6 mg, 62.3 μL, 4 Eq, 361 μmol) were then added via syringe, and the reaction was stirred at room temperature overnight. The resulting mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give the title compound, Example 21 (2.0 mg, 3.3% yield). LCMS (ESI) [M+H] + =552.3.

[0510] Example 24

[0511] [ka]

[0512] (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 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), (£)-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 backfilled with N (three times). DMF (3.0 mL) and diisopropylethylamine (46.6 mg, 62.3 μL, 4 eq, 361 μmol) were then added via syringe, and the reaction was stirred overnight at room temperature. The resulting mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give Example 24 (1.8 mg, 2.8% yield). LCMS (ESI) [M+H] + =607.3.

[0513] Example 25

[0514] [ka]

[0515] (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 To a 1-dram vial containing 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 a N glovebox. DMF (1.4 mL) was added after the vial was opened. The vial was resealed and removed from the glovebox, and DIPEA (81.6 mg, 110 μL, 7 Eq, 631 μmol) was added through the septum. The reaction mixture was stirred at room temperature 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 min, the reaction mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give Example 25 (22.8 mg, 36.6% yield). LCMS (ESI) [M+H] + =578.3.

[0516] Example 26

[0517] [ka]

[0518] 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 To a 1-dram vial 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)-3,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 1 Eq, 92.8 μmol) and dichloromethane (0.5 mL). Trifluoroacetic acid (106 mg, 70.7 μL, 10 Eq, 928 μmol) was then added slowly, the vial was capped, and stirred at room temperature. After complete consumption of the starting material by LCMS, the reaction was concentrated and used without further purification. The crude residue was reconstituted in dichloromethane (1.0 mL) and added 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 stirred at room temperature. After 16 h, the reaction was filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-10% in dichloromethane) to give Example 26 (4.2 mg, 8.9% yield). LCMS (ESI) [M+H] += 511.2.

[0519] Example 27

[0520] [ka]

[0521] 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 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 2-cyanoacrylate (75.3 mg, 3 Eq, 270 μmol), and HATU (171 mg, 5 Eq, 451 μmol). The vial was then capped and placed in a N glovebox. The vial was then opened and DMF (1.4 mL) was added. The vial was resealed and removed from the glovebox, and DIPEA (117 mg, 157 μL, 10 Eq, 902 μmol) was added through the septum. After 30 min, the reaction mixture was filtered and then purified by preparative reverse-phase HPLC (acetonitrile / water gradient with 0.1% TFA) to give Example 27 (10.0 mg, 18.4% yield). LCMS (ESI) [M+H] + =603.3.

[0522] Example 42

[0523] [ka]

[0524] Step 1. (E)-4-(4-Methoxypiperidin-1-yl)but-2-enoic acid

[0525] [ka]

[0526] To a stirred mixture of (£)-4-bromobut-2-enoic acid (50 mg, 0.30 mmol) and 4-methoxy-piperidine HCl (51 mg, 0.33 mmol) in DMF (1 mL) was added diisopropylethylamine (0.12 g, 0.91 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was used directly in the next step.

[0527] 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

[0528] [ka]

[0529] 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) at room temperature, and the mixture was stirred for 10 minutes. The resulting mixture was concentrated in vacuo to give the crude product. The crude was diluted with ethyl acetate (20 mL x 2) and washed with NaHCO (20 mL). The organic layer was dried over MgSO 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] + .

[0530] 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

[0531] [ka]

[0532] 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 (£)-4-(4-methoxypiperidin-1-yl)but-2-enoic acid (58 mg, 0.29 mmol) and diisopropylethylamine (from Step 1) in DMF (1 mL). The reaction was stirred at room temperature for 30 minutes.

[0533] The reaction mixture was filtered and purified by preparative HPLC, eluting with 10-40% ACN / water / 0.1% TFA. The fractions were diluted with ethyl acetate (20 mL), washed with saturated NaHCO (20 mL), the organic layer was filtered through MgSO, and the solvent was evaporated to give (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%). 1H NMR(499MHz,クロロホルム-d)δ=8.50(d,J=7.4Hz,1H),8.23(s,1H),8.00(s, 1H),7.63(d,J=2.7Hz,1H),7.60(dd,J=2.6,8.6Hz,1H),7.57(d,J=2.5H z,1H),7.10(d,J=8.5Hz,2H),6.94(td,J=6.2,15.3Hz,1H),6.89(dd,J=2.7,7.4Hz,1H),6.85(d,J=2.5Hz,1H),6.73(d,J=2.7Hz,1H),6.11(br d,J=15.3Hz,1H),4.83-4.72(m,1H),4.65(br t,J=8.5Hz,1H),4.46-4.37(m,1H),4.37-4.25(m,2H),3.33(s,3H),3.23(br d,J=3.3Hz,1H),3.21-3.14(m,2H),2.74(br s,2H),2.34-2.19(m,5H),1.90(br d,J=12.0Hz,2H),1.63(br d,J=8.8Hz,2H). LCMS(ESI-MS)m / z=594.3[M+H] + .

[0534] Example 50

[0535]

change

[0536] Engineering 1.tert-ブチル4-(4-クロロピロロ[2,1-f][1,2,4 ]トリアジン-5-イル)-4-ヒドロキシピペリジン-1-カルボキシレート

[0537]

change

[0538] To a reaction tube equipped with a stir bar was added 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (100 mg, 430 μmol). The tube was sealed, evacuated, and backfilled with N (3 times). Dry THF (4.0 mL) was added via syringe, and the reaction mixture was cooled to −78° C. over 15 minutes. nBuLi (33.1 mg, 215 μL, 2.4 mol, 516 μmol) was then added slowly via syringe, and the reaction mixture was stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (103 mg, 516 μmol) in THF (1.0 mL) was then added via syringe, and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was then quenched with saturated NaHCO and allowed to warm to room temperature. Water (10 mL) was then added, and the reaction mixture was extracted with DCM (3 times 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification by column chromatography (10-100% EtOAc in hexanes) gave tert-butyl 4-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-4-hydroxypiperidine-1-carboxylate (77 mg, 51%), which was used in the next step without further purification. LCMS (ESI) [M+H] + =352.1.

[0539] 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)-4-hydroxypiperidine-1-carboxylate

[0540] [ka]

[0541] To a 40 mL scintillation vial with a stir bar was added 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). The vial was capped, evacuated, and backfilled with N (three times), then dry isopropanol (12.0 mL) was added via syringe, and the reaction mixture was stirred at room temperature. After 1 h, the reaction mixture was washed with saturated NaHCO (10 mL) and extracted with DCM (three times 10 mL). Purification by column chromatography with 10-100% EtOAc / EtOH in hexanes (3:1 mixture) gave 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.

[0542] 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

[0543] [ka]

[0544] To a 1-dram vial 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 (100 mg, 180 μmol) and TFA (246 mg, 166 μL, 2.16 mmol). The reaction mixture was stirred for 1.5 hours and then concentrated in vacuo. The crude product was used in the next step without further purification. LCMS (ESI) [M+H] + =456.2.

[0545] 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

[0546] [ka]

[0547] To a 2-dram vial with a stir bar was added 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), and the reaction mixture was stirred at room temperature. After 45 min, the reaction mixture was directly purified by preparative HPLC in 10-50% CAN in 0.1% TFA water. Fractions containing the desired product mass were combined, neutralized with saturated aqueous NaHCO3 (10 mL), and extracted with DCM (4 x 15 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give (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(499MHz,chloroform-d)δ ppm 11.22(s,1H)8.47(d,J=7.4Hz,1H)8.06(s,1H)7.99(s,1H)7.79(d,J=2.5Hz,1H)7.72(dd,J=8.6,2.6Hz,1H)7.4 8(d,J=2.7Hz,1H)7.07(d,J=8.8Hz,1H)6.91(dd,J=7.5,2.6Hz,1H)6.67-6.81(m,2H)6.43-6.53(m,2H)5.36(br s,1H)4.57(br d,J=11.8Hz,1H)3.92(br d,J=12.0Hz,1H)3.67(br t,J=12.5Hz,1H)3.23(br t,J=12.2Hz,1H)3.10(br d,J=6.0Hz,2H)2.27(s,6H)2.22(s,3H)1.89-2.19(m,4H).

[0548] Example 51

[0549] [ka]

[0550] Step 1. 1-Benzhydryl-3-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol

[0551] [ka]

[0552] To a reaction tube equipped with a stir bar was added 5-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (865.0 mg, 3.721 mmol). The tube was sealed, evacuated, and backfilled with N (three times). Dry THF (18.0 mL) was added via syringe, and the reaction mixture was cooled to −78° C. over 10 minutes. n-BuLi (309.9 mg, 2.015 mL, 2.4 mol, 4.837 mmol) was then added slowly via syringe, and the reaction mixture was stirred for 30 minutes. 1-Benzhydryl-azetidin-3-one (1.104 g, 4.651 mmol) in THF (6.0 mL) was then added via syringe, and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched with saturated NaHCO and allowed to warm to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. Purification by column chromatography (10-100% EtOAc in hexanes) gave 1-benzhydryl-3-(4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)azetidin-3-ol (456 mg, 31.4%). 1 H NMR(499MHz,chloroform-d)δ 8.19(s,1H),7.84(d,J=2.5Hz,1H),7.42(br d,J=7.4Hz,6H),7.27-7.30(m,4H),7.17-7.24(m,3H),7.01(d,J=2.5Hz,2H),4.46(s,1H),3.79(br d,J=7.9Hz,2H),3.58(br d,J=7.9Hz,2H). LCMS(ESI)[M+H] + =391.1.

[0553] 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-benzhydrylazetidin-3-ol

[0554] [ka]

[0555] To a 2-dram vial with a stir bar was added 1-benzhydryl-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). The vial was capped, evacuated, and backfilled with N (3 times), then dry isopropanol (2.0 mL) was added via syringe and the reaction mixture was heated to 50 °C. After 1 h, the reaction was removed from the heat, diluted with saturated NaHCO (20 mL), and extracted with DCM (3 times 20 mL). Purification by column chromatography with 10-100% EtOAc / EtOH in hexanes (3:1 mixture) gave 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-benzhydrylazetidin-3-ol (69.9 mg, 91.9%). 1H NMR(499MHz,chloroform-d)δ 10.14(br s,1H),8.46(d,J=7.4Hz,1H),8.20(s,1H),8.00(s,1H),7.60-7.69(m,3H),7.55(d,J=2.7Hz,1H),7.39-7.51(m,5H),7.29(br t,J=7.4Hz,4H),7.21(br d,J=7.1Hz,3H),6.96-7.10(m,2H),6.85(dd,J=7.4,2.7Hz,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.

[0556] 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

[0557] [ka]

[0558] To a 1-dram vial equipped with a stir bar was added 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). The vial was capped, evacuated, and backfilled with N (3 times). Anhydrous MeOH (5 mL) was then added through the septum, and the reaction vial was then heated to 40 °C with stirring at 1600 rpm. After 3 h, the reaction mixture was cooled to room temperature, neutralized with saturated aqueous NaHCO (20 mL), and extracted with DCM (3 times 15 mL). The organic layer was then washed with brine, dried over MgSO4 and concentrated. The crude product was used immediately in the next step without further purification. LCMS (ESI) [M+H] + =429.2.

[0559] 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

[0560] [ka]

[0561] To the crude residue from the previous step (Step 3), 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) were added. The reaction mixture was then stirred at room temperature. After 1 h, the reaction mixture was directly purified by preparative HPLC using 10-100% CAN in 0.1% TFA in water. The collected fractions were combined, neutralized with saturated aqueous NaHCO3 (10 mL), and extracted with DCM (3 x 10 mL). The organic layer was then washed with brine, dried over MgSO4, and concentrated to give (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 or Example 51 (1.89 mg, 2.7% yield over two steps). 1 H NMR(499MHz,chloroform-d)δ ppm 10.63(s,1H)8.48(d,J=7.4Hz,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=8.8Hz,1H)6.83-6.92(m,2H)6.75-6.80(m,1H)6.67(d,J=3.0Hz,1H)6.19-6.27(m,1H)4.52-4.66(m,3H)4.40(br d,J=11.0Hz,1H)3.26(br d,J=5.5Hz,2H)3.08(s,1H)2.29-2.38(m,6H)2.19-2.25(m,3H).

[0562] Example 52

[0563] [ka]

[0564] 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)-4-methoxypiperidine-1-carboxylate

[0565] [ka]

[0566] To a 1-dram vial 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 (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 to room temperature overnight. The reaction was quenched with MeOH (1.0 mL) and stirred at room temperature for 1 hour. Purification by column chromatography (0-15% MeOH in DCM) gave 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-methoxypiperidine-1-carboxylate (24 mg, 15%). 1H NMR(499MHz, methanol-d4)δ 8.72(d,J=7.4Hz,1H),8.27(s,1H),7.94(s,1H),7.82(d,J=2.5Hz,1H),7.73(dd,J=8.6,2.6Hz,1H),7.61(d,J=2. 7Hz,1H),7.15(d,J=8.8Hz,1H),7.04(dd,J=7.5,2.6Hz,1H),6.79(d,J=2.5Hz,1H),6.73(d,J=2.7Hz,1H),4.01(br d,J=12.9Hz,2H),3.17-3.40(m,5H),2.30(br d,J=13.7Hz,2H),2.23(s,3H),1.94-2.03(m,2H),1.47(s,9H). LCMS(ESI)[M+H] + =570.3.

[0567] 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

[0568] [ka]

[0569] To a 1-dram vial 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 room temperature for 20 minutes. The reaction mixture was then concentrated in vacuo and used directly in the next step without further purification. LCMS (ESI) [M+H] + =470.2.

[0570] 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

[0571] [ka]

[0572] To a 1-dram vial with a stir bar was added 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). DMF (2 mL) was then added, followed by diisopropylethylamine (33.0 mg, 44.4 μL, 255 μmol), and the reaction mixture was stirred at room temperature. After 1 h, the reaction mixture was directly purified by preparative HPLC in 10 to 100% ACN in water with 0.1% TFA. The fractions containing the desired product mass were combined, neutralized with saturated aqueous NaHCO (7 mL), and extracted with DCM (3 x 10 mL). The combined organic fractions were washed with brine, dried over anhydrous MgSO, and concentrated to give (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, i.e., Example 52 (4.27 mg, 11.0%). 1H 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=2.7Hz,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.

[0573] Example 72

[0574] [ka]

[0575] 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

[0576] [ka]

[0577] 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-butylmethyl(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 fraction was lyophilized to give 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] + .

[0578] 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

[0579] [ka]

[0580] A 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 minutes and concentrated in vacuo. The crude was diluted with DCM (10 mL) and washed with NaHCO (5 mL). The mixture was filtered through a phase separator column and the solvent was evaporated to give 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] + .

[0581] 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

[0582] [ka]

[0583] 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 2 h. 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 MgSO and the solvent was evaporated to give 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%). 1H NMR(499MHz,DMSO-d6)δ=9.67-9.57(m,1H),8.93(d,J=7.4Hz,1H),8.40-8.35(m,1H),7.99-7.95 (m,1H),7.82-7.74(m,2H),7.67(d,J=2.7Hz,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] + .

[0584] Example 86

[0585] [ka]

[0586] Step 1. Methyl (E)-3-bromo-1-((2-cyanoethylidene)amino)-1H-pyrrole-2-carboxylate

[0587] [ka]

[0588] 3,3-Diethoxypropanenitrile (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) at room temperature. 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 chromatography with ethyl acetate / petroleum ether = 1:1 to give 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] + .

[0589] Step 2. 5-Bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile

[0590] [ka]

[0591] To a solution of methyl (E)-3-bromo-1-((2-cyanoethylidene)amino)-1H-pyrrole-2-carboxylate (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 give the crude product. The residue was purified by silica gel column chromatography 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] + .

[0592] 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

[0593] [ka]

[0594] 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), EtN (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 give the crude product. The residue was purified by silica gel column chromatography 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-methyl-phenyl)amino)-5-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (800 mg, 45.9% yield). LCMS (ESI-MS) m / z=460.0 [M+H] + .

[0595] 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

[0596] [ka]

[0597] 4,4'-Di-tert-butyl-2,2'-bipyridine (29 mg, 0.11 mmol) and NiCl2 in DCE (1 mL) . A mixture of dme (33 mg, 0.11 mmol) was heated to 60° C. under a nitrogen atmosphere for 10 minutes. The solution was allowed to cool to room temperature (Solution 1). Ir[dF(CF)ppy](dtbpy)PF (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 NaCO (230 mg, 2.17 mmol) in DCE (10 mL) under a nitrogen atmosphere, followed by the addition of solution 1 via syringe. The resulting mixture was kept under nitrogen, stirred at room temperature, and irradiated with a blue LED (450 nm) in a Penn Photoreactor m for 5 h. The reaction mixture was purified by preparative 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), which was used in the next step without further purification. LCMS (ESI-MS) m / z=537.2 [M+H] + .

[0598] 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

[0599] [ka]

[0600] 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 in vacuo to give 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] + .

[0601] Step 6. (E)-4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5-(1-(4-(dimethylamineo)-but-2-enoyl)azetidin-3-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

[0602] [ka]

[0603] 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 hour and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 60% gradient in 10 min to give the desired crude 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 H 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=2.6Hz,1H),6.35(s,1H),6.16(d,J=15.5Hz,1H),4.14-4.10(m,1H),3.85-3.80 (m,2H),3.68-3.65(m,2H),3.35(d,J=6.3Hz,2H),2.49(s,4H),2.47-2.45(m,2H),2.29(s,3H).

[0604] Example 87

[0605] [ka]

[0606] Step 1. 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

[0607] [ka]

[0608] 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 NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica column chromatography (0-3% MeOH in DCM) to give the desired product 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, 56.7% yield). LCMS (ESI-MS) m / z = 596.3 [M+H] +

[0609] 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

[0610] [ka]

[0611] 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 hours and concentrated to give the crude product. The crude product was purified by preparative 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(400MHz,chloroform-d)δ 8.51(d,J=7.6Hz,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=2.9Hz,1 H),6.13(d,J=15.1Hz,1H),4.85-4.62(m,2H),4.48-4.27(m,3H),3.54(dd,J=4.9,2.0Hz,2H),2.25(s,3H),1.70-1.68(m,2H).

[0612] Example 88

[0613] [ka]

[0614] Step 1. 5-Bromoimidazo[5,1-f][1,2,4]triazin-4(3H)-one

[0615] [ka]

[0616] 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 NaSO, filtered, and concentrated in vacuo to give 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] + .

[0617] 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

[0618] [ka]

[0619] 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), KCO (2.57 g, 18.60 mmol), and Pd(dppf)Cl (754 mg, 0.93 mmol) in dioxane (20 mL) and water (6 mL) was stirred overnight at 100 °C 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 NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography eluting with 0% to 30% ethyl acetate in petroleum ether to give 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] + .

[0620] Step 3. 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

[0621] [ka]

[0622] DIEA (1.43 g, 14.18 mmol) was added to a stirred mixture of 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, 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 give 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)-3,6-dihydropyridine-1(2H)-carboxylate (2 g crude), which was used in the next step without further purification. LCMS (ESI-MS) m / z=540.2 [M+H] + .

[0623] Step 4. 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

[0624] [ka]

[0625] 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) under a nitrogen atmosphere. The resulting mixture was degassed and then stirred at room temperature under hydrogen pressure for 2 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (4 x 100 mL). The combined filtrate was concentrated under reduced pressure to give 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 crude), which was used in the next step without further purification. LCMS (ESI-MS) m / z=542.2 [M+H] + .

[0626] 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

[0627] [ka]

[0628] 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 give the crude product. The residue was purified by column chromatography eluting with MeOH in DCM from 0% to 10% to give 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] + .

[0629] 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

[0630] [ka]

[0631] 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), (£)-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 give the crude product. The crude product was purified by column chromatography, eluting with MeOH in DCM from 0% to 10%, to give 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 H NMR(400MHz,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),3.0 9-3.03(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).

[0632] Example 89

[0633] [ka]

[0634] (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 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 NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH in DCM from 0% to 10%, to give 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] + . 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).

[0635] Example 90

[0636] [ka]

[0637] Step 1. 3-Chloro-5-nitro-2-(3-(trifluoromethyl)phenoxy)pyridine

[0638] [ka]

[0639] To a solution of 3-(trifluoromethyl)phenol (4.2 g, 25.91 mmol) in THF (80 mL) was added NaH (60% in mineral oil, 1.12 g, 46.6 mmol), and the resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. 2,3-Dichloro-5-nitropyridine (5 g, 25.9 mmol) was then added to the mixture, which was then 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 (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate = 5:1 to give 3-chloro-5-nitro-2-(3-(trifluoromethyl)-phenoxy)pyridine (7.91 g crude). LCMS (ESI-MS) m / z = 319.0 [M+H] + .

[0640] Step 2. 5-Chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine

[0641] [ka]

[0642] 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 CaCl (1.39 g, 12.53 mmol) in EtOH (223 mL) and water (40 mL). The resulting mixture was then 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 NaSO, filtered, and concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate = 1:1 to give 5-chloro-6-(3-(trifluoromethyl)phenoxy)pyridin-3-amine (4.8 g, 52% yield). LCMS (ESI-MS) m / z = 289.0 [M+H] + .

[0643] Step 3. 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

[0644] [ka]

[0645] EtN (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 at room temperature overnight and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC with 10% to 50% ACN in water (10 mmol / L NH4HCO3) 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] + .

[0646] 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

[0647] [ka]

[0648] 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]...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog 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 alkyl, haloalkyl, or 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, and each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl moieties contains 1 to 4 J １ optionally substituted with a group, Or R １ and R ２ form a saturated or unsaturated carbocyclic or heterocyclic ring by combining with the carbon atom to which they are attached, and said saturated or unsaturated carbocyclic or heterocyclic ring is １ optionally substituted with a group, 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, each of which contains 1 to 4 J ２ optionally substituted with a group, provided that L １ is CH ２ When L １ is not attached to a carbon or nitrogen atom of a saturated ring, L １ａ is -C ０ -C ６ Alkylene -C(O)N(H)-, -C ０ -C ６ Alkylene-S(O) ２ N(H)-, R ３ is a 4-9 membered heterocycle containing at least one nitrogen ring atom, and R ３ is 1 to 4 J ３ optionally substituted with a group, R ３ One nitrogen atom is -L ２ -R or substituted with R ３ is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, said 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom being ３ group, and one nitrogen atom of said 7- to 11-membered spirocyclic group is optionally substituted with -L ２ is substituted with —R, R ３ａ is 1 to 4 J ２ C optionally substituted with a group １ -C ６ Alkylene -NR ａ R ｂ and W is a bond, —C(O)—, or —S(O) ２ - and X is 1 to 4 J ２ aryl, heteroaryl, heterocycloalkyl, or cycloalkyl optionally substituted with a group; Y is -C ０ -C ４ Alkylene-N(R ｄ ))-L ２ -R, -C(O)-4 to 7-membered heterocycloalkyl containing at least one nitrogen atom and substituted with 1 to 2 oxo groups, -4 to 7-membered heterocycloalkyl-L ２ R, -C ０ -C ４ Alkylene-1-yl-1H-pyrrole-2,5-dione, —C ０ -C ４ Alkylene -C(H)=C(O)-NH ２ , -C ０ -C ４ Alkylene -C(H)=C(H)-C(O)-O-alkyl, -C ０ -C ４ alkylene-ethynylene-C(O)—O-alkyl, —C ０ -C ４ Alkylene -C(H)=C(H)-CN, -C ０ -C ４ Alkylene -N=C=S, -C ０ -C ４ -ethynyl, -C ０ -C ４ Alkylene-ethynyl, -C ０ -C ４ Alkylene -CN, -C ０ -C ４ Alkylene-C(H)=N-N(H)Boc, -C ０ -C ４ Alkylene -C(O)-CH ２ -Br, -C ０ -C ４ Alkylene -CH ２ -Cl, -C ０ -C ４ Alkylene-oxiranyl, -C ０ -C ４ Alkylene -SH, -C ０ -C ４ Alkylene-F, and -C ０ -C ４ alkylene -C(H)=O, C ０ -C ４ the alkylene portion is optionally substituted with 1 to 4 groups independently selected from halogen, cycloalkyl, alkoxy, alkoxyalkyl, or hydroxy; R ４ is H, halo, alkyl, or —O-alkyl; L ２ is -SO ２ - or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C １ -C ４ Alkylene -NR ａ R ｂ , -CH ２ -CN, or haloalkyl, and one halogen of the haloalkyl is L ２ on the carbon atom adjacent to Q is independently a halogen, a haloalkyl, an alkyl, an alkene, an alkyne, or —C １ -C ６ Alkylene -NR ａ R ｂ , -C １ -C ６ Alkylene-OR ｃ , cyano, hydroxyalkyl, -C ０ -C ６ Alkylene -C(O)OH, -C １ -C ６ alkylene-C(O)O-alkyl, alkoxyalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-cycloalkenyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-7 to 11-membered spirocyclic cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-7 to 11-membered spirocyclic heterocycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-heterocycloalkenyl; Alternatively, -L ２ -R is -C=N-OH, J １ are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, -C ０ -C ４ Alkylene -N(H)R ｃ , alkoxy, and alkoxyalkyl; J ２ are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; J ３ are each bonded to a carbon atom and are independently selected from the group consisting of halogen, haloalkyl, CN, alkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, or optionally 1 to 4 J ３ two of the groups form an oxo group or a 3- to 6-membered spiro group, or optionally 1 to 4 J ３ two of the groups are on different ring carbons and are joined to form a 1-3 carbon bridge; J ４ are each independently halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, oxo, and —C ０ -C ４ Alkylene -NR ａ R ｂ and wherein J is selected from the group consisting of ４ The group may contain up to two oxo groups and up to one -C ０ -C ４ Alkylene -NR ａ R ｂ It is assumed that the aryl group can only contain aryl groups. R ａ and R ｂ are each independently H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, and —C optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl. ０ -C ３ selected from the group consisting of alkylene-alkynyl; R ｃ is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl, alkoxy, and alkoxyalkyl; R ｄ is selected from the group consisting of H, alkyl, and haloalkyl; The compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

2. R １ But C １ -C ４ Alkyl, C １ -C ４ haloalkyl, or 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-C １ -C ４ 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 selected from 1 to 3 J １ optionally substituted with a group, Or R １ and R ２ are combined with the carbon atoms to which they are attached to form a ring selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered cycloalkyl, and 4-7 membered heterocycloalkyl, each of which contains 1-3 J １ optionally substituted with a group, G is -L １ -R ３ or -W-X-Y; L １ is a bond, -C(O)-, -S(O) ２ -, -N(H)-, -N(C １ -C ６ alkyl)-, C １ -C ３ alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, or 4- to 7-membered cycloalkyl; １ -C ３ Alkylene, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 7-membered heterocycloalkyl, and 5- to 7-membered cycloalkyl each have 1 to 3 J ２ optionally substituted with a group, provided that L １ is CH ２ When L １ is not attached to a carbon or nitrogen atom of a saturated ring, R ３ is a 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom, and said 4- to 7-membered heterocyclic ring containing at least one nitrogen ring atom is ３ group, and one nitrogen atom of said 4- to 7-membered heterocycle is optionally substituted with -L ２ is substituted with —R, Or R ３ is a 7- to 11-membered spirocyclic group containing at least one nitrogen ring atom, and said 7- to 11-membered spirocyclic group is ３ optionally substituted with a group, R ３ One nitrogen atom of ２ is substituted with —R, W is a 9a bond, —C(O)—, or —S(O) ２ - and X is a 5- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 5- to 7-membered heterocycloalkyl, or a 5- to 7-membered cycloalkyl, and the 10-membered aryl, said 5- to 10-membered heteroaryl, said 5- to 7-membered heterocycloalkyl, and said 5- to 7-membered cycloalkyl are selected from the group consisting of 1 to 3 J ２ optionally substituted with a group, Y is -C ０ -C ４ Alkylene-N(R ｄ )-L ２ -R, -C(O)-4 to 6-membered heterocycloalkyl containing at least one nitrogen atom and substituted with 1 to 2 oxo groups, -4 to 7-membered heterocycloalkyl-L ２ R, -C ０ -C ４ Alkylene-1-yl-1H-pyrrole-2,5-dione, —C ０ -C ４ Alkylene -C(H)=C(O)-NH ２ , -C ０ -C ４ Alkylene -C(H)=C(H)-C(O)-O-alkyl, -C ０ -C ４ alkylene-ethynylene-C(O)—O-alkyl, —C ０ -C ４ Alkylene -C(H)=C(H)-CN, -C ０ -C ４ Alkylene -N=C=S, -C ０ -C ４ -ethynyl, -C ０ -C ４ Alkylene-ethynyl, -C ０ -C ４ Alkylene -CN, -C ０ -C ４ Alkylene-C(H)=N-N(H)Boc, -C ０ -C ４ Alkylene -C(O)-CH ２ -Br, -C ０ -C ４ Alkylene -CH ２ -Cl, -C ０ -C ４ Alkylene-oxiranyl, -C ０ -C ４ Alkylene -SH, -C ０ -C ４ Alkylene-F, and -C ０ -C ４ alkylene -C(H)=O, -C ０ -C ４ The alkylene portion is halogen, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, -C １ -C ６ Alkyl-C １ -C ６ optionally substituted with 1 to 4 groups independently selected from the group consisting of alkoxy, or hydroxy; R ４ But, H, halo, C ０ -C ４ Alkyl, or —O—C ０ -C ４ is alkyl, L ２ But, -SO ２ - or -C(O)-, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C １ -C ４ Alkylene -NR ａ R ｂ , -CH ２ -CN or C １ -C ６ haloalkyl, C １ -C ６ One halogen of haloalkyl is L ２ on the carbon atom adjacent to Q is independently halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl, —C １ -C ４ Alkylene -NR ａ R ｂ , Cyano, C １ -C ６ Hydroxyalkyl, —C １ -C ６ Alkylene -C(O)OH, -C １ -C ６ Alkylene-C(O)O-C １ -C ６ Alkyl, -C １ -C ４ Alkylene-C １ -C ６ Alkoxy, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ Alkylene-C ３ -C ７ cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ Alkylene-C ３ -C ７ cycloalkenyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-7 to 11-membered spirocyclic heterocycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-4 to 7 membered heterocycloalkenyl; Alternatively, -L ２ -R is -C=N-OH, J １ are each independently a halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, hydroxy, C １ -C ６ Hydroxyalkyl, —C ０ -C ４ Alkylene -N(H)R ｃ , C １ -C ６ Alkoxy, and —C １ -C ６ Alkyl-C １ -C ６ alkoxy; J ２ are each independently a halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, hydroxy, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkoxy, and —C １ -C ６ Alkyl-C １ -C ６ alkoxy; J ３ are R ３ and independently a halogen, —C １ -C ６ Haloalkyl, CN, C １ -C ６ Alkyl, hydroxy, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkoxy, and —C １ -C ６ Alkyl-C １ -C ６ alkoxy, or optionally 1 to 4 J ３ two of the groups form an oxo group or a 3- to 6-membered spiro group, or optionally 1 to 4 J ３ two of the groups are on different ring carbons and are joined to form a 1-3 carbon bridge; J ４ are each independently a halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, hydroxy, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkoxy, -C １ -C ６ Alkyl-C １ -C ６ Alkoxy, oxo, and -C ０ -C ４ Alkylene -NR ａ R ｂ and wherein J is selected from the group consisting of ４ The group may contain up to two oxo groups and up to one -C ０ -C ４ Alkylene -NR ａ R ｂ It is assumed that the aryl group can only contain aryl groups. R ａ and R ｂ are independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, —C １ -C ６ Alkyl-C １ -C ６ Alkoxy and alkyl, C １ -C ６ Haloalkyl, C １ -C ６ hydroxyalkyl, or —C １ -C ６ Alkoxy C １ -C ６ C optionally substituted with alkyl ０ -C ３ Alkylene-C ２ -C ６ alkynyl, R ｃ But H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, —C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C ３ -C ７ is selected from the group consisting of cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; ３ -C ７ The cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and C １ -C ６ Alkoxy-C １ -C ６ optionally substituted with 1 to 3 groups selected from the group consisting of alkyl; R ｄ But H, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

3. The following formula: 【Chemistry 2】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof of any of the foregoing compounds.

4. 4. The compound of claim 3 having the formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of formula (IIa) or (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof.

5. The following formula: 【Chemistry 3】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof of any of the foregoing compounds.

6. G is -L １ -R ３ 6. The compound of any one of claims 1 to 5, wherein:

7. G, 【Chemistry 4】 wherein: L １ is a bond, -C(O)-, -S(O) ２ -, C １ -C ３ alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl; １ -C ２ Alkylene, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered cycloalkyl each contain 1 to 2 J ２ optionally substituted with a group, provided that L １ is CH ２ When Z １ is CH ２ Assuming that neither N nor N exists, L ２ is -SO ２ - or -C(O)-, Z １ is -N(H)-, -C(R ５ )- or a 4- to 7-membered spiro group optionally containing 1 to 2 nitrogen atoms; R ５ is H, halogen, C １ -C ３ alkyl, or CN; Z ２ and Z ３ are each independently -C １ -C ３ Alkylene or -C ２ -C ３ alkenylene, -C １ -C ３ Alkylene and —C ２ -C ３ Alkenylene is a group having 1 to 4 J ３ optionally substituted with a group, R is ethenyl optionally substituted with 1 to 3 Q groups; ethynyl optionally substituted with Q groups; C １ -C ４ Alkylene -NR ａ R ｂ , -CH ２ -CN or C １ -C ４ haloalkyl, C １ -C ４ One halogen in haloalkyl is L ２ on the carbon atom adjacent to Q is independently a halogen, C １ -C ４ Haloalkyl, C １ -C ４ Alkyl, -C １ -C ４ Alkylene -NR ａ R ｂ , -C １ -C ４ Alkylene-cyano, C １ -C ４ Hydroxyalkyl, —C １ -C ４ Alkylene -C(O)OH, -C １ -C ４ Alkylene-C(O)O-C １ -C ４ Alkyl, -C １ -C ３ Alkylene-C １ -C ４ Alkoxy, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ Alkylene-C ３ -C ７ cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ Alkylene--C ３ -C ７ cycloalkenyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-7 to 11-membered spirocyclic heterocycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-4 to 7 membered heterocycloalkenyl; J ２ are each independently a halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, hydroxy, C １ -C ４ Hydroxyalkyl, C １ -C ４ Alkoxy, and —C １ -C ４ Alkyl-C １ -C ４ alkoxy; J ３ are each independently a halogen, —C １ -C ４ Haloalkyl, CN, C １ -C ４ Alkyl, hydroxy, C １ -C ４ Hydroxyalkyl, C １ -C ４ Alkoxy, and —C １ -C ４ Alkyl-C １ -C ４ alkoxy, or optionally 1 to 4 J ３ two of the groups form an oxo group or a 3- to 6-membered spiro group, or optionally 1 to 4 J ３ two of the groups are on different ring carbon atoms and are linked to form a 1-3 carbon bridge; J ４ are each independently a halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, hydroxy, C １ -C ４ Hydroxyalkyl, C １ -C ４ Alkoxy, -C １ -C ４ Alkyl-C １ -C ４ Alkoxy, oxo, and -C ０ -C ４ Alkylene -NR ａ R ｂ and wherein J is selected from the group consisting of ４ The group may contain up to two oxo groups and up to one -C ０ -C ４ Alkylene -NR ａ R ｂ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, provided that the compound may only comprise the group:

8. G, 【Chemistry 5】 wherein: Z １ is -N(H)-, -C(R ５ )- or a 4-6 membered spiro group optionally containing 1-2 nitrogen atoms; R ５ is H, halogen, C １ -C ３ alkyl, or CN; Z ２ Each has 1 to 2 J ３ -C optionally substituted with a group １ -C ３ Alkylene or -C ２ -C ３ is alkenylene, Z ３ is 1 to 2 J ３ -C optionally substituted with a group １ -C ２ is alkylene, R is ethenyl optionally substituted with 1 to 3 Q groups, ethynyl optionally substituted with Q, C １ -C ４ Alkylene -NR ａ R ｂ , -CH ２ -CN or C １ -C ３ haloalkyl, C １ -C ３ one halogen of the haloalkyl is on the carbon atom adjacent to —C(O)—; Q is independently a halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, -C １ -C ３ Alkylene -NR ａ R ｂ , -C １ -C ３ Alkylene-cyano, C １ -C ３ Hydroxyalkyl, —C(O)OH, —C １ -C ３ Alkylene-C(O)O-C １ -C ３ Alkyl, -C ０ -C ３ Alkylene-C １ -C ３ Alkoxy, 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ Alkylene-C ３ -C ６ cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ Alkylene--C ３ -C ６ cycloalkenyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-7 to 11-membered spirocyclic heterocycloalkyl, 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4 to 6-membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4- to 6-membered heterocycloalkenyl; J ２ are each independently a halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, hydroxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkoxy, and —C １ -C ３ Alkyl-C １ -C ３ alkoxy; J ３ are each independently a halogen, —C １ -C ３ Haloalkyl, CN, C １ -C ３ Alkyl, hydroxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkoxy, and —C １ -C ３ Alkyl-C １ -C ３ alkoxy, or optionally J ３ two of the groups are on different ring carbon atoms and are joined to form a one to two carbon bridge; J ４ are each independently a halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, hydroxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkoxy, -C １ -C ３ Alkyl-C １ -C ３ Alkoxy, oxo, and -C ０ -C ３ Alkylene -NR ａ R ｂ and wherein J is selected from the group consisting of ４ The group may contain up to two oxo groups and up to one -C ０ -C ３ Alkylene -NR ａ R ｂ 8. The compound of claim 7, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, provided that the compound may only comprise the group:

9. R ３ but, 【Chemistry 6】 【Chemistry 7】 and In the formula, R ３ The heterocycle containing at least one nitrogen ring atom of ３ optionally substituted with a group, J ３ are each independently a halogen, —C １ -C ３ Haloalkyl, CN, C １ -C ３ Alkyl, hydroxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Alkoxy, and —C １ -C ３ Alkyl-C １ -C ３ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, selected from the group consisting of alkoxy.

10. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, wherein G is -X-Y.

11. X is 1 to 3 J ２ and Y is a 5- to 10-membered heteroaryl optionally substituted with a -C group. ０ -C ４ Alkylene-N(H)-L ２ 11. The compound of claim 10, wherein R is -R, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof.

12. R is halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, -C １ -C ３ Alkylene -NR ａ R ｂ , -C １ -C ３ Alkylene-cyano, C １ -C ３ Hydroxyalkyl, —C １ -C ３ Alkylene-C(O)O-C １ -C ３ Alkyl, -C １ -C ３ Alkylene-C １ -C ３ Alkoxy, 1 to 3 J ４ -C optionally substituted with a group １ -C ３ Alkylene-C ３ -C ６ cycloalkyl, 1 to 3 J ４ -C optionally substituted with a group １ -C ３ Alkylene-C ３ -C ６ cycloalkenyl, 1 to 3 J ４ -C optionally substituted with a group １ -C ３ alkylene-4 to 6-membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group １ -C ３ 12. The compound of any one of claims 1 to 9 or 11, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, which is ethenyl optionally substituted with 1 to 2 groups independently selected from the group consisting of alkylene-4 to 6 membered heterocycloalkenyl.

13. R is, 【Chemistry 8】 wherein: Q １ are each independently selected from the group consisting of H, F, and Cl; Q ２ is H, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl, -C １ -C ４ Alkylene -NR ａ R ｂ , 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ４ 12. The compound of any one of claims 1 to 9 or 11, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, selected from the group consisting of alkylene-4 to 7 membered heterocycloalkenyl.

14. R ２ is —O-heteroaryl, —O-heterocycloalkyl, —NH-heteroaryl, or —N(H)-heterocycloalkyl, and the heteroaryl or heterocycloalkyl moiety is selected from 1 to 3 J １ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, optionally substituted with a group.

15. R ２ contains at least one nitrogen atom and 1 to 2 J １ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein the compound is -O-(5-10 membered)heteroaryl optionally substituted with a group.

16. R ２ However, each has 1-2 J １ optionally substituted with a group, 【Chemistry 9】 16. The compound of any one of claims 1 to 15, wherein:

17. R ２ However, each has 1-2 J １ optionally substituted with a group, 【Chemistry 10】 wherein: J １ are each independently a halogen, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, hydroxy, C １ -C ３ Hydroxyalkyl, —C ０ -C ３ Alkylene -N(H)R ｃ , C １ -C ６ Alkoxy, and —C １ -C ６ Alkyl-C １ -C ６ alkoxy; R ｃ is H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, —C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C ３ -C ７ is selected from the group consisting of cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; ３ -C ７ The cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each selected from halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and C １ -C ６ Alkoxy-C １ -C ６ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, optionally substituted with 1 to 3 groups selected from the group consisting of alkyl.

18. R ２ but, 【Chemistry 11】 18. The compound of any one of claims 1 to 17, wherein:

19. The following formula: 【Chemistry 12】 【Chemistry 13】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q １ are each independently selected from the group consisting of H, F, and Cl; Q ２ is H, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl, -C １ -C ３ Alkylene -NR ａ R ｂ , 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4 to 7 membered heterocycloalkenyl, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof; Q １ are each independently selected from the group consisting of H, F, and Cl; Q ２ are independently H, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl, -C １ -C ３ Alkylene -NR ａ R ｂ , 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, selected from the group consisting of alkylene-4 to 7 membered heterocycloalkenyl.

20. The following formula: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein: Q １ are each independently selected from the group consisting of H, F, and Cl; Q ２ is H, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl, -C １ -C ３ Alkylene -NR ａ R ｂ , 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ alkylene-4 to 7 membered heterocycloalkyl, and 1 to 3 J ４ -C optionally substituted with a group ０ -C ３ 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, selected from the group consisting of alkylene-4 to 7 membered heterocycloalkenyl.

21. At least one Q ２ 21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analogue thereof, wherein

22. One Q ２ But, -C １ -C ３ Alkylene -NR ａ R ｂ 21. The compound of claim 19 or 20, wherein:

23. One Q ２ But 1 to 3 J ４ C optionally substituted with a group ０ -C ３ 21. The compound of any one of claims 19 or 20, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, which is alkylene-4 to 7 membered heterocycloalkyl.

24. 2. The compound of claim 1 selected from Table 1, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier.

26. 26. The pharmaceutical composition of claim 25, further comprising a second pharmaceutical agent.

27. 27. A method of treating a subject having a disease or disorder mediated by Her2, comprising administering to the subject an effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, deuterated analogue, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of claims 25-26.

28. 28. The method of claim 27, wherein the disease or condition is cancer associated with a Her2 YVMA insertion mutation.

29. 28. The method of claim 27, wherein the disease or condition is a cancer selected from the group consisting of 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 cancer.

30. The method of any one of claims 27 to 29, wherein the disease or condition is non-small cell lung cancer.

31. 31. The method of any one of claims 27 to 30, further comprising administering one or more additional therapeutic agents.

32. the one or more additional therapeutic agents are i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) a bleomycin; iii) antibiotics selected from isin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine; and trimetrexate; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA4 inhibitor; v) an antibody drug conjugate selected from ado-trastuzumab emtansine and trastuzumab deruxtecan; vi) enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, megestrol (magesto). vii) a hormone or hormone antagonist selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; viii) a taxane selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; ix) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine;x) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; xi) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xii) an antiangiogenic agent selected from erlotinib, gefitinib, xiii) a kinase inhibitor selected from nib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine, and vatalanib; xiii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiv) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; xv) an IDO inhibitor; xvi) 3-AP (3- amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hs 32. The method of claim 31, wherein the therapeutic agent is one or more of: a chemotherapeutic agent selected from p90 inhibitors, farnesyltransferase inhibitors, and aromatase inhibitors (anastrozole, letrozole, exemestane), xvii) a BRAF inhibitor, xviii) a Mek inhibitor, xix) a c-Kit mutant inhibitor, xx) an EGFR inhibitor, xxi) an epigenetic modulator, xxii) other adenosine axis blockade agents selected from CD39, CD38, A2AR, and A2BR, or xxiii) an agonist of a TNFA superfamily member, and xxiv) an anti-ErbB2 mAb.

33. 33. The method of claim 32, wherein the one or more additional therapeutic agents is ado-trastuzumab emtansine or trastuzumab deruxtecan.

34. 33. The method of claim 32, wherein the one or more additional therapeutic agents is pembrolizumab or nivolumab.

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